23 Full

Physiol Rev 93: 23 67, 2013
doi:10.1152/physrev.00043.2011
SATELLITE CELLS AND THE MUSCLE STEM CELL

NICHE
Hang Yin, Feodor Price, and Michael A. Rudnicki
Regenerative Medicine Program, Ottawa Hospital Research Institute, Ottawa, Ontario, Canada
Yin H, Price F, Rudnicki MA. Satellite Cells and the Muscle Stem Cell Niche. Physiol
L
Rev 93: 23 67, 2013; doi:10.1152/physrev.00043.2011.Adult skeletal muscle
in mammals is a stable tissue under normal circumstances but has remarkable ability
to repair after injury. Skeletal muscle regeneration is a highly orchestrated process
involving the activation of various cellular and molecular responses. As skeletal muscle
stem cells, satellite cells play an indispensible role in this process. The self-renewing proliferation of
satellite cells not only maintains the stem cell population but also provides numerous myogenic
Downloaded from http://physrev.physiology.org/ by 10.220.33.1 on June 16, 2017

cells, which proliferate, differentiate, fuse, and lead to new myofiber formation and reconstitution
of a functional contractile apparatus. The complex behavior of satellite cells during skeletal muscle
regeneration is tightly regulated through the dynamic interplay between intrinsic factors within
satellite cells and extrinsic factors constituting the muscle stem cell niche/microenvironment. For
the last half century, the advance of molecular biology, cell biology, and genetics has greatly
improved our understanding of skeletal muscle biology. Here, we review some recent advances,
with focuses on functions of satellite cells and their niche during the process of skeletal muscle
regeneration.
I. INTRODUCTION: SATELLITE CELLS AS... 23 elucidated many cellular and molecular mechanisms that
II. FUNCTIONS OF SATELLITE CELLS IN... 30 underlie skeletal muscle regeneration. These studies have
III. ANATOMIC AND FUNCTIONAL... 41 contributed to the development of therapeutic strategies.
IV. CONCLUDING REMARKS AND... 53 These strategies serve to alleviate the physiological and
pathological conditions associated with poor muscle regen-
eration observed in sarcopenia and muscular dystrophy.
I. INTRODUCTION: SATELLITE CELLS AS
ADULT STEM CELLS IN MUSCLE Here, we concentrate on the functions of satellite cells and
the regulation of their niche during the process of skeletal
Skeletal muscle is a form of striated muscle tissue, account- muscle regeneration. We first describe the current under-
ing for 40% of adult human body weight. Skeletal muscle standing of satellite cells with respect to their characteris-
is composed of multinucleated contractile muscle cells (also tics, heterogeneity, and embryonic origin. We then provide
called myofibers). During development, myofibers are an integrated view of the roles played by satellite cells dur-
formed by fusion of mesoderm progenitors called myo- ing muscle regeneration and normal postnatal muscle
blasts. In neonatal/juvenile stages, the number of myofibers growth. We also discuss the contribution of several nonsat-
remains constant, but each myofiber grows in size by fusion ellite cell populations in muscle regeneration and their lin-
of satellite cells, a population of postnatal muscle stem cells. eage relationships with satellite cells. Next, we focus on the
Adult mammalian skeletal muscle is stable under normal satellite cell niche with emphasis on the regulatory mecha-
conditions, with only sporadic fusion of satellite cells to nisms associated with each niche component. We further
compensate for muscle turnover caused by daily wear and review the links between malfunction of satellite cells and
tear. However, skeletal muscle has a remarkable ability to their niche factors during aging. This review focuses on
regenerate after injury. Responding to injury, skeletal mus- satellite cells and their niche in mammalian models, paying
cle undergoes a highly orchestrated degeneration and regen- limited attention to the studies of satellite cell biology in
erative process that takes place at the tissue, cellular, and other model organisms.
molecular levels. This results in the reformation of inner-
vated, vascularized contractile muscle apparatuses. This re-
generation process greatly relies on the dynamic interplay A. A Brief History of Satellite Cells
between satellite cells and their environment (stem cell
niche). During the last half century, advances in molecular Half a century ago, Alexander Mauro observed a group of
biology, cell biology, and genetics has greatly improved our mononucleated cells at the periphery of adult skeletal mus-
understanding of skeletal muscle regeneration. In particu- cle myofibers by electron microscopy (329). These cells
lar, extensive research on satellite cells and their niche has were named satellite cells due to their sublaminar location
0031-9333/13 Copyright 2013 the American Physiological Society 23

YIN, PRICE, AND RUDNICKI
and intimate association with the plasma membrane of fiber, can give rise to hundreds of satellite cells and thou-
myofibers. sands of myonuclei. Most importantly, transplanted satel-
lite cells on a single myofiber were able to support
The direct juxtaposition of satellite cells and myofibers im- subsequent rounds of muscle regeneration (105). These ob-
mediately raised a hypothesis that these cells may be in- servations demonstrate that satellite cells are bona fide mus-
volved in skeletal muscle growth and regeneration (329). cle stem cells.
Indeed, experiments by [3H]thymidine labeling and elec-
tron microscopy demonstrated that satellite cells undergo Asymmetric division is a common manner of stem cell self-
mitosis, assume a cytoplasm-enriched morphology, and renewal. Close examination of satellite cell divisions on
contribute to myofiber nuclei (355, 437). Later on, [3H]thy- single myofibers revealed that satellite cells can undergo
midine tracing experiments indicated that satellite cells are both asymmetric division and symmetric division (280).
mitotically quiescent in adult muscle but can quickly enter The fashion of symmetric versus asymmetric division
the cell cycle following muscle injury (499). The same study largely depends on the relative position of the daughter cells
also demonstrated that satellite cells give rise to proliferat- in relation to the myofiber. This finding strongly argues that
ing myoblasts (myogenic progenitors cells), which were pre- satellite cell self-renewal is governed by the structure and
viously shown to form multinucleated myotubes in vitro signaling present in their immediate niche (280). Further

(276, 499, 574). More definitive evidence came from in investigation has revealed an important role for noncanoni-
vitro cultures of individually dissected myofibers, whereby cal Wnt signaling in the regulation of satellite cell self-re-
the behaviors of single myofibers and their resident satellite newal (293).
cells during regeneration can be tracked by phase-contrast
microscopy (51, 277). It was observed that myofiber necro- The aforementioned observations, together with those from
sis is accompanied by satellite cell outgrowth, clonal expan- other studies, formed the basis of our current view of satel-
sion, and later fusion to form functional regenerated myo- lite cells as muscle stem cells whose functions are dictated
tubes. These experiments support the notion that it is the by their surrounding niche.
satellite cell, rather than the myonuclei, that contribute to
postnatal muscle growth and repair. B. Identification and Isolation
of Satellite Cells
The pivotal function of the satellite cell in muscle regener-
ation stimulated research to determine their regulatory
Classically, satellite cells were identified based on a unique
mechanisms. This started with the finding that quiescent
anatomical location: beneath the surrounding basal lamina
satellite cells on single myofibers were activated to enter the and outside the myofiber plasma membrane. This anatom-
cell cycle by a mitogen originating from crushed skeletal ical location gives satellite cells a wedged appearance
muscles (53). In search of this mitogen, it was found that the when viewd by electrictron microscropy (329). This tech-
proliferation and differentiation of satellite cell-derived nique also revealed other morphological characteristics of
myoblasts cultured in vitro respond to various growth fac- satellite cells: large nuclear-to-cytoplasmic ratio, few organ-
tors in a dose-dependent manner (10, 11). Numerous studies elles, small nucleus, and condensed interphase chromatin.
further revealed that the proliferation and differentiation of This morphology is in harmony with the notion that most
satellite cells during muscle regeneration is profoundly influ- satellite cells, in healthy unstressed muscles, are mitotically
enced by innervation, the vasculature, hormones, nutrition, quiescent (in G0 phase) and transcriptionally inactive (472).
and the extent of tissue injury (121, 224, 250, 332, 360, 410). In addition to electron microscopy, satellite cells can be
Interestingly, satellite cells in contact with the plasma mem- identified by phase-contrast microscopy on single myofiber
brane of intact myofibers were found to have reduced sen- explants (53). Based on the same principle, the behaviors of
sitivity to mitogen stimulation (50). All of these findings led satellite cells on single myofiber explants can be recorded by
to an intriguing notion that satellite cells reside in a special utilizing live cell imaging techniques (490). The identifica-
microenvironment in vivo, which profoundly affects their tion of satellite cells by fluorescence microscopy relies on
behavior. specific biomarkers (FIGURE 1). In adult skeletal muscle, all
or most of satellite cells express the paired domain tran-
By definition, stem cells found in adult tissues can both scription factors Pax7 (478) and Pax3 (72), myogenic reg-
replicate themselves (self-renew) and give rise to functional ulatory factor Myf5 (116), homeobox transcription factor
progeny (differentiate). Although the ability of satellite cells Barx2 (336), cell adhesion protein M-cadherin (244), ty-
to differentiate into myofibers was clearly proven, their rosine receptor kinase c-Met (13), cell surface attachment
ability to self-renew was once questioned. The first evidence receptor 7-intergin (73, 192), cluster of differentiation
of satellite cell self-renewal came from a single myofiber protein CD34 (37), transmembrane heparan sulfate pro-
transplantation assay. It was found that as few as seven teoglycans syndecan-3 and syndecan-4 (113), chemokine
satellite cells, when transplanted into irradiated regenera- receptor CXCR4 (429), caveolae-forming protein caveo-
tion-insufficient mice along with their resident single myo- lin-1 (192, 552), calcitonin receptor (177), and nuclear en-
24 Physiol Rev VOL 93 JANUARY 2013 www.prv.org

SATELLITE CELLS AND THE MUSCLE STEM CELL NICHE
A
Satellite cell markers
Itga7 Vcam1 CalcR Synd3/4 CD34
Itgb1 Transcription factors
Ncam1 CXCR4 MyoD Pax7
Myf5 Pax3
Cav1 Fzd7
Membrane proteins
cMet Notch
cMet Synd3/4
Cav1 CD34
MyoD Notch CXCR4
Pax7 Pax3
Ncam1 Fzd7
Vcam1 Mcad
CalcR Lamin A/C
Itga7 Emerin
Emerin Myf5 Itgb1

Lamin A/C
Mcad
B Satellite Stem Cell
Symmetric division Asymmetric division

Basal lamina
Myonuclei
Sarcoplasm
Sarcolemma
Symmetric division Symmetric division
Satellite Myogenic Cell

FIGURE 1. Characteristics of the satellite cell. A: numerous proteins are expressed in satellite cells and have
been used as markers to distinguish between surrounding cell types within skeletal muscle. Due to heteroge-
neity in satellite cell populations, it is unlikely that all of these markers are expressed in a given satellite cell at
a specific time. Nevertheless, this panel summarizes the cellular location of markers used to identify satellite
cells. B: the satellite cell population is heterogeneous and can be classified in a hierarchical manner based on
function and gene expression. Evidence from lineage tracing experiments identified a subpopulation of satellite
cells having never expressed the myogenic transcription factor Myf5 (satellite stem cells) are placed hierar-
chically above satellite cells that have expressed Myf5 at some point during development (satellite myogenic
cells). Satellite stem cells, upon asymmetric division (typically in a apical-basal orientation), will give rise to two
daughter cells, only one of which has activated Myf5. Functional differences in regenerative potential exist
between satellite stem cells and satellite myogenic cells. Following transplantation, satellite stem cells prefer-
entially repopulate the satellite cell niche and contribute to long-term muscle regeneration. In contrast, satellite
myogenic cells preferentially differentiate upon transplantation in vivo.
velope proteins lamin A/C and emerin (192). Of these, Pax7 monkey (334), mouse (478), pig (402), chick (216), sala-
is the canonical biomarker for satellite cells as it is specifi- mander (353), frog (96), and zebrafish (219). Of note, some
cally expressed in all quiescent and proliferating satellite of the aforementioned satellite cell markers (e.g., 7-in-
cells (478) across multiple species, including human (334), tergin, CD34) are also expressed on other cell types within
Physiol Rev VOL 93 JANUARY 2013 www.prv.org 25

skeletal muscle, and thus should not be utilized alone to stemness, and lineage potential to assume nonmyogenic
unequivocally identify satellite cells. Satellite cells can be fates.
identified by fluorescence microscopy via combined immu-
nofluorescence labeling of laminin and M-cadherin, which With regard to gene expression, it was first observed that
respectively label the basal lamina and plasma membrane of only a subset of satellite cells expresses Pax3, a close para-
satellite cells contacting the myofibers (517). In vivo, satel- log to Pax7 (350, 431). Although Pax3 satellite cells tend
lite cell populations can be visualized with the aid of newly to be associated with skeletal muscle of certain anatomical
developed bioluminescence imaging techniques (454, 558). locations (e.g., diaphragm and truck muscles), the differ-
ence of Pax3 expression does not seem to correlate with
Multiple methodologies have been developed to isolate sat- their embryonic origins, metabolic fiber types, or types of
ellite cells from skeletal muscle. The choice of methods innervating motor neurons. Examination of the expression
largely depends on the isolation scale and the subsequent of satellite cell markers CD34, M-cadherin, and Myf5 by
experiment. In small scale, limited amounts of satellite cells immunofluorescence staining revealed that a subpopulation
can be released from single myofiber explants by physical of satellite cells do not express these markers (37). Similarly,
trituration (446) or enzymatic digestion (107). In large human satellite cells also manifest heterogeneity in their
scale, satellite cells can be isolated from skeletal muscles by Pax7, neuronal cell adhesion molecule (NCAM), c-Met,

fluorescent-activated cell sorting (FACS). In the latter and Dlk1 expression (311). By RT-qPCR, two recent stud-
method, single cells are released from muscle tissue chunks ies showed that satellite cells from head or body muscles are
by enzymatic digestion, followed by immunofluorescence distinct in their molecular signatures (225, 456). Notably,
labeling of satellite cell-specific cell surface markers (posi- the heterogeneity of gene expression in single satellite cells
tive selection) and definitive cell surface markers for non- was investigated in a recent study, wherein the expression of
satellite cell populations (negative selection). As Pax7 is Pax7, Pax3, Myf5, and MyoD was interrogated by RT-
specifically expressed in satellite cells within skeletal mus- qPCR for 40 individually FACS-isolated muscle stem cells
cle, satellite cells, in both quiescent and proliferating stages, (CD45/CD11b/CD31/Sca-1/7-intergin/CD34)
can be FACS-sorted by fluorescent protein expression in (454). All of these muscle stem cells express Pax7, indicat-
tamoxifen-injected animals carrying both a Pax7CreER allele
ing they are satellite cells. In addition to the varied expres-
and a fluorescence Cre reporter allele (e.g., R26R-EYFP). In
sion of Pax3, it was also found that 25% of investigated
addition, two transgenic mouse strains, which carry fluo-
satellite cells also express MyoD, a basic helix-loop-helix
rescence proteins driven by Nestin- or Pax7-regulatory ele-
transcription factor critical for myogenic commitment and
ments, are also useful for isolating satellite cells by FACS
differentiation. A recent study discovered a small subpopu-
(63, 127).
lation of satellite cells, characterized by their surface mark-
ers Sca-1/ABCG2 (as compared with Sca-1/ABCG2
Protocols have been developed to isolate satellite cells in
for most satellite cells), is able to exclude Hoechst 33342
bulk utilizing their characteristic proliferation and adhesion
dye and thus belongs to the skeletal muscle side population
characteristics under defined culturing conditions (144,
(satellite-SP cells) (518). After transplantation into dam-
364, 425). It is noteworthy that the satellite cell progeny
cultured on regular collagen-coated plastic dishes and un- aged muscle, satellite-SP cells can both fuse to regenerating
der activation conditions, also called satellite cell-derived myofibers and return to quiescence in the satellite cell niche.
primary myoblasts, are molecularly and functionally dis- However, by lineage tracing, ABCG2 cells (including sat-
tinct from the satellite cells freshly isolated from muscles ellite-SP cells) seem to only have minor contribution to
(160, 177, 350). In addition, the gene expression profile of myofiber regeneration (146).
these cultured primary myoblasts differs from that of acti-
vated satellite cells in vivo (398). These essential differences Satellite cells are also heterogenic in their differentiation
are possibly due to the lack of a satellite cell niche in in vitro potential. Satellite cells on single myofibers isolated from
culturing conditions. One challenge in future studies is to various skeletal muscle sources were transplanted into irra-
understand the components and role of the satellite cell diated muscles of mdx/nude mice, which underwent re-
niche to better control and manipulate their quiescence, peated regeneration and were depleted of endogenous sat-
activation, proliferation, and differentiation. ellite cells (105). It was observed that the number of regen-
erated myofibers contributed by tibialis anterior (TA)
originated grafts was significantly less than that derived
C. Heterogeneity of Satellite Cell Population from either extensor digitorum longus (EDL) or soleus mus-
cle. Although the potential contribution from donor myo-
Satellite cells were considered to be a homogeneous popu- fibers cannot be precisely evaluated, this observation
lation of committed muscle progenitors (52). However, re- strongly suggests inherent differences in proliferation/dif-
cent evidence demonstrated that the satellite cell population ferentiation potential of satellite cells and/or composition of
is heterogeneous and that satellite cells differ in their gene satellite cell subpopulations from various muscles. In line
expression signatures, myogenic differentiation propensity, with this view, continuous BrdU labeling of satellite cells in

vivo revealed two satellite cell populations that are distinct asymmetric division in vivo or in vitro (108, 109, 489). For
in terms of their mitotic rates (471). It was found that the example, Numb, an inhibitor of Notch signaling and a cell-
majority (80%) of satellite cells readily enter the cell cycle fate determinant, was found to asymmetrically distribute in
(responsive population), whereas the remaining 20% of sat- some but not all satellite cell divisions (108, 489). By pulse
ellite cells (reserve population) do this in a much slower labeling or tandem pulse labeling of growing/regenerat-
manner. It has been proposed that the reserve population ing muscles with halogenated thymidine analogs, it was
maintains in the quiescent state at the beginning of muscle further discovered that all older chromosomes (the
growth/regeneration and only moves into this proliferative template chromosome during DNA replication during S
state in response to the need for extensive muscle growth/ phase) cosegregate into the more stemlike daughter cell,
regeneration (471). In line with this view, a recent study whereas younger chromosomes are inherited by the
traced satellite cell divisions by a fluorescent dye PKH26, more differentiated daughter cell during asymmetric divi-
which revealed the minority of PKH26high slow-dividing sions of satellite cells both in vivo and in vitro (109, 489).
satellite cells retained long-term self-renewal ability (388). According to the immortal DNA strand hypothesis (75),
Notably, a recent study thoroughly compared the gene ex- this preferential retention of older chromosomes protects
pression profiles and proliferation/differentiation potential stem cells against the accumulation of mutations intro-
of satellite cells isolated from limb and facial muscles of duced during DNA replications (109, 489). Alternatively, it

adult and aged mice (387). This study revealed broad satel- has been also proposed that the nonrandom segregation of
lite cell heterogeneity at both the population and single-cell sister chromatids, and hence their different epigenetic
levels. Despite their heterogeneous gene expression profiles, states, is essential to the gene expression patterns and cel-
satellite cells isolated from limb (EDL) and facial (masseter) lular fates of satellite stem cells and satellite progenitor cells
muscles are comparable in their ability to repair a limb (TA) (289). In summary, the aforementioned findings support
muscle injury after transplantation. This finding suggests satellite cell heterogeneity whereby the existence of a hier-
that although satellite cells from various muscles have dis- archy delineates a small population of true stem cells (sat-
tinct gene expression and behaviors in vitro, their regener- ellite stem cells) from a more committed myogenic progen-
ation potential in vivo might be largely determined by host itor population of satellite cells. The satellite stem cells are less
stem cell niche and microenvironment. committed to the myogenic lineage and tend to retain older
template DNA during division. Through asymmetric division,
Most importantly, recent studies revealed satellite cell hetero- satellite stem cells self-renew to replenish the stem cell pool
geneity in terms of their stemness and indicate that only a small and produce more committed myogenic progenitors that par-
percentage of satellite cells are true stem cells (109, 280, 489). ticipate in skeletal muscle growth and regeneration.
By immunofluorescence staining of freshly isolated single
myofibers from Myf5-nLacZ mice, our group demonstrated Satellite cells also exhibit heterogeneity in respect to their cell
that 13% of quiescent satellite cells on EDL muscles are fate potential. Our group first revealed that satellite cells have
LacZ, making them distinct from the LacZ satellite cells an intrinsic potential to differentiate into multiple mesenchy-
(280). As Myf5 is a myogenic regulatory factor, the absence of mal lineages (23). When cultured on solubilized basement
Myf5 expression suggests a less committed cell fate for those membrane matrix (matrigel), satellite cells from single myofi-
LacZ satellite cells. Moreover, by the Cre-LoxP based lineage bers spontaneously differentiate into myocytes, adipocytes,
tracing technique, our group further discovered that 10% of and osteocytes. This finding indicates that satellite cells func-
satellite cells in Myf5Cre;R26R-YFP mice do not express YFP tionally resemble bone marrow-derived mesenchymal stem
(Pax7/YFP satellite cells), indicating that this small percent cells. This notion is substantiated by another study wherein
of satellite cells have never expressed Myf5 as did the majority satellite cells were found to assume the adipocyte lineage,
of satellite cells (Pax7/YFP). Remarkably, these two distinct which can be enhanced upon oxygen-rich culture conditions
satellite cell subpopulations also differ in terms of their regen- (120). By clonal analysis, it was found that myogenic and
erative potential: the Pax7/YFP satellite cells were able to adipogenic satellite cells are two separate populations in the
reconstitute the stem cell niche and repaired muscles in a sus- satellite cell compartment, although both populations express
tainable manner, whereas the Pax7/YFP satellite cells di- the myogenic marker Pax7 as well as the adipogenic markers
rectly underwent myogenic differentiation when transplanted peroxisome proliferator-activated receptors (PPAR) and
in regenerating muscles of Pax7/ mice. We further demon- CCAAT/enhancer binding proteins (C/EBPs) (485). This sim-
strated that only Pax7/YFP satellite cells could undergo ilar molecular signature may reflect a common developmental
asymmetric cell divisions, giving rise to a Pax7/YFP satellite origin of satellite cells and adipogenic progenitors in embry-
stem cell and a Pax7/YFP satellite committed progenitor onic somites (discussed in sect. IIE). Satellite cell heterogeneity
cell. These findings indicate that a hierarchical lineage progres- with regard to myogenic and nonmyogenic potential was thor-
sion from the Pax7/YFP (satellite stem cell) to the Pax7/ oughly investigated by in vitro differentiation and in vivo
YFP (satellite committed progenitors) exists within the total transplant assays (486). In this study, myofiber-associated sat-
satellite cell population. Consistent with this notion, multiple ellite cells were isolated from undamaged skeletal muscle by a
studies reported that only a subset of satellite cells undergo two-step enzymatic digestion and sorted by FACS based on

their differential expression of cell surface markers, CD45 and satellite cells in soleus muscle is generally two- to fourfold
Sca-1. It was found that the vast majority of myogenic satellite higher than that in tibialis anterior muscle or EDL muscle
cells are within the CD45/Sca-1 population and exhibited (190, 466, 500). Within the same muscle, the number of
no in vitro differentiation potential into fibroblasts or adi- satellite cells found on slow muscle myofibers (type I) is
pocytes. In contrast, the minor population of CD45/Sca-1 generally higher than those on fast myofibers (type IIa and
satellite cells can differentiate into both fibroblasts and adi- type IIb) (190, 324, 383). The biological meaning and the
pocytes in culture, a similarity that is shared with CD45/ potential regulatory mechanisms underlying these phenom-
Sca-1 mesenchymal stem cells found in multiple tissues (316, ena are poorly understood. However, it is conceivable that
401, 417, 441, 509, 519). Despite the plasticity of satellite cells these variances may reflect intrinsic heterogeneity of satel-
in vitro, it is important to note that myogenesis is the predom- lite cells on different myofibers and implicate a potential
inant fate of satellite cells in vivo as fibrosis or adipose infiltra- role of myofibers as a niche factor in regulating the homeo-
tion is not normally observed in young healthy muscle. Fur- stasis of their resident satellite cells.
thermore, recent studies indicate that intramuscular adi-
pocytes and fibroblasts can also arise from fibrocyte/adipocyte Along a myofiber, the distribution of satellite cells is not
progenitors (FAPs), which reside in the muscle interstitium random. It has been reported that the density of satellite
(252, 541; and discussed in sect. IIIB1). Indeed, lineage tracing cells is higher at the ends of the myofibers, where the longi-

experiments indicate that adipocytes derived from myofibers tudinal growth of skeletal muscles happens (14). A higher
isolated from MyoDiCre;R26R-EYFP mice have never tran- incidence of satellite cells has been observed at perisynaptic
scribed MyoD (507). As the vast majority of adult satellite cells regions compared with that at extrasynaptic regions (190,
were permanently labeled with EYFP in this experiment, this 269, 567). Moreover, satellite cells have been observed in
finding argues that most satellite cells from myofiber cultures close proximity to capillaries (100, 466). In fact, 88% of
do not spontaneously differentiate into adipocytes. Further satellite cells in adult human muscles were observed to be
investigation with more definitive lineage tracing (e.g., located within a 21-m distance of a capillary (100). This
Pax7CreER;R26R-EYFP) methods would clarify the exact con- tight association with capillaries seemed to be compromised
tribution of satellite cells to other nonmyogenic lineages both by denervation (130). These observations indicate that
in vitro and in vivo. homing of satellite cells is influenced by their niche, both by
local motor neurons and blood vessels (discussed in sect.
As discussed here, multiple lines of evidence demonstrate that IIIB).
satellite cells represent a heterogeneous population. However,
our understanding of this heterogeneity is far from complete. It is noteworthy that some reported variation in satellite cell
First, although several markers can separate the total satellite numbers may be partially due to techniques or statistical
cell population into functional subpopulations, it is still un- analysis employed in satellite cell counting. For example,
known whether these subpopulations are homogeneous in satellite cell counting based on immunofluorescence label-
their function and gene expression. Further studies to identify ing of satellite cell specific markers relies on the comparable
additional satellite markers will potentially help distinguish expression levels of these markers on all satellite cells under
the various satellite cell lineages. Moreover, future inves- investigation. As such, special caution should be taken into
tigations should attempt to identify the intrinsic differ- account when interpreting data between independent ex-
ences between satellite cell subpopulations at the molec- periments.
ular and functional levels during muscle regeneration.
Such findings would elucidate regulatory mechanisms gov-
erning the transition between different satellite cell subpopu- E. Origins of Adult Satellite Cells
lations and potentially distinct roles of satellite cell subpopu-
lations during muscle regeneration. In addition, it would be of 1. Embryonic origins
great importance to understand the dynamics of satellite cell
heterogeneity in response to various environmental cues with By classic techniques of developmental biology, it has long
regard to research in muscle regeneration and disease. been established that skeletal muscles within both the adult
trunk and limbs develop from embryonic somites (462).
However, the exact origin of adult satellite cells was ob-
D. Variance of Satellite Cells Number scure until recently.
and Location
Early experiments using a quail-chick chimera technique
In addition to the heterogeneity of satellite cells, the quantity of suggested a somitic origin of satellite cells in amniotes (18).
satellite cells differs between muscles, myofiber types, develop- Embryonic somites are segments of paraxial mesoderm
mental stages, and species. In general, satellite cells account for formed on both sides of the body axis. In this experiment,
30 35% of the sublaminal nuclei on myofibers in early post- somites from donor quail embryos were transplanted into
natal murine muscles, and this number declines to 27% in host chick embryos. After embryonic development, the con-
adult muscles (9, 227, 450, 469). In adults, the percentage of tribution of quail cells to the chick satellite cell compart-

ment was determined using Feulgen staining, which distin- cells, which were absent from the primary myotome at ear-
guishes quail-specific interphase nuclei from those of chick. lier stages, count for the majority of all proliferating cells in
It was found that donor cells from quail somites integrated embryonic/fetal trunk muscles (203, 434). Some of the pro-
into the chick limb and contributed to both terminally dif- liferating Pax3/Pax7 progenitor cells persist into late fe-
ferentiated muscle fibers and satellite cells. This finding in- tal development stages and are enveloped beneath the basal
dicated a common somitic origin for all myogenic cell lin- lamina of developing myofibers (203, 434). These cells,
eages, including satellite cells. However, the progenitor cell which reside in the satellite cell compartment, are presumed
types at the origin and the developmental route remain to subsequently become the postnatal satellite cells in trunk
unknown. muscles. Besides proliferation, progenitor cells also exit the
cell cycle and begin differentiating into embryonic/fetal
Advances in mouse genetics, particularly the generation of truck muscles. Cell cycle withdrawal is concomitant with
Pax3 and Pax7 knock-in reporter alleles, allows precise the expression of the myogenic regulatory factors MyoD
tracing of Pax3/Pax7-expressing myogenic progenitor cells and Myf5 (453).
during muscle development in a temporal and spatial man-
ner (265, 326, 350, 432, 433). These reporters together During EMT, another group of proliferating progenitor
with labeling of cells by electroporation (40, 203), retrovi- cells, expressing Pax3 (but not Pax7 in mouse), delaminate

rus (464), Cre-LoxP based lineage tracing (263, 300, 464), from the ventral-lateral border of the dermomyotome and
and traditional quail-chick transplantation (203, 464), migrate to the limb bud mesenchyme (265, 392, 464). These
jointly shed light on the embryonic origins of adult satellite progenitor cells still maintain their multipotency as they
cells. Accumulating evidence indicates that adult satellite give rise to the limb vascular, lymphatic endothelia, and
cells originate from the dermomyotome (203, 265, 434, limb muscles (226, 264). At E11.5 of mouse embryo devel-
464), an epithelial structure formed on the dorsal part of the opment, some progenitor cells start to express Pax7 in the
somite. The dermomyotome contains multipotent pro- anterior limb buds (433). The expression of Pax7 specifies
genitor cells, which eventually give rise to multiple adult these cells to the myogenic lineage (242). Similar to the
tissues/cell types including dermal fibroblasts, endothe- myotome-located progenitors, these Pax3/Pax7 progen-
lial cells, vascular smooth muscle, brown fat tissue, and itor cells in limb buds undergo proliferation/differentiation
all skeletal muscles of the trunk and limbs (71). The cell while a portion withdraw from cell cycle and become satel-
fate decisions largely depend on the relative position of lite cells.
these multipotent progenitor cells with respect to adja-
cent tissues such as the notochord, neural tube, dorsal All together, these observations indicate that Pax3/Pax7
ectoderm, and myotome (71). embryonic progenitor cells are the major source of adult
satellite cells in truck and limb muscles; it is, however, note-
Embryonic muscle development takes place in two succes- worthy that the aforementioned observations from lineage
sive stages. During the first stage, a group of postmitotic tracing and immunofluorescence labeling experiments can-
mononucleated myocytes, expressing Myf5 and Mrf4, mi- not exclude the possibility that some adult satellite cells may
grate out from the border regions of the dermomyotome originate from other sources during fetal and postnatal
and form primitive muscles beneath the dermomyotome muscle development. For example, embryonic dorsal aorta
(204, 261). These primitive muscles constitute the primary explants, when cultured and disaggregated in vitro, can
myotome and are the source of fetal and adult trunk mus- efficiently give rise to myogenic precursors (129). These
cles. During the second stage of muscle growth, the central myogenic precursors are similar to satellite cells in their
portion of the dermomyotome undergoes an epithelial-to- gross morphology and expression of molecular markers.
mesenchymal transition (EMT). During EMT, tightly Given that adult satellite cells also express endothelial
packed epithelial cells tease apart and turn in a loose mes- markers, it was proposed that some adult satellite cells orig-
enchymal state prior to assuming different developmental inated from the embryonic dorsal aorta (129). However,
fates: cells in the medial dermomyotome will develop into recent studies revealed that both skeletal muscles and
brown fat, dermis, and trunk muscle, while cells in the smooth muscles found in dorsal aorta are derived from the
lateral dermomyotome will give rise to endothelia and limb same Pax3 cell population in the paraxial mesoderm
muscles. The different cell fates assumed by the same group (155). Thus it is also possible that the observed similarities
of progenitor cells are proposed to be due to asymmetric cell are merely reminiscent of a common embryonic origin be-
division (40, 101). EMT is accompanied by the extensive fore myogenic specification.
cell migration (203, 265, 434, 464). With the breakdown of
dermomyotome, a group of proliferating progenitor cells, Distinct from trunk and limb muscles, head muscles have
expressing both Pax3 and Pax7, migrate from the central multiple embryonic origins. The majority of head muscles,
region of the dermomyotome into the previously formed including branchiomeric muscles and most extraocular
primary myotome. Upon arrival, some progenitor cells con- muscles, arise from the cranial paraxial mesoderm (CPM)
tinue to proliferate and replenish the progenitor pool. These (225, 540). Posterior neck muscles and tongue develop

from occipital somites. Similar to progenitor cells migrating inhibitor) or within regenerating muscle in vivo. Although
to limb buds, the progenitor cells for tongue delaminate still not experimentally tested on myofibers formed during
from the ventral-lateral border of occipital somites. A small development, these intriguing observations jointly suggest
fraction of extraocular muscles also arise from the that some adult satellite cells may be recycled from multi-
prechordal mesoderm (PM). On the basis of observations nucleated myofibers in vivo during postnatal muscle growth
from lineage tracing experiments, it has been found that or regeneration. Future studies may employ the fusion-de-
adult satellite cells of the various head muscles originate pendent lineage tracing technique in chimeric mice to inves-
from their corresponding embryonic muscles and express tigate the physiological relevance of this alternative source
distinct combinations of signature genes (225). Unlike of satellite cells.
trunk and limb progenitors, most progenitor cells for head
muscles (except for tongue) express MesP1 rather than
Pax3. II. FUNCTIONS OF SATELLITE CELLS IN
MUSCLE REGENERATION
2. Alternative origins of adult satellite cells
Skeletal muscles consist of myofibers, neurons, vasculature
Accumulating evidence indicates that some adult satellite networks, and connective tissues, of which the structural

cells may have alternative origins other than dermomyo- and functional element of skeletal muscle is the myofiber.
tome-derived Pax3/Pax7 progenitor cells. Each myofiber is surrounded by the endomysium (also
called the basement membrane or basal lamina). Bundles of
First, multiple studies have demonstrated that several types myofibers are surrounded by the perimysium, while the en-
of nonsatellite cells can reconstitute the satellite cell niche tire muscle is contained within the epimysium. Each myofi-
and turn into bona fide satellite cells (Pax7-expressing myo- ber is anchored at its extremities to tendons or tendon-like
genic cells) after transplantation into regenerating skeletal fascia at the myotendinous junctions (MTJs) (531). Myofi-
muscles (for details, see sect. IID). It remains, however, bers are composed of actin and myosin myofibrils repeated
largely unknown to what extent these cells contribute to the as a sarcomere, which is the basic functional unit of skeletal
adult satellite cell pool and muscle development under muscle. Responding to the signals from motor neurons,
physiological conditions. Notably, a recent study utilizing myofibers depolarize and release calcium from the sarco-
TN-APCreERT2 and VE-cadherinCreERT2 alleles showed that plasmic reticulum (SR). This drives the movement of actin
alkaline phosphatase (ALPL) expressing pericytes, but not and myosin filaments relative to one another and leads to
VE-cadherin-expressing endothelial cells, can develop into sarcomere shortening and muscle contraction.
postnatal satellite cells and participate in normal develop-
ment of limb muscles (135). Based on their physiological properties, skeletal muscle fibers
can be grouped into a slow-contracting/fatigue-resistant type
It is noteworthy that some adult satellite cells in mammals and a fast-contracting/fatigue-susceptible type. Myofibers also
may be derived from dedifferentiation of fetal/adult myofi- vary in terms of their myosin heavy chain (MyHC) isoforms
bers. It has long been established that the dedifferentiation (fast or slow) and metabolism types (oxidative or glycolytic).
of terminally differentiated multinucleated myofibers oc- The choice of myosin gene expression is under the dynamic
curs in injured skeletal muscle of urodele amphibians, such regulation of thyroid hormone and work load (reviewed in
as the newt (69). Nevertheless, it remains controversial as to Ref. 28). Recent studies demonstrated that the specification of
whether mammalian myotubes in vitro or myofibers in vivo myosin expression is also regulated by intronic microRNAs
can undergo a similar dedifferentiation process. Studies uti- within MyHC genes (545, 546).
lizing immortalized murine myoblast cell lines (e.g., C2C12
or pmi28 cells) have shown that some myotubes formed by Mammalian skeletal muscle during adulthood is a stable post-
these cells can dedifferentiate into mononucleated myo- mitotic tissue with infrequent turnover of myonuclei (467).
genic cells in the presence of protein extract from regener- Minor lesions inflicted by day-to-day wear and tear can be
ating newt muscles (331), bioactive compounds like myos- repaired without causing cell death, inflammatory responses,
everin or its derivatives (149, 443), ciliary neurotrophic or histological changes. For instance, local plasma membrane
factor (CNTF) (95), or by genetic manipulations such as damage caused by spontaneous eccentric muscle contractions
overexpression of Msx1 (379), Twist1 (232), Barx2 (335), can be efficiently repaired by recruiting intracellular vesicles to
or knockdown of Rb1 in conjunction with a deficiency for patch the damaged membrane (30, 508). This repair process
Cdkn2a (p16Ink4a) (395). By a novel fusion-dependent lin- involves dysferlin and caveolin-3 (30, 181), and mutations of
eage tracing technique, two recent studies reported that these genes cause limb girdle muscular dystrophy 2B (LGMD-
differentiated myotubes formed by satellite cell-derived pri- 2B) (36, 314) and 1C (LGMD-1C) (344), respectively. In con-
mary myoblasts (397) or muscle-derived cells (MDCs) trast, severe muscle injuries due to either traumatic lesions
(359) can dedifferentiate into Pax7-expressing mononu- (e.g., extensive physical activity such as resistance training, or
cleated myogenic cells in vitro in response to an inhibitor exposure to myotoxin) or genetic defects (e.g., muscular dys-
cocktail (a tyrosine phosphatase inhibitor plus an apoptosis trophies) are accompanied by myofiber necrosis, inflamma-

tory responses, activation of satellite cells, proliferation, and In this section, we examine the extensive cellular and mo-
differentiation of satellite cell-derived myoblasts (FIGURE 2). lecular dynamics during muscle regeneration, with empha-
This process, starting from myofiber necrosis and ending with sis on satellite cell. We also review the potential of nonsat-
new myofiber formation, is called muscle regeneration. It ellite cell lineages on muscle regeneration. At the end of this
should be stressed that satellite cells play a pivotal role during section, we briefly describe the function of satellite cells in
muscle regeneration under either physiological conditions normal postnatal muscle development, and compare and
(e.g., extensive exercise) (400, 457) or pathological conditions contrast this with muscle regeneration in adulthood.
(e.g., myotoxin induced injury) (301, 361, 457). This notion is
clearly supported by the findings that ablation of the total
satellite cell pool (all Pax7 cells) in adulthood completely A. An Introduction to Muscle Regeneration
abolished muscle regeneration (301, 361, 457). It has been
reported that several types of nonsatellite cells can undergo Muscle regeneration occurs in three sequential but overlap-
myogenic differentiation and contribute to muscle regenera- ping stages: 1) the inflammatory response; 2) the activation,
tion after transplantation into regenerating muscle (24, 210, differentiation, and fusion of satellite cells; and 3) the mat-
287, 345, 413). Nevertheless, the contribution of these cells to uration and remodeling of newly formed myofibers.
adult muscle regeneration seems to be negligible compared

with satellite cells, implying the physiological relevance of Muscle degeneration begins with necrosis of damaged mus-
nonsatellite cell-based myogenesis might depend on Pax7 ex- cle fibers. This event is initiated by dissolution of the myo-
pression and/or the existence of considerable numbers of sat- fiber sarcolemma, which leads to increased myofiber per-
ellite cells. meability. Disruption of myofiber integrity is reflected by
Differentiation
Return to Return to
quiescence quiescence
Activation Activation
Basal lamina
Quiescence Proliferation Differentiation
Pax7+ / Myf5 / MyoD / MyoG Pax7+ / Myf5 / MyoD / MyoG Pax7 / Myf5+ / MyoD+ / MyoG+
Pax7+ / Myf5+ / MyoD / MyoG Pax7+ / Myf5 / MyoD+ / MyoG Pax7 / Myf5 / MyoD+ / MyoG+
Pax7+ / Myf5+ / MyoD+ / MyoG Pax7 / Myf5+ / MyoD / MyoG+
Pax7+ / Myf5+ / MyoD / MyoG Pax7 / Myf5 / MyoD / MyoG+
Pax7 / Myf5 / MyoD / MyoG
FIGURE 2. Satellite cell activation, differentiation, and fusion. The myogenic program is orchestrated by key
transcription factors that dictate the progression from quiescence, activation, proliferation, and differentia-
tion/self-renewal of satellite cells. This results in the transformation of individual satellite cells into a syncytial
contractile myofiber. Initially satellite cells are mitotically quiescent (G0 phase) and reside in a sublaminar niche.
Quiescent satellite cells are characterized by their expression of Pax7 and Myf5 but not MyoD or Myogenin.
Damage to the environment surrounding satellite cells results in the deterioration of the basal lamina and their
exit from the quiescent state (satellite cell activation). Proliferating satellite cells and their progeny are often
referred to as myogenic precursor cells (MPC) or adult myoblasts. Adult myoblasts express the myogenic
transcription factors MyoD and Myf5. Following proliferation, adult myoblasts begin differentiation by down-
regulating Pax7. The initiation of terminal differentiation and fusion begins with the expression of Myogenin,
which in concert with MyoD will activate muscle specific structural and contractile genes. During regeneration,
activated satellite cells have the capability to return to quiescence to maintain the satellite cell pool. This ability
is critical for long-term muscle integrity.

increased plasma levels of muscle proteins and microRNAs, Muscle regeneration can be characterized by a series of
such as creatine kinase (17) and miR-133a (292), which are morphological characteristics based on histological and im-
usually restricted to the myofiber cytosol. Similarly, the munofluorescence staining. On muscle cross-sections,
compromised sarcolemmal integrity also allows the uptake newly formed myofibers can be readily distinguished by
of low-molecular-weight dyes, such as Evans blue or pro- their small caliber and centrally located myonuclei. These
cion orange, by the damaged myofiber, which is a reliable myofibers are often basophilic in the beginning of regener-
indication of sarcolemmal damage associated with exten- ation due to protein synthesis and the expression of embry-
sive exercise and muscle degenerative diseases (218, 328, onic/developmental forms of MyHC (217, 562). On muscle
396). Moreover, myofiber necrosis is accompanied by in- longitudinal sections and on isolated single myofibers, the
creased calcium influx or calcium release from the SR, centrally localized myonuclei were observed in discrete seg-
which in turn activates calcium-dependent proteolysis and ments of regenerating myofibers or along the entire new
drives tissue degeneration (reviewed in Refs. 7, 19, 39). In myofiber, which suggests that cell fusion during regenera-
tion happens in a focal, rather than diffuse, manner (58).
this process, calpain, a calcium-activated protease, has been
Occasionally, concentrated regenerative processes may ap-
shown to cleave myofibrillar and other cytoskeletal proteins
pear as local protrusions (also called budding) on myofi-
(reviewed in Ref. 145). Myofiber necrosis also activates the
bers. Muscle regeneration can often lead to architectural

complement cascade and induces inflammatory responses
changes of the regenerated myofibers, which are presum-
(389). Subsequent to inflammatory responses, chemotactic ably due to incomplete fusion of regenerating fibers within
recruitment of circulating leukocytes occurs at local sites of the same basal lamina (57, 58, 64, 465). Newly formed
damage (reviewed in Ref. 530). Neutrophils are the first myotubes may not fuse to each other, resulting in clusters of
inflammatory cells to infiltrate the damaged muscle, with a small caliber myofibers within the same basal lamina. Al-
significant increase in their number being observed as early ternatively, they may fuse only at one end, leading to the
as 1 6 h after myotoxin- or exercise-induced muscle dam- formation of forked (also called branching or splitting)
age (168). Following neutrophil infiltration, two distinct myofibers. Myofiber branching was commonly observed in
subpopulations of macrophages sequentially invade the in- muscles from patients suffering neuromuscular diseases, in
jured muscle and become the predominant inflammatory hypertrophied muscles, and in aging muscles, suggesting
cells (91). The early invading macrophages, characterized this phenotype may relate to abnormal muscle regenerative
by the surface markers CD68/CD163, reach their highest capacity (59, 90). Small regenerating myofibers may also
concentration in damaged muscle at 24 h after the onset form outside the basal lamina in the interstitium, due to
of injury and thereafter rapidly decline. These CD68/ migration of satellite cells or other types of myogenic cells.
CD163 macrophages secrete proinflammatory cytokines, Finally, the reconstitution of myofiber integrity may be pre-
such as tumor necrosis factor- (TNF-) and interleukin vented by scar tissue that separates the two regenerative
(IL)-1, and are responsible for the phagocytosis of cellular sites, leading to the formation of a new myotendinous junc-
debris. A second population of macrophages, characterized tion.
by the surface markers CD68/CD163, reach their peak
at 2 4 days after injury. These macrophages secrete anti- At the end of muscle regeneration, newly formed myofibers
inflammatory cytokines, such as IL-10, and persist in dam- increase in size, and myonuclei move to the periphery of the
aged muscle until the termination of inflammation. Nota- muscle fiber. Under normal conditions, the regenerated
bly, the CD68/CD163 macrophages also reportedly fa- muscles are morphologically and functionally indistin-
cilitate the proliferation and differentiation of satellite cells guishable from undamaged muscles.
(80, 81, 303, 341, 503).
B. Satellite Cell Activation
A highly orchestrated regeneration process follows mus- and Differentiation
cle degeneration. A hallmark of this stage is extensive cell
proliferation. Blocking cell proliferation by colchicine In intact muscle, satellite cells are sublaminal and mitoti-
treatment (411) or irradiation (423) drastically reduced cally quiescent (G0 phase). Quiescent satellite cells are char-
muscle regenerative capacity. Experiments by [3H]thymi- acterized by their expression of Pax7 but not MyoD or
dine labeling have clearly demonstrated that the prolifer- Myogenin (116). Examination of -galactosidase activity in
ation of satellite cells and their progeny provide a suffi- Myf5-LacZ mice indicated that the Myf5 locus is active in
cient source of new myonuclei for muscle repair (498, 90% of quiescent satellite cells, which suggests most sat-
499, 554; reviewed in Ref. 79 and discussed in sect. IIB). ellite cells are committed to the myogenic lineage (37).
It is commonly agreed that following proliferation, myo-
genic cells differentiate and fuse to existing damaged fi- Upon exposure to signals from a damaged environment,
bers or fuse with one another to form myofibers de novo. satellite cells exit their quiescent state and start to prolifer-
This process, in many but not all respects, recapitulates ate (satellite cell activation). Proliferating satellite cells and
embryonic myogenesis. their progeny are often referred to as myogenic precursor

cells (MPC) or adult myoblasts. Satellite cell activation is After regeneration, these transplanted MyoD/ myoblasts
governed by multiple niche factors and signaling pathways not only give rise to myonuclei but also contribute to the
(discussed in detail in sect. IIIA). Satellite cell activation is satellite cell pool (22). On the other hand, ectopic expres-
not only restricted to the site of muscle damage. In fact, sion of MyoD in NIH-3T3 and C3H10T1/2 fibroblasts is
localized damage at one end of a muscle fiber leads to the sufficient to activate the complete myogenic program in
activation of all satellite cells along the same myofiber and these cells (234). Taken together, these observations indi-
migration of these satellite cells to the regeneration site cate that expression of MyoD is an important determinant
(473). Satellite cell activation is also accompanied by exten- of myogenic differentiation, and in the absence of MyoD,
sive cell mobility/migration. It has been observed that sat- activated myoblasts have a propensity for proliferation and
ellite cells can migrate between myofibers and even muscles self-renewal (452). In contrast to the MyoD/ mice,
across barriers of basal lamina and connective tissues dur- Myf5/ mutant mice show a myofiber hypertrophy phe-
ing muscle development, growth, and regeneration (241, notype (187), and the proliferation of Myf5/ myoblasts is
251, 557). Recently, sialomucin CD34, whose expression is compromised (187, 542). Together, these results implicate
high on quiescent satellite cells but dramatically reduced a distinct role for Myf5 in adult myoblast proliferation,
during satellite cell activation, was demonstrated to act as while MyoD is essential for differentiation. Notably, the
an antiadhesive molecule to facilitate migration and pro- disparate functions of Myf5 and MyoD in adult muscle

mote the proliferation of satellite cells at very early stages of regeneration parallel the proposed roles for these transcrip-
muscle regeneration (8). In addition, dynamic regulation of tion factors throughout the development of distinct myo-
Eph receptors and ephrin ligands in activated satellite cells genic lineages during embryogenesis (188, 213, 256 259;
and regenerating myofibers have been shown to direct sat- reviewed in Ref. 260). Together, the aforementioned obser-
ellite cell migration (506). vations suggest a hypothesis that satellite cells enter differ-
ent myogenic programs depending on whether Myf5 or
Unlike quiescent satellite cells, myogenic precursor cells are MyoD expression predominates (450). Predominance of
characterized by the rapid expression of myogenic tran- MyoD expression would drive the program toward early
scription factors MyoD (111, 114, 116, 175, 207, 497, 572, differentiation, as exemplified by the behavior of Myf5/
585) and Myf5 (111, 116). Of note, the presence of MyoD, myoblasts (349). In contrast, predominance of Myf5 ex-
desmin, and Myogenin in satellite cells was observed as pression would direct the program into enhanced prolifer-
early as 12 h after injury, which is before any noticeable sign ation and delayed differentiation, as shown by the behavior
of satellite cell proliferation (426, 497). This early expres- of MyoD/ myoblasts (452). Finally, myoblasts coex-
sion of MyoD is proposed to be associated with a subpop- pressing both Myf5 and MyoD would exhibit the interme-
ulation of committed satellite cells, which are poised to diate growth and differentiation propensities as shown by
differentiate without proliferation (426). In contrast, the most of satellite cell-derived myoblasts. This hypothesis is
majority of satellite cells express either MyoD or Myf5 by consistent with the observation that MyoD and Myf5 have
24 h following injury (111, 116, 585) and subsequently different expression profiles throughout the cell cycle.
coexpress both factors by 48 h (111, 116). The ability of MyoD expression peaks in mid G1, whereas Myf5 expres-
satellite cells to upregulate either MyoD or Myf5 suggests sion is maximal at the G0 and G2 phases of the cell cycle
these two transcription factors may have different functions (273). Therefore, disruptions to the MyoD/Myf5 ratio may
in adult myogenesis. determine the choice of myogenic programs. This hypothe-
sis also explains the spectrum of proliferation and differen-
First, MyoD/ mutant mice display markedly reduced tiation potential observed in different primary myoblast
muscle mass (338). This atrophy phenotype is reportedly clones cultured in vitro.
due to delayed myogenic differentiation (564, 573). Simi-
larly, muscle regeneration is also impaired in MyoD/ Several studies have revealed that MyoD expression in pro-
mice, resulting in an increased number of myoblasts within liferating myoblasts is positively regulated by serum re-
the damaged area (338). These MyoD/ myoblasts persist sponse factor (SRF), which binds to the serum response
for extended periods of time, fail to differentiate, and do not element (SRE) within the MyoD regulatory region (186,
fuse into myotubes. This is consistent with the notion that 285). In proliferating myoblasts, SRF only drives low levels
MyoD/ myoblasts, when cultured in myogenic differen- of MyoD expression (286), whose activity is inhibited by
tiation conditions, continue to proliferate and eventually cyclin D1 induced cyclin dependent kinase 4 (Cdk4) (587).
give rise to a decreased number of differentiated mononu- However, the induction of MEF2 expression prior to differ-
cleated myocytes (114, 452, 573). Intriguingly, trans- entiation enables MEF2 to out-compete SRF for the SRE
planted MyoD/ myoblasts have been reported to survive binding site and leads to high levels of MyoD expression
and engraft into MyoD/ regenerating muscles with im- and initiation of differentiation (286). This function of
proved efficacy (compared with wild-type myoblasts). This MEF2 is further regulated by a member of the myocardin
phenotype is reportedly due to their increased stem cell family of transcription factors, MASTR, whose expression
characteristics and repressed apoptotic potential (22, 231). is upregulated in response to muscle injury (348).

Notably, our group recently revealed a pro-proliferation their target genes (45, 405). A large portion of target genes
function of MyoD in myoblasts (191). We found that the induced by MyoD, Myogenin, and Mef2s are muscle-spe-
isoform of p38 kinase (p38) phosphorylates MyoD, which cific structural and contractile genes, such as those encoding
negates the transcriptional activation potential of MyoD actins, myosins, and troponins. The expression of these
and leads to a repressive MyoD complex occupying the genes is essential for the proper formation, morphology,
Myogenin promoter (191). This positive effect of p38 on and function of skeletal muscle and thus they are regulated
myoblast proliferation is also supported by the observation by multiple mechanisms (41).
that Myogenin is prematurely expressed in p38-deficient
muscle, which displays markedly reduced myoblast prolif- First, the transcriptional activities of MyoD, Myogenin,
eration (191). These results also support the notion that the and Mef2s are regulated by posttranscriptional modifica-
functional state of MyoD depends on cofactors present in tions (reviewed in Ref. 420). The and isoforms of p38
the MyoD transcriptional complex. kinase (p38-/) have an important role in the expression of
muscle-specific genes (405) and in muscle terminal differen-
Moreover, multiple studies demonstrated that MyoD ex- tiation (571). The function of p38-/ is at least partially
pression does not always warrant myogenic commitment. responsible for the phosphorylation of Mef2s as inhibition
Monitoring satellite cell lineage progression revealed that of p38-/ disrupts the transcriptional activities of Mef2s.

some Pax7/MyoD proliferating myoblasts could retract In contrast, the expression of constitutively active forms of
back to a Pax7/MyoD state and eventually return to p38-/ promotes myogenesis (117, 221, 390, 420, 571,
quiescence (127, 216, 584; discussed in sect. IIC). In addi- 589). p38-/ activity stimulates the binding of MyoD and
tion, the reciprocal inhibition of Pax7 with MRFs (MyoD Mef2s to the promoters of muscle-specific genes, leading to
and Myogenin) has been revealed in C3H10T1/2 fibro- the recruitment of chromatin remodeling complexes, and
blasts and MM14 myoblasts in vitro (385). It was found ultimately the RNA polymerase II holoenzyme (405, 424,
that Pax7 decreases MyoD transcription activity and stabil- 491). Similarly, the transcriptional activity of Myogenin is
ity, whereas Myogenin represses Pax7 transcription likely regulated by protein kinase A (PKA) (308) and protein ki-
via the HMGB1-RAGE axis (385, 438). Based on these nase C (PKC)(309). Protein inhibitors of MRFs also control
observations, it was proposed that the ratio of Pax7 and myogenic gene expression. The transcriptional activity of
MyoD activities are critical for satellite cell fate determina- MRFs relies on heterodimerization with E proteins (ITF1,
tion (385). A high ratio of Pax7 to MyoD (as seen in quies- ITF2, E12, E47) (291, 362, 363). This heterodimerization is
cent satellite cells) keeps satellite cells in their quiescent negatively regulated by a group of inhibition of DNA bind-
state. An intermediate ratio of Pax7 to MyoD allows satel- ing proteins (Ids: Id1, Id2, Id3, and Id4), which are also
lite cells to proliferate, but not differentiate. Satellite cells helix-loop-helix proteins but lack the basic DNA-binding
with a low Pax7-to-MyoD ratio begin to differentiate, and domain (42, 43). Id proteins heterodimerize with E proteins
further reduction in Pax7 levels are observed following ac- and prevent their association with MRFs, thus abrogating
tivation of Myogenin. myogenic gene expression (43). Similar results occur when
Mist1 directly interacts with MyoD and prevents MyoD
After limited rounds of proliferation, the majority of satel- from binding E-boxes (298). MyoD activity can be further
lite cells enter the myogenic differentiation program and inhibited by the sequestration of E proteins, by Twist (504).
begin to fuse to damaged myofibers or fuse to each other to Finally, the transcriptional activity of MyoD is also deter-
form new myofibers. The initiation of terminal differentia- mined by specific cofactors present on the promoters of
tion starts with the expression of Myogenin and Myf6 (also myogenic genes (reviewed in Ref. 450). In vitro, MyoD
called Mrf4) (114, 116, 207, 497, 572). The induction of associates with histone acetyltransferases (HATs) p300 and
Myogenin expression primarily depends on MyoD and is p300/CBP (CREB-binding protein)-associated factor
proposed to enhance expression of a subset of genes previ- (PCAF) on E-box motifs of its target genes (419). This as-
ously initiated by MyoD (83). Target genes of MyoD and sociation is presumed to induce histone acetylation and
Myogenin have been revealed by candidate approaches transcriptional activation (45). MyoD also interacts with
(405), ChIP-on-chip experiments (44, 56, 83), and more histone deactylases (HDACs), which negatively regulate the
recently by ChIP-Seq analysis (84). These investigations transcriptional activity of MyoD either directly (325) or in
jointly reveal a convoluted hierarchical gene expression cir- a Mef2-dependent manner (319).
cuitry centered on MyoD and its immediate downstream
targets: Myogenin and Mef2 transcription factors (Mef2s). Besides MRFs and their regulators, other factors have been
Based on the temporal expression pattern of MyoD, Myo- shown to be involved in myogenic differentiation. Micro-
genin and Mef2s, a feed-forward regulatory circuit is pro- RNAs are 20 22nt noncoding small RNAs, which function
posed. In this hypothesis, myogenic differentiation is an to repress translation and reduce the stability of their target
irreversible procedure and is driven by the sequential ex- mRNAs. Recent studies demonstrated that MRFs, such as
pression of key transcription factors (master regulators), Myf5, MyoD, and Myogenin, activate the expression of a
which are destined to transduce gene expression signals to collection of myogenic microRNAs (e.g., miR-1, miR-133,

miR-206 together called MyomiRs). These myogenic program, orchestrated by key transcription factors, dictates
microRNAs, in conjunction with other microRNAs, mod- the balance between proliferation and differentiation and
ulate the expression levels of key myogenic transcription drives the functional transformation from individual prolif-
factors and regulators, such as Pax3 (119, 196, 231), Pax7 erating myogenic cells to a syncytial contractile myofiber.
(94, 139), SRF (93), c-Met (526, 577), and Dek (98) during Although numerous studies have shed light on this complex
satellite cell activation/proliferation and differentiation process, there are still many interesting questions that re-
(also reviewed in Refs. 374, 565). Furthermore, recent stud- main to be answered. For example, what are the intrinsic
ies have demonstrated the requirement for caspase-3 and its and extrinsic mechanisms that determine the scale of satel-
activation of CAD (caspase-activated DNase) in initiating lite cell proliferation in vivo, which essentially generate suf-
myoblasts differentiation in vitro (164, 290). Activation of ficient but not excessive numbers of myogenic cells for mus-
CAD by caspase-3 induces double-stranded DNA breaks cle regeneration? Similarly, what mechanisms regulate the
(DSBs) in the genome and the association of CAD with magnitude of muscle regeneration in response to variable
various target promoters. One such promoter is the cyclin- levels of damage and eventually prevent muscle atrophy or
dependent kinase (CDK) inhibitor p21(Waf1/Cip1) which hypertrophy? With the recent advances in high-throughput
following binding by CAD is activated (290). MyoD also sequencing and system biology, is it possible to elucidate a
induces the expression of p21(Waf1/Cip1) (209, 215) and core regulatory network of myogenic gene expression and

subsequent permanent cell cycle arrest. p21 is known to employ such knowledge on directing myogenic determina-
dephosphorylate the retinoblastoma protein (Rb) and cause tion and differentiation from multipotent cells? The an-
the inactivation of the Rb-associated E2F family of tran- swers to these questions will improve our understanding of
scription factors known to activate S-phase genes (reviewed muscle regeneration and facilitate future development of
in Ref. 559). Thus, through this pathway, MyoD induces therapeutic approaches to cure muscle diseases.
permanent cell cycle withdrawal in myoblasts. Consis-
tently, myoblasts in p21/ mice are defective in cell cycle C. Satellite Cell Self-Renewal
arrest and myotube formation, leading to increased apopto-
sis (555, 588). Similarly, Rb-deficient myoblasts cannot
A hallmark of stem cells is the ability to self-renew. Stem
complete cell cycle withdrawal and arrest during both S and
cells can divide and self-renew in two fashions: asymmet-
G2 phases of the cell cycle (378).
ric cell division and symmetric cell division. In asymmet-
ric cell division, one parental stem cell gives rise to two
After exiting the cell cycle, myogenic cells undergo cell-to-
functionally different daughter cells: one daughter stem
cell fusion to repair damaged myofibers or form nascent
cell and another daughter cell destined for differentia-
multinucleated myofibers. The cellular events in this com- tion. In symmetric cell division, one parental stem cell di-
plex process have been extensively studied (274, 312, 418, vides into two daughter stem cells of equal stemness. In
428, 553). Akin to embryonic myogenesis, de novo forma- either fashion, the number of stem cells is maintained at a
tion of myofibers during muscle regeneration happens in constant level. Stem cell self-renewal by asymmetric cell
two stages. In the first stage, individual differentiated myo- division is exemplified by neuronal stem cells (590). Stem
blasts fuse to one another and generate nascent myotubes cell self-renewal by symmetric cell division is frequently
with few nuclei. In the second phase, additional myoblasts observed in hematopoietic stem cells and mammalian male
incorporate into the nascent myotubes, forming a mature germline stem cells (spermatogonia) (570).
myofiber with increased size and expression of contractile
proteins. In recent years, studies in myoblast fusion in vitro The self-renewing capability of satellite cells is clearly dem-
have identified a cadre of cell surface, extracellular, and onstrated by their remarkable ability to sustain the capacity
intracellular molecules, which are important for these two of muscle to regenerate. For example, in a single myofiber
stages of myogenic cell fusion (reviewed in Ref. 238). For transplantation experiment (105), 722 satellite cells to-
example, cell membrane proteins 1-integrin (474), VLA-4 gether with their intact myofibers were transplanted into
integrin (445), integrin receptor V-CAM (445), caveo- irradiated muscles of immunodeficient dystrophic (scid-
lin-3 (180), and transcription factor FKHR (Forkhead in mdx) mice. It was found that one grafted myofiber can give
human rhabdomyosarcoma, also called FOXO1a) have rise to over 100 new myofibers, which contain 25,000
been shown to act in myoblast-to-myoblast fusion. 30,000 differentiated myonuclei. In addition, the grafted
Whereas the cytokine IL-4 (238) and calcium and cal- satellite cells can undergo a 10-fold expansion via self-re-
modulin activated NFATC2 (nuclear factor of activated newal. The expanded satellite cells are functional as they
T cell isoforms C2) pathway (237) is critical for the fu- can be activated and support further rounds of muscle re-
sion of myoblasts with nascent myotubes. generation (105). Similarly, the self-renewing capability of
satellite cells was further proven by single satellite cell trans-
As discussed here, activation of satellite cells following mus- plantation experiments (454). In this study, single Lin/7-
cle injury results in the expansion of the myogenic cell pool integrin/CD34 cells freshly isolated by FACS were trans-
and leads to the initiation of the myogenic program. This planted into irradiated muscles of scid-mdx mice. It was

observed that progeny from these single cells not only gen- ther revealed that symmetric self-renewal is promoted by a
erated myofibers, but also migrated to the satellite cell niche niche factor, Wnt7a, during muscle regeneration (293; dis-
and persisted in host muscles (454). cussed in sect. IIIA1A). Therefore, the mode of satellite cell
self-renewal is governed by the satellite cell niche.
An intriguing question is how satellite cells renew them-
selves. By using the Cre-LoxP based permanent lineage trac- With regards to activated satellite cells returning to quies-
ing technique (Myf5Cre;R26R-loxP-stop-loxP-YFP), our cence, observations on the dynamic expression of Pax7,
group first demonstrated that satellite cells can undergo MyoD, and Myogenin in ex vivo cultured single myofibers
both asymmetric and symmetric divisions within their nat- suggest it is possible (127, 216, 584). After myofiber isola-
ural niche environment in mildly damaged EDL muscle tion (the isolation procedure per se is a form of injury to
(280). The choice of asymmetric versus symmetric division initiate muscle regeneration), satellite cells are activated
is largely correlated to the mitotic spindle orientation rela- and rapidly start to express MyoD (572, 584). It has been
tive to the longitude axis of the myofiber. Asymmetric divi- observed that almost all myoblasts express MyoD after
sions are only observed for Pax7/Myf5 satellite cells, 24 h of in vitro culture (584). While most of these
which give rise to one satellite stem cell (Pax7/Myf5) and proliferating Pax7/MyoD myoblasts differentiate into
one satellite myogenic (Pax7/Myf5) cell. Asymmetric di- Pax7/MyoD/Myogenin cells after 72 h of culture, some

vision predominantly happens when the mitotic spindle is Pax7/MyoD myoblasts (also called reserve cells) none-
perpendicular to the myofiber axis (apical-basal division) theless have been observed to repress MyoD expression and
with the satellite stem cell (Pax7/Myf5) in close contact maintain Pax7 expression and eventually withdraw from
with the basal lamina (basal) and the Pax7/Myf5 satellite the cell cycle (216, 584). These Pax7/MyoD satellite cells
myogenic cell adjacent to the myofiber plasma membrane acquired the quiescence marker Nestin, albeit at a much
(apical). Occasionally, it was observed that Pax7 expression later (3 4 wk in culture) stage (127). These observations
is dampened in the apical satellite cell, suggesting a progres- suggest that quiescent satellite cells renew by lineage regres-
sion towards terminal differentiation. Furthermore, the sion from committed myogenic cells at least in vitro, and
asymmetric nature of this kind of division is also under- this renewal may be promoted by Pax7 (584). In addition,
scored by the observation that the apical Pax7/Myf5 the capability of activated satellite cells to generate reserve
cells express higher levels of the Notch ligand Delta-1, cells may be an important mechanism to maintain the size
whereas the basal Pax7/Myf5 satellite cells express of the satellite cell pool, as reduction of such capability was
higher levels of the Notch-3 receptor. Symmetric divisions suggested to lead to decreased numbers of satellite cells with
were observed for both Pax7/Myf5 satellite cells and age (128). Intriguingly, this lineage regression has also been
Pax7/Myf5 satellite cells and in either case the mitotic recently observed in vivo (482). Sprouty-1, a negative reg-
spindle was frequently parallel to the myofiber axis (planar ulator of receptor tyrosine kinase (RTK) signaling, plays a
division) and both daughter cells were in contact with the critical role in satellite cell renewal (482). Sprouty-1 is ex-
myofiber plasma membrane and the basal lamina. pressed in quiescent but not proliferating satellite cells (177,
482). Upon injury, released fibroblast growth factor (FGF)
When both satellite stem cells and satellite myogenic cells and hepatocyte growth factor (HGF) act through the RTK/
are freshly sorted and transplanted into Pax7/ muscles ERK pathway to stimulate satellite cell proliferation (482).
lacking any functional endogenous satellite cell, both cell Most satellite cells entered the cell cycle during regeneration
types can colonize the host muscle. However, only Pax7/ as indicated by BrdU labeling. It was confirmed that some
Myf5 satellite cells can efficiently reconstitute the satellite satellite cell-derived myogenic progenitors withdrew from
cell compartment (7-fold more efficient than Pax7/ the cell cycle, returned to the satellite cell compartment, and
Myf5). These observations indicate that Pax7/Myf5 regained Sprouty-1 expression, indicative of satellite cell
satellite cells represent a bona fide stem cell population, renewal in vivo. In the absence of Sprouty-1, it was ob-
which can undergo self-renewal by both asymmetric divi- served that satellite cell-derived myogenic progenitors pro-
sion and symmetric division (280). liferate and differentiate normally, but markedly reduced
numbers of satellite cells exist after regeneration. Further
Although asymmetric self-renewal may be sufficient under investigations revealed that Sprouty-1 is required only for a
physiological conditions, satellite stem cells may favor sym- distinct subset of myogenic progenitors to return to their
metric self-renewal divisions to replenish and expand their quiescence state (482). These results indicate that Sprouty-1
population in response to acute need for a large number of is essential for some satellite cells to regain quiescence fol-
satellite cells after injury or disease state (354). Indeed, it lowing regeneration. The function of Sprouty-1 in this pro-
was observed that Pax7/Myf5 satellite stem cells repre- cess is most likely due to its inhibitory effect on the ERK
sent 10% of total satellite cells in intact muscles, whereas pathway and subsequent enhanced cell cycle withdrawal. It
this percentage increases to 30% at 3 wk after injury should be stressed that this renewal of satellite cells at a
(280). In search of intrinsic and extrinsic cues regulating population level and the aforementioned self-renewal of
Pax7/Myf5 satellite stem cell self-renewal, our group fur- satellite cells at a single-cell level are not mutually exclu-

sive but rather represent two different perspectives of the signaling and chemokine receptor 2 (CCR2) have been im-
same regeneration process. Future studies are needed to plicated in guiding bone marrow cells towards muscle in-
identify the essential differences between Sprouty-1-de- jury sites (429, 510). However, it has also been reported
pendent and Sprouty-1-independent populations and un- that SDF-1/CXCR4 signaling is dispensable for the homing
derstand whether these differences reflect any other func- of CD45 hematopoietic lineage cells to injured muscle,
tional distinction. In addition, it would be interesting to which are instead responsive to HGF/c-Met signaling (447).
investigate the regulatory mechanisms governing Sprouty-1 Overall, it is noteworthy that bone marrow transplantation
expression, for example, whether the reappearance of has not been reported to robustly or therapeutically ame-
Sprouty-1 is regulated by Pax7 or Wnt signaling. liorate any muscle disease. Future studies are required to
define the subpopulation(s) of bone marrow cells, which
have long-term myogenic potential in vivo especially in the
D. Contributions and Therapeutic Potential context of muscle diseases. Also, it would be interesting to
of Nonsatellite Cells in Trauma-Induced investigate whether bone marrow-derived cells are involved
Muscle Regeneration in postnatal muscle growth since satellite cells with similar
markers have been identified in adult muscles.
1. Bone marrow stem cells

2. Muscle side population cells
The myogenic potential of bone marrow cells was demon-
strated by either intravenous injection of bone marrow cells Similar to bone marrow, skeletal muscle contains a unique
into subjects following muscle injury or directly via intra- cell population termed muscle side population (SP) cells,
muscular injection of whole bone marrow into injured mus- which can be isolated based on their ability to efflux
cles. Both of these methods led to the incorporation of bone Hoechst 33342 dye (210, 245). The majority of muscle SP
marrow-derived cells into newly formed myofibers within cells are characterized by CD45/c-Kit/Sca-1/ABCG2/
regenerating muscles (54, 166, 210). Because of the ex- Pax7/Myf5/Desmin and reside in the skeletal muscle
tremely low efficacy of incorporation, doubts persist re- interstitium juxtaposed to blood vessels, which make them
garding the ability of bone marrow-derived cells to recon- distinct from satellite cells and bone marrow-derived SP
stitute the satellite cell niche (210). Nevertheless, lineage cells (24, 146, 210, 439, 464). Multiple lines of evidence
tracing experiments demonstrated that bone marrow cells, indicate that muscle SP cells are heterogenic (24, 464). Ini-
when systematically injected into irradiated mice, were able tially, a minor population of CD45 muscle SP cells was
to reconstitute the satellite cell niche and expressed satellite identified (24, 464, 478). These CD45 muscle SP cells
cell markers, such as Myf5, c-Met, and 7-integrin (287). persist in Pax7/ germline null mice and can efficiently
These bone marrow-derived satellite cells can undergo differentiate into hematopoietic cells in culture (24, 478). In
myogenic differentiation in vitro and give rise to myofibers addition, CD45 muscle SP cells also have myogenic poten-
when injected into damaged muscles (287). Adult bone tial when isolated from both wild-type and Pax7/ mice.
marrow contains hematopoietic stem cells (HSC) and stro- They can be induced to differentiate into myogenic cells
mal cells (also called mesenchymal stem cells). Due to a lack following coculture with primary myoblasts or through the
of a standardized definition, conflicting results exist regard- forced expression of Pax7 or MyoD (24, 477). In addition,
ing the exact bone marrow-derived progenitor cell type(s) lineage tracing experiments have revealed that only the
that contribute to muscle regeneration. Bone marrow-resid- main population of CD45 muscle SP cells arise from em-
ing hematopoietic stem cells, isolated by cell surface mark- bryonic Pax3 hypaxial somitic cells, suggesting the minor
ers c-Kit/Sca-1 or CD45/Sca-1, or CD45/c-Kit/ CD45 SP cells might have distinct origins, possibly from
Sca-1 are able to incorporate into newly forming myofi- endothelial, hematopoietic stem, or bone marrow cells
bers (1, 78, 112, 581), although it was unclear whether the (464). This is consistent with results from transcriptome
progeny of these cells were able to occupy the satellite cell analysis of muscle SP cells in resting and regenerating mus-
niche. It was also demonstrated that Mac-1low bone mar- cles, which indicate the increased expression of c-Kit and
row SP cells, particularly those c-Kit/CD11b immature CD45 in the muscle SP population 5 days after injury (337).
cells, were able to generate myofibers (147, 382). On the Furthermore, it was also demonstrated that somite-derived
other hand, mesenchymal stem cells were able to incorpo- CD45 SP cells have more myogenic potential than CD45
rate into myofibers in injured muscles (140, 488) and gave SP cells when cultured in vitro, suggesting that the develop-
rise to Pax7 satellite cells, which can support multiple mental origin of SP cells affect their intrinsic myogenic ca-
rounds of muscle regeneration (140). Interestingly, the high pacity (464). Lastly, a recent study revealed that a subpop-
myofiber turnover rate induced by muscle stress and injury ulation of satellite cells also have an SP phenotype (518).
seems to facilitate bone marrow cell engraftment into regen- These SP cells that reside in the satellite cell compartment,
erating muscles (1, 68, 287, 460, 487). These results further termed satellite-SP cells, are characterized by CD45/Sca-
emphasize the importance of the microenvironment on sat- 1/ABCG2/Pax7/Syndecan-4, which makes them dis-
ellite cell specification. In accordance with this, stromal cell- tinct from the majority of CD45 SP cells in muscle. Fol-
derived factor-1 (SDF-1)/chemokine receptor 4 (CXCR4) lowing direct injection into regenerating muscles, the grafted

muscle SP cells were found in myofibers and the satellite cell Although not directly assessed by lineage tracing, these ob-
niche, which suggests that these cells can contribute to long- servations together support a hypothesis that PICs may con-
term muscle regeneration (24). Importantly, when introduced tribute to the satellite cell population during postnatal mus-
intravenously into mdx mice, muscle SP cells from wild-type cle growth and during adult muscle regeneration (345). In
mice incorporate into host myofibers and restore their dys- addition, Pax7 expression is presumably essential for the
trophin expression (27, 210), suggesting these cells are able myogenic specification of PICs as PICs isolated from
to migrate to regenerating muscles through the blood- Pax7/ mice cannot give rise to myogenic cells in vitro
stream. Indeed, compared with satellite cells and their de- (345). Of note, Pax3 lineage tracing experiments further
rivatives, muscle SP cells are much more efficient at engraft- indicated that PICs do not arise from embryonic Pax3
ing into mdx hosts after systemic delivery (368). Interest- myogenic progenitor cells, indicating PICs and satellite cells
ingly, the systemic delivery of wild-type SP cells into mdx are derived from distinct lineages (345).
mice can also repopulate the bone marrow of an irradiated
host, although at lower efficacy compared with bone mar- These intriguing observations also raised several issues re-
row-derived SP cells (210). garding the identity and lineage progression of the Sca-1/
CD34/CD45/(50% PW1) interstitial cells. A recent
Muscle SP cells constitute a distinct cell population based study indicated that FAPs isolated from adult muscle are

on their unique properties. However, it is still unclear characterized by similar markers Sca-1/CD34/CD45
whether the SP phenotype per se is of any importance to the (also CD31) but only give rise to adipogenic and fibro-
muscle regeneration process. Although muscle SP cells out- genic lineages in vitro (252 and discussed in sect. IIIB1A).
perform the main population in muscle regeneration, future Coculture with myogenic cells cannot promote the myo-
studies are needed to carefully compare muscle SP cells with genic potential of FAPs (252). Accordingly, FAPs also do
other defined myogenic precursors, such as non-SP satellite not assume the myogenic lineage in vivo when transplanted
cells, based on their myogenic potential. into either uninjured or injured muscles. These discrepant
observations on PICs and FAPs lead to two possibilities:
3. PW1 interstitial cells 1) FAPs are depleted of CD31 cells and thus the myogenic
potential resides in these CD31 cells; or more likely
It has been reported that some interstitial cells, characterized 2) PICs and FAPs represent the same cell population but in
by their expression of PW1 (also called peg3), might be in- young and adult stages, respectively. Notably, muscle SP
volved in perinatal skeletal muscle growth (345). Intriguingly, cells (Sca-1/ABCG2) are also CD34 and thus could be
a recent study from the same group reported that adult stem originating from the same lineage as FAPs and PICs (226).
cells/progenitors residing in multiple tissues/organs can be di- Future studies may provide direct answers in terms of the
rectly identified and isolated from PW1-reporter mice (46). lineage origin and hierarchy of these cell types. Future in-
PW1 is encoded by a 8.5 kb long, intronless transcript, vestigations should also focus on the mechanisms that reg-
which is strongly transcribed in skeletal muscle in both ulate the myogenic potential of these interstitial cells.
embryonic and postnatal stages (435). Within skeletal mus-
cle, PW1 expression was detected in both satellite cells and 4. Muscle-derived stem cells
a group of Sca-1/CD34/Pax7 interstitial cells (PIC)
(351, 376, 476). In transgenic mice with a dominant nega- A series of studies have demonstrated that a distinct cell
tive form of PW1 (PW1) driven by a Myogenin promoter, population, termed muscle-derived stem cells (MDSCs), can
embryonic and fetal muscle development is normal but post- be isolated from skeletal muscles based on their weak ad-
natal muscle growth is severely impaired with a profound phe- hesion characteristics and long-term proliferation behav-
notype, to some extent, reminiscent to that of Pax7/ germ- iors in culture (247, 294, 421, 422). Further characteriza-
line mutant mice (376, 478). Compared with wild-type tion of MDSCs indicated that these cells are CD45/M-
mice, the number of quiescent satellite cells is markedly Cadherin/CD34/Flk-1/Sca-1/Desmin, which makes
reduced in postnatal muscle of PW1 mice (376). In con- them distinct from satellite cells and hematopoietic cells but
trast, the number of Pax7/PW1 interstitial cells (PIC) is more similar to muscle SP cells (294, 421). MDSCs and
significantly increased within postnatal muscles from satellite cell-derived myoblasts in culture appear to repre-
Pax7/ mice (345), which is accompanied by progressive sent two distinct populations as evidenced by the finding
loss of Pax7 satellite cells (345, 380, 478). Interestingly, that MDSCs can be isolated from Pax7/ germline null
PICs have myogenic potential when cultured in vitro (345). mice (318). Like muscle SP cells, the myogenic differentia-
This myogenic potential is enhanced by coculture with sat- tion of MDSCs depends on Pax7 (318). A unique charac-
ellite cells and is compromised in PICs isolated from teristic of MDSCs is their multipotency (294, 421, 536). It
Pax7/ mice (345). Importantly, when transplanted into has been reported that MDSCs can differentiate into myo-
injured muscles, FACS isolated Sca-1/CD34/CD45 genic, adipogenic, osteogenic, chondrogenic, and hemato-
PICs give rise to both interstitial cells and Pax7 satellite poietic lineages (reviewed in Ref. 404). After intra-arterial
cells, whereas Sca-1/CD34/CD45 cells (enriched for transplantation, MDSCs contribute to regenerated myofi-
satellite cells) only derive into Pax7 satellite cells (345). bers, incorporate into the satellite cell niche, and also give

rise to endothelial and neural cells (421). Interestingly, like stimulated -sarcoglycan expression in mesoangioblast-de-
muscle SP cells, MDSCs can also repopulate the hematopoi- rived myofibers (475). Taken together, investigations on
etic lineage in irradiated murine hosts, and the reconstituted mesoangioblasts have revealed great therapeutic potential
bone marrow can in turn contribute to muscle regeneration for the amelioration of human dystrophic diseases. Future
(82). In addition, MDSCs are more efficient than myoblasts studies may focus on identifying the adult counterparts of
at forming dystrophin myofibers when directly trans- these cells and characterizing their myogenic potentials.
planted into mdx mice (243). Due to the prolonged isola-
tion procedure of MDSCs and the accompanied dynam- 6. Pericytes
ics of gene expression, it is difficult to trace the origin of
MDSCs in vivo based on cell surface markers. Future
Pericytes (also called Rouget cells or Mural cells) are con-
investigation by candidate lineage tracing and clonal
tractile connective tissue cells residing beneath the micro-
analysis may help to elucidate the lineage relationship
vascular basement membrane. Pericytes originate from the
between MDSC and other myogenic cells.
embryonic sclerotome and are believed to regulate the
5. Mesoangioblasts blood flow in capillaries (415, 284, 406). As a multipotent
stem cell population, pericytes can differentiate into adi-

Mesoangioblasts arise from the embryonic dorsal aorta and pocytes (161), chondrocytes (161), and osteoblasts (142) in
are characterized by CD34/c-Kit/Flk-1/NKX2.5/ vitro. Two recent studies indicated that pericytes, which do
Myf5/Oct4 expression (129, 343). Mesoangioblasts are not express Pax7, Myf5, or MyoD, can differentiate into
highly proliferative when cultured in vitro, and long-term skeletal muscles both in vitro and in vivo (135, 136), sug-
cultured mesoangioblasts are multipotent, being able to gesting pericyte-mediated myogenesis may follow a myo-
give rise to multiple mesodermal lineages, such as bone, genic differentiation program distinct from that of satellite
cartilage, smooth, cardiac, and skeletal muscle following cells. FACS sorted human pericytes display the following
transplantation (343). Although the contribution of me- cell surface marker combination: CD45/CD34/CD56/
soangioblasts to normal muscle development is controver- CD144/CD146/PDGFR-1/NG2 proteoglycan, which
sial, multiple studies have demonstrated that mesoangio- makes them distinct from embryonic mesoangioblasts, he-
blasts can be employed to facilitate muscle regeneration, matopoietic cells, or satellite cells (136). Intriguingly, cells
particularly for dystrophic muscles. First, it was found that carrying the same surface marks can be isolated from
-sarcoglycan/ mesoangioblasts can be transduced in various tissues, including pancreas, adipose, and pla-
vitro with -sarcoglycan expressing lentiviral vector and centa and differentiate into skeletal muscle cells when
robustly generate -sarcoglycan myofibers following cultured in vitro, irrespective of their origins (118). The
transplantation into -sarcoglycan/ mice (a model for fact that pericytes also display cell surface markers char-
limb girdle muscular dystrophy) via intra-artery injection acteristic of mesenchymal stem cells (CD10/CD13/
(458). The high efficiency of normal myofiber reconstitu- CD44/CD73/CD90) raised the hypothesis that peri-
tion observed in this study suggests that intrinsic properties cytes may represent a significant portion of mesenchymal
of mesoangioblasts may help them travel to regenerating stem cells in the adult (85, 118, 163). Xenographic trans-
muscles via the bloodstream. In addition, mesoangioblasts plantation of human pericytes into combined immune defi-
can release immunosuppressive and tolerogenic molecules, cient-X-linked, mouse muscular dystrophy (scid-mdx) mice
which supposedly help mesoangioblasts incorporate into through the femoral artery gave rise to numerous myofibers
allogeneic dystrophic hosts (211). The myogenic potential expressing human dystrophin (136). Interestingly, a small
of mesoangioblasts isolated from human patient biopsies portion (35%) of transplanted pericytes incorporated be-
suffering from dermatomyositis (DM), polymyositis (PM) neath the basal lamina of myofibers, indicating that peri-
and inclusion-body myositis (IBM) were compared (352). It cytes are able to occupy the satellite cell niche in dystrophic
was observed that mesoangioblasts from the IBM patients muscle. Importantly, pericyte transplantation significantly
could not differentiate into myofibers when cultured in improved the physiological performance of treated dystro-
vitro or xenotransplanted into injured mouse muscles. In- phic muscles, indicating that pericyte-derived myofibers are
terestingly, this defect can be rescued by either transient functional. Similar promising results were achieved in a
overexpressing of MyoD or knockdown of a MyoD inhib- prototype experiment, wherein pericytes isolated from
itor protein, bHLH-B3, which suggests that the myogenic Duchenne patients were transduced in vitro with a human
program of mesoangioblasts is MyoD-dependent (352). mini-dystrophin expressing lentiviral vector and trans-
Several investigations demonstrated that factors involved in planted into scid-mdx mice (136). The myogenic potential,
normal muscle regeneration also facilitate mesoangioblast- together with their abilities to be cultured in vitro and pene-
based muscle regeneration. For example, HMGB1, SDF-1, trate the blood vessel wall, makes pericytes a promising can-
CXCR4, and 4-integrin have been shown to enhance the didate for future cell-based therapies to treat muscular dystro-
migration of mesoangioblasts from blood vessels toward phy. Future research may investigate whether transplanted
injured muscles (182, 399). Similarly, pretreatment of me- pericytes possess sufficient long-term myogenic capability in
soangioblasts with nitric oxide before transplantation also dystrophic muscles.

7. CD133 cells with other myogenic cells, such as satellite cells. Recently,
several strategies have been established to achieve persistent
Recent studies demonstrated that a fraction of CD133 engraftment and avoid teratoma formation. In one study,
(also called AC133) mononucleated cells in adult peripheral Pax3 was transiently expressed to induce paraxial meso-
blood have myogenic potential (535). Freshly isolated hu- derm formation during embryoid body differentiation, and
man CD133 cells can undergo myogenic differentiation PDGFR-, a paraxial mesoderm marker, was subsequently
when cocultured with myogenic cells or exposed to Wnt- used to isolate a homogeneous population of proliferating
producing cells in vitro (535). Importantly, when xeno- myogenic progenitors (124). The transplantation of this
transplanted via intra-arterial or intramuscular injection, population into mdx mice resulted in improved muscle
these CD133 cells can fuse with regenerating muscles in function, and teratoma formation was prevented. In an-
scid-mdx mice and improve the force generation of treated other study, PDGFR- cells were directly isolated from ES
muscles. Moreover, donor human CD133 cells, express-
cells in an earlier stage without Pax3 induction (455). It was
ing satellite cell markers M-Cadherin and Myf5, were de-
found that these early paraxial mesodermal cells, when
tected in the satellite cell compartment after transplanta-
transplanted into injured muscles, could give rise to bona
tion, indicating they can reconstitute the satellite cell
fide satellite cells that can further differentiate into func-
niche (535). A small subpopulation of CD133/ CD34

tional myofibers. Similarly, transient expression of Pax7
double positive cells can be identified in the blood and
skeletal muscle interstitium (233). Similar to blood-de- seems to facilitate the myogenic specification of ES cells
rived CD133 cells, human muscle-derived CD133 cells (125). Recently, it was shown that SM/C-2.6 cells iso-
manifested remarkable myogenic differentiation capacity in lated from cultured embryoid bodies can differentiate
regenerating muscle (372). As CD133 cells can be readily into skeletal muscle myofibers both in vitro and in vivo
isolated from the blood, manipulated in vitro and delivered (88). When transplanted into injured muscles, these cells
through the circulation, a couple of studies have explored can incorporate into the satellite cell compartment and
their application to treating Duchenne muscular dystrophy express satellite cell markers, such as Pax7 and M-cad-
(DMD). In one of these studies, CD133 cells isolated from herin. Importantly, these ES-derived satellite cells un-
human dystrophic muscles were genetically engineered ex dergo extensive self-renewal during subsequent muscle
vivo to restore dystrophin expression and subsequently de- injury and can be further transplanted with high engraft-
livered into scid-mdx mice (41). Treated dystrophic muscles ment efficiency (88).
were improved in terms of muscle morphology, function,
and dystrophin expression, although the long-term effect of Over the last five years, various types of differentiated so-
this treatment has not been documented so far. The safety matic cells have been successfully induced into pluripotent
of this CD133 cell therapy (without dystrophin correc- stem cells (iPS cells) via a process involving transcription
tion) was later confirmed in human DMD patients by au- factor based reprogramming (371, 384, 515, 516, 582).
tologous transplantation (534). Taken together, CD133 Given their adult somatic origin and pluripotent nature, iPS
cells are one of the most promising candidates for cell-based cells hold tremendous potential for cell-based therapy. In an
therapy of DMD. Future studies should focus on whether attempt to apply iPS cells to muscle regeneration, a recent
these cells can survive long term and support repeated bouts study demonstrated that SM/C-2.6 cells isolated from
of regeneration in DMD patients. mouse iPS cells have comparable regenerative potential to
those from mES cells (346). In addition, conditional expres-
8. Embryonic stem cells and induced pluripotent sion of Pax7 in human iPS cells was successful in inducing
stem cells
large quantities of myogenic progenitors, which were able
to efficiently engraft and produce abundant human-derived
Embryonic stem (ES) cells are pluripotent stem cells, which
dystrophin myofibers in dystrophic mouse muscle (123).
can differentiate into all three germ layers and hence have
Notably, a new strategy of iPS cell-based therapy to treat
been extensively studied for cell-based therapies. In an early
study, mouse ES cells cocultured with muscle cells were DMD was reported recently (267). In this study, iPS cells
transplanted into irradiated mdx mice by intramuscular in- were derived from mdx mice or a human DMD patient, and
jection (47). Donor-derived myofibers were occasionally the genetic deficiency of dystrophin in these cells was cor-
found on the surface of the host muscles. The low efficacy of rected by transferring a human artificial chromosome
engraftment in this study suggested that selective markers (HAC) containing a complete genomic dystrophin sequence
might be necessary to enrich myogenic precursors from ES via microcell-mediated chromosome transfer (MMCT).
cell cultures. In a later study, a subpopulation of CD73/ These genetically corrected iPS cells can differentiate into
N-CAM human ES cells, which are enriched for mesen- muscle-like tissues and can be used to generate chimeric
chymal precursors, were injected into regenerating muscle mice, wherein tissue-specific expression of dystrophin was
of scid mice (31). It was observed that human donor cells observed (267). These inspiring results warrant future in-
gave rise to myoblasts and established prolonged engraft- vestigations on regulatory mechanisms governing the myo-
ment; however, the overall efficiency was not compared genic specification of ES and iPS cells.

E. Satellite Cells in Perinatal/Juvenile satellite cells express Pax7 (478). The apparent distinct re-
Muscle Growth quirement for Pax7 in juvenile but not adult muscle regen-
eration may suggest that Pax7 is only necessary for the
In neonatal mouse muscle, satellite cells account for 30 initial establishment of perinatal satellite cells and/or de
35% of the sublaminal nuclei on myofibers (9, 227, 471). novo myogenic specification of other nonsatellite cell lin-
This proportion of satellite cells decreases while the number eages, which presumably contribute to the total satellite cell
of myonuclei increases over postnatal growth (150). Exper- pool during postnatal growth. In contrast, the maintenance
iments by [3H]thymidine labeling indicate that satellite cells of satellite cell establishment might be Pax7 independent
are proliferative in growing muscle, give rise to myonuclei, and the rare occasion of de novo myogenic specification
and continue to fuse with myofibers (355, 470, 481). The from other nonsatellite cell lineages may be negligible in
cell cycle time of juvenile satellite cells in growing rat mus- adulthood. In this sense, the sustained expression of Pax7 in
cles was determined to be 32 h, with 14 h within the S adult satellite cells may be due to sustained interactions
phase (471). This high proliferation rate of juvenile satellite with their niche, rather than a necessity for Pax7 function.
cells is likely due to a large requirement for muscle growth In support of this hypothesis, genetically marked hemato-
at this stage. Like their adult counterparts, juvenile satellite poietic stem cells (bone marrow derived CD45/c-Kit/Sca-
cells are also likely heterogeneous. By continuous BrdU la- 1/Lin cells) have been shown to express Pax7 once they

beling and tandem BrdU/[3H]thymidine labeling, two sub- are present in the satellite cell niche (148, 581).
populations of satellite cells in growing muscle have been
identified (471). A fast-cycling satellite cell population, ac-
counting for 80% of the cells, was readily labeled over the III. ANATOMIC AND FUNCTIONAL
first 5 days of continuous BrdU infusion. In contrast, slow- DIMENSIONS OF THE SATELLITE
dividing satellite cells incorporated BrdU at a much slower CELL NICHE
rate, and some of them were not labeled with BrdU even
after an additional 9 days. Moreover, only a small portion Based on the stem cell niche concept, behaviors of tissue-
of the satellite cells labeled with BrdU during the first 5 days specific stem cells are determined by structural and bio-
could be labeled with [3H]thymidine during a second 5-day chemical cues emanating from the surrounding microenvi-
continuous infusion. This observation suggests that 1) the ronment (380). In recent years, adult stem cells and their
majority of fast-cycling satellite cells only undergo a limited corresponding niches were identified in numerous tissues
number of mitotic divisions prior to fusion, and 2) the num- including bone marrow (566), brain (322), testis (240), liver
ber of fast-cycling satellite cells in growing muscle are main- (528), intestine (55), heart (302), white fat (441, 519), and
tained by the slow-cycling satellite cells through asymmetric skin (174). Similar to these adult stem cells, satellite cells are
divisions (471). Interestingly, the functional difference and also present in a highly specified niche, which consists of the
lineage relationship between these two satellite cell popula- extracellular matrix (ECM), vascular and neural networks,
tions during postnatal muscle growth largely resemble that different types of surrounding cells, and various diffusible
of satellite cells and myoblasts during adult muscle regen- molecules (FIGURE 3). Furthermore, satellite cells, as one of
eration. This analogy may reflect a common scheme of myo- the niche components, also influence each other by means of
genesis in both postnatal muscle growth and adult muscle cell-cell interaction and autocrine or paracrine signals. The
regeneration. dynamic interactions between satellite cells and their niche
specifically regulate satellite cell quiescence, self-renewal,
Despite their similarities, studies have revealed distinct ge- proliferation, and differentiation. In this fashion, muscle
netic requirements for both juvenile and adult satellite cell atrophy or excessive growth is prevented, and the satellite
populations. Pax7 is required for the maintenance of a func- cell pool is maintained during regeneration. Understanding
tional myogenic cell population in the perinatal/juvenile the interactions between satellite cells and their niche is of
stage, as muscle growth and regeneration are severely im- paramount importance for the development of therapies to
paired in Pax7 germline null mutants during this period treat both age-related skeletal muscle atrophy (sarcopenia)
(279, 393, 478). In contrast, Pax7 seems to be dispensable and skeletal muscle diseases. In the following section, we
for adult muscle regeneration in Pax7 conditional knockout will define the scope of the satellite cell niche and discuss
mutants, wherein Pax7 expression is ablated only in the how these niche factors affect satellite cells during muscle
adult stage (299). In conditional Pax7 knockout mice, sat- regeneration.
ellite cells, expressing M-cadherin but not Pax7, were ob-
served in the satellite cell compartment in adult muscle after
one round of regeneration, and these cells can support a A. The Immediate Niche
second round of regeneration (299). The regenerative ca-
pacity of Pax7 satellite cells was not due to a compensa- 1. Satellite cell: regulatory signaling pathways
tory mechanism by Pax3, as muscle regeneration is not
impaired by simultaneous deletion of both Pax7 and Pax3 A) WNT SIGNALING. Wnt signaling controls diverse biological
in adulthood. It is well known that both juvenile and adult processes, such as cell proliferation, cell fate determination,

Signaling within the Immediate Niche

Satellite cell
Fibronectin
bFGF
Decorin Wnt7a
Proteoglycans
Basal lamina
SDF-1
Myotube Sarcolemma
Laminin
IGF
Entactin

HGF Glycoproteins
Collagen EGF
Perlecan
Signaling within the Local Milieu
Pericytes
Fibroblast
Motor Perimysium
neurons
(axons)
Connective
tissue
Capillaries
Adipocytes
Muscle fascicle
Signaling within the Systemic Milieu

Immune cells Androgens
Monocytes
Macrophages
Neutrophils
Tibia
IL-6
Myofibers
fiib
_Neutrophils Fibula
Satellite cells
Nitric Oxide
Epithelial cells
Endothelial cells
Fibroblasts
Macrophages
Myofibers

cell adhesion, cell polarity, and morphology. Wnt signaling of Wnt signaling at early stages of myoblast proliferation.
is activated by binding of extracellular Wnt family glyco- This counteracting effect is reflected by the levels of the
proteins with Frizzled receptors and low-density lipopro- active form of GSK3-, which are high in the early Notch
tein receptor-related protein (LRP5, LRP6) pairs. The Friz- activating stage and low in later Wnt activating stage. It was
zled receptor can initiate two distinct signaling pathways: proposed that low activity of Wnt signaling in early prolif-
the Wnt/-catenin and Wnt/PCP pathways. Wnt/-catenin eration allows the expansion of enough myoblasts by Notch
pathway is characterized by the regulation of -catenin sta- signaling for later differentiation (65). Notably, although
bilization and its entry into the nucleus. The Wnt/PCP path- this study reported that the mRNA levels of Wnt ligands
way is involved in planar cell polarization (PCP) and estab- and Frizzled receptors within isolated myofibers increase in
lishment of polarized cellular structures (183). late culture, it is still possible that Wnt ligands may origi-
nate from other sources in vivo, such as the ECM, and may
In the Wnt/-catenin pathway, the level and subcellular function through preexisting Frizzled receptors on satellite
localization of -catenin determine the ultimate output. cells.
Normal levels of -catenin dimerize and associate with
both transmembrane cadherins and cytoskeleton-bound Perez-Ruiz et al. (407) proposed that -catenin promotes
-catenin, which promotes cell adhesion and controls cell self-renewal of satellite cells and prevents them from imme-

shape. The normal levels of cytoplasmic -catenin are main- diate myogenic differentiation. By retrovirus-based overex-
tained by constitutive degradation of excess -catenin by pression and RNAi knockdown of proliferating Pax7/
GSK3-. In the cytoplasm, GSK3- and -catenin complex MyoD satellite cells on single myofibers, it was found that
with Axin and adenomatous polyposis coli (APC), leading constitutive expression of stabilized -catenin, or inhibition
to -catenin phosphorylation by GSK3-. Phosphorylated of degradation by GSK3 leads to downregulation of
-catenin is bound by the -TrCP component of the ubiq- MyoD and Myogenin expression. In contrast, when
uitin ligase complex and degraded by the proteosome. -catenin was downregulated by RNAi or when its target
GSK3- is constitutively active but can be inhibited by Di- genes were repressed by the dominant-negative -catenin-
shevelled (Dvl), which is activated by Wnts binding to a ERD, fewer Pax7/MyoD myoblasts were observed. As
Frizzled and LRP receptor pair. Thus, when Wnt signaling -catenin levels determined the observed cellular changes, it
is active, elevated levels of cytoplasmic -catenin enter the was proposed that the Wnt/-catenin pathway is involved
nucleus and interact with Tcf/Lef transcription factors to (407). It should be stressed that although MyoD expression
regulate gene expression (373). can be regulated by directly changing -catenin levels, the
physiological relevance of this phenomenon still largely de-
Accumulating evidence indicates that Wnt/-catenin signal- pends on the availability of Wnt ligands and expression of
ing is involved in satellite cell function during muscle regen- Frizzled receptors on satellite cells. In addition, a recent
eration, although its defined roles remain controversial. study revealed that -catenin directly interacts with MyoD
First, Brack et al. (65) suggested that Wnt signaling pro- to enhance MyoD binding to E-box elements to initiate the
motes myogenic commitment and terminal differentiation myogenic program (271). However, in vivo studies are re-
in adult myogenesis. By examining the effects of exogenous quired to further confirm and elaborate on the mechanism
Wnt3a and sFRP3 as activator and inhibitor of Wnt signal- whereby -catenin interacts with MyoD.
ing, respectively, it was found that regenerating muscles in
vivo and myoblasts derived from cultured single myofibers Otto et al. (391) proposed that Wnt ligands are important
are responsive to Wnt signaling only at a late stage of dif- regulators of proliferation for satellite cells during adult
ferentiation. Activation of Wnt/-catenin signaling in- muscle regeneration. mRNAs for Wnt ligands (Wnt1,
creased both Desmin expression in myogenic cells in vitro Wnt3a, Wnt5a, Wnt11) were expressed in single myofibers
and the size of newly formed myofibers in vivo, whereas (together with satellite cells) upon 2 days of culture in vitro.
inhibition of Wnt signaling caused the opposite effects. In- These data along with reporter assays indicated that Wnt
terestingly, Notch signaling seems to antagonize the effects signaling is active at this point. It was found that exogenous
FIGURE 3. The satellite cell niche. A: satellite cells reside between the basal lamina and the sarcolemma of adult skeletal myofibers and as such are
influenced by structural and biochemical cues emanating from this microenvironment. A complex set of diffusible molecules (e.g., Wnt, IGF, and FGF)
are exchanged between the satellite cell and the myofiber to maintain quiescence or promote activation. In addition, numerous extracellular matrix
components and cellular receptors are present either on the surface of the sarcolemma, satellite cell, or contained within the basal lamina. These
components comprise the immediate niche of the satellite cell and dictate rapid changes in the satellite cell state. B: the muscle fascicle defines the
extremities of the local milieu an environment that is more diverse compared with the immediate niche due to the heterogeneity of cell types and
signaling factors. The local milieu surrounding the satellite cell is made up of other myofibers in addition to interstitial cells, capillaries, and
neuromuscular junctions. Each of these cell types influences the surrounding environment and thereby affects the state of the satellite cell.
C: the systemic milieu contains the greatest diversity with which the satellite cell is influenced. Exposure of satellite cells to the hosts immune
system, and circulating hormones along with the skeleton and surrounding skeletal muscles present the broadest environment for the satellite
cell. Changes that occur in the systemic milieu affect the satellite cell gradually. Prolonged exposure of signals from the systemic milieu plays an
important role in the ability of satellite cells to participate in multiple rounds of regeneration.

Wnt1, Wnt3a, and Wnt5a induced satellite cell prolifera- satellite cells returned to the sublaminar position. It was
tion, whereas exogenous Wnt4 and Wnt6, whose expres- determined that Wnt7a acts through the Frizzled7 receptor
sion is absent from regenerating muscle, inhibited the pro- to specifically activate the Wnt/PCP pathway and induce
liferation. This is consistent with the inhibitory effect of cell polarity both ex vivo and in vitro. Activation of the
ECGC, a potent Wnt signaling inhibitor, on satellite cell Wnt/PCP pathway by recombinant Wnt7a simulated the
proliferation (391). Importantly, the expression and subcel- symmetrical division of satellite cells and hence expanded
lular location of the active form of -catenin (Act--Cat) the satellite stem cell population on single myofiber ex-
was carefully examined by immunofluorescence staining in plants. Knockdown of Wnt/PCP downstream component,
this study. Nuclear Act--Cat was observed only after Vangl2, by RNAi caused the opposite effects, confirming
MyoD expression and was absent in Myogenin cells, the involvement of Wnt/PCP pathway in this process. In
which suggests Wnt signaling is inactive either before satel- vivo, Wnt7a injection into regenerating muscles remark-
lite cell activation or after differentiation determination. ably improved muscle regeneration as evidenced by in-
This temporal progression of Wnt signaling was further creased muscle mass and myofiber size. We postulated that
confirmed in mouse regenerating muscles and human dys- the activation of Wnt/PCP pathway promotes the planar
trophic muscle biopsies. Thus Otto et al. (391) concluded alignment of two daughter cells along the myofiber during
that activating Wnt ligands function to promote satellite satellite cell division. This alignment and the induced cell

cell proliferation during muscle regeneration, whereas in- polarity may facilitate the attachment of both daughter cells
hibitory Wnt ligands antagonize the proliferation by seclud- to the basal lamina and hence maintain their stem cell fate
ing -catenin to the cell membrane in quiescent satellite (293). Although it is still unknown, one possible source of
cells. Perplexingly, the pro-proliferation function of Wnt3a endogenous Wnt7a is the regenerative myofiber, given its
signaling revealed by this study seems to oppose the pro- close proximity to satellite cells and perfect alignment to the
differentiation function reported by Brack et al. (65). This basal lamina (65, 413). Intriguingly, a recent study revealed
might be due to different sources of Wnt ligands, either synergistic functions of Wnt/-catenin and Wnt/PCP path-
from cultured Wnt-expressing cells or from recombinant ways in oriented elongation of myocytes during embryonic
protein, which in turn affect Wnt concentration and effec- muscle patterning (205). Thus it is enticing to further spec-
tive time. ulate that the activated Wnt/-catenin pathway in regener-
ating myofibers may induce Wnt7a secretion and activation
In addition to -catenin-dependent gene activation, recent of the Wnt/PCP pathway in adjacent satellite stem cells,
studies indicate that the binding of Wnt ligands with Frizzled/ which in turn would direct their symmetric division and
LRP receptors can also lead to a transduction cascade to replenish the satellite cell pool.
establish PCP, which is referred to as the Wnt/PCP pathway
(reviewed in Ref. 492). In this signaling pathway, signaling Wnt signaling is also implicated in satellite cell-related
from Wnt ligand/receptor binding activates Rho/Rac small transdifferentiation. Our group reported that muscle resid-
GTPase and Jun NH2-terminal kinase (JNK) via Dishev- ing CD45/Sca1 cells increased in number and underwent
elled. Dishevelled activates Rac, which further activates myogenic differentiation in injured muscles but not in intact
JNK to assist in the subsequent regulation of cytoskeleton muscles (413). CD45/Sca1 cells express Frizzled recep-
organization and gene expression. The Wnt/PCP signaling tors and upregulated -catenin during regeneration, sug-
pathway plays an important role in the development of gesting the Wnt/-catenin pathway is required for the myo-
anterior-posterior extension of the neural tube and the es- genic commitment of these cells. Indeed, the myogenic com-
tablishment of the aligned cellular structure in epithelium. mitment of CD45/Sca1 cells can be induced by lithium
treatment, or coculture with myoblasts or Wnt secreting
Emerging evidence reveals that satellite cells are under the cells. Daily injections of Wnt signaling inhibitors, sFRPs,
regulation of Wnt/PCP signaling pathway. Our group dem- severely reduced the myogenic recruitment of CD45/
onstrated that quiescent satellite cells can be separated into Sca1 cells during regeneration. These data further suggest
two functional subpopulations based on their Myf5 expres- that Wnt signaling is required for muscle regeneration and
sion: Pax7/Myf5 satellite stem cells and Pax7/Myf5 may increase the myogenic potential of CD45/Sca1 cells
satellite progenitor cells (280). Of interest, we determined (413). Similarly, it was reported that -catenin is required
that mRNAs of the Frizzled7 receptor are preferentially and sufficient for myogenic commitment of P19 embryonic
present in Pax7/Myf5 quiescent satellite stem cells (293). carcinoma cells (408). Of note, a recent study showed that
However, upon injury, Frizzled7 is ubiquitously expressed Wnt signaling is important for transdifferentiation of satel-
in all satellite cells and their proliferating progeny. In a lite cells into fibrogenic cells (66). Activated satellite cells
frozen injury model, Wnt1, Wnt2, Wnt5b, Wnt8b, from old mice have higher Wnt signaling activity and a
Wnt10a, Wnt16a, Frizzled receptors, and sFRP inhibitors greater tendency to assume fibrogenic fate in vitro, com-
were increased in muscles 3 days postinjury (acute phase of pared with those from young mice. Exposure of activated
regeneration). In contrast, an increase of Wnt7a and satellite cells from old mice to young serum or pairing with
Wnt10a was detected in muscles 6 days postinjury, when young mice in a heterochronic parabiotic system reversed

the Wnt signaling activity and associated fibrogenic ten- regeneration (108). Reversely, constitutive Notch activa-
dency, suggesting they are not intrinsic. Conversely, acti- tion in satellite cells from Pax7-CreER;ROSANotch resulted
vated satellite cells from young mice exposed to aged serum in increased Pax7 satellite cells and impaired muscle re-
or linked parabiotically activated Wnt signaling and be- generation (560). In aged muscles, the expression of Notch
came fibrogenic. These observations indicated that the fi- in satellite cells remains unchanged (107). However, the
brogenic transdifferentiation of satellite cells is influenced induction of Delta in myofibers is no longer responsive to
by an unknown circulating factor (66). As the effect of this muscle injury, which results in reduced satellite cell prolif-
factor can be neutralized by a recombinant secreted form of eration and impaired muscle regeneration (107).
Frizzled, it was believed that an increase in Wnt ligands in
old mice may account for the fibrogenic transformation At the onset of myogenic differentiation, however, the in-
observed (66). Notably, an alternative possibility is that activation of Notch signaling in myoblasts is required for
certain Wnt inhibitors are decreased in old mice. This pos- their fusion (108). Two mechanisms exist to downregulate
sibility is supported by a recent finding that a Wnt binding Notch signaling. The first involves Numb, a Notch signal-
protein, Klotho, is a circulating hormone and can affect ing inhibitor, which is asymmetrically partitioned during
tissue aging (281, 313). Wnt signaling also controls the satellite cell/myoblast division (108, 489). The daughter cell
balance between myogenic and adipogenic potentials of inherits Numb and activates the expression of Desmin lead-

myoblasts in vitro. First, downregulation of Wnt/-catenin ing to differentiation (108). Numb inhibits Notch signaling
signaling mediated by Wnt10b was implicated in the in- by inducing ubiquitination of the NICD, which abolishes its
crease of adipogenic differentiation of aged myoblasts activity (21). Second, the activation of Wnt signaling in
(527). Similarly, it was observed that in Wnt10b/ mice, differentiating myoblasts antagonizes Notch signaling and
the adipogenic potential of myoblasts increased and exces- facilitates terminal differentiation (65). This is supported by
sive lipid accumulated in regenerating myofibers (549). A observations that activation of Notch signaling is associ-
recent mechanistic study indicated that Wnt10b activated ated with phosphorylation of tyrosine 216 of GSK-3b,
the Wnt/-catenin pathway and that SREBP-1c-mediated whereas Notch inhibitor treatment or activation of Wnt
lipogenesis and insulin resistance reciprocally counteract signaling in myoblasts coincided with dephosphorylation of
each other and thus determine the myogenic and adipogenic this residue (65). Although the precise mechanism remains
fate of myoblasts (2). The above-mentioned experiments ambiguous, the crosslink between Wnt signaling and Notch
serve to demonstrate the complexities involved in Wnt reg- signaling at Dishevelled and Presenilin has been reported
ulation of myogenesis. Future studies focused on in vivo (131). In addition, -catenin has been reported to associate
regulation of a myogenic to adipogenic switch will elabo- with MyoD and facilitate the transcription activity of
rate on the physiological relevance of the above experimen- MyoD (271). Thus it would be interesting to investigate
tal evidence. whether MyoD/-catenin can drive the expression of Notch
signaling inhibitors, such as Numb, Itch, or the newly re-
B) NOTCH SIGNALING. Notch signaling regulates cell prolifer- ported bHLH transcription factor Stra13 (511).
ation, differentiation, and cell fate determination (21). The
activation of Notch signaling pathway is initiated by the As both Notch receptors and their ligands are transmem-
binding of Delta and Jagged family of ligands to Notch brane proteins, Notch signaling is an important signaling
transmembrane receptors, the result of which induces se- pathway mediating cell-cell communications. Our group
quential enzymatic cleavage of the Notch receptor and re- recently demonstrated that Megf10, a multiple EGF repeat-
lease of an active truncated form of Notch, termed the containing membrane protein, may function similar to
Notch intracellular domain (NICD). Upon enzymatic cleav- Delta and Jagged in Notch signaling activation (235).
age, the NICD translocates from the cytoplasm to the nu- Notch-mediated cell-cell communications, presumably
cleus and activates the CSL (CBF1, Suppressor of Hairless conveyed between bumping satellite cells or between sat-
and Lag-1) family of transcription factors, leading to target ellite cells and the myofiber, may serve as a controlling
gene expression. mechanism for satellite cell quiescence and the number of
satellite cells on a single myofiber under physiological con-
Notch signaling plays key roles in skeletal muscle regener- ditions. In line with this view, double knockout mice of
ation (reviewed in Ref. 320). Upon muscle injury, the Notch Hey1 and HeyL, two downstream target genes of Notch
ligand Delta is quickly upregulated in both activated satel- signaling, showed remarkably reduced number of satellite
lite cells and in myofibers (108). The upregulation of Delta cells, which is likely due to failure of satellite cells in keeping
in satellite cells is accompanied by the appearance of the quiescence in adult muscle (176).
NICD, indicative of activated Notch signaling. Activation
of Notch signaling stimulates the proliferation of satellite Three Notch receptors are abundantly expressed on satel-
cells and their progeny and thus leads to the expansion of lite cells: Notch1, Notch2, and Notch3. A recent study sug-
proliferating myoblasts. Indeed, inhibition of Notch signal- gests that Notch3 may act as a Notch1 repressor by activat-
ing abolishes satellite cell activation and impairs muscle ing Nrarp, a negative-feedback regulator of Notch signaling

(272). In line with this view, Notch3-deficient mice showed ical inhibition of sphingomyelin-to-S1P processing reduced
markedly increased numbers of sublaminar quiescent satel- the number of activated satellite cells and perturbed muscle
lite cells and muscle hyperplasia after repetitive muscle in- regeneration. This action of S1P on satellite cell activation
juries, which are phenotypically opposite to those from and muscle regeneration is in line with the proliferative,
Notch1 mutants. proinflammatory (through COX-2) and antiapoptotic
(through inhibition of caspase-3 and BAX) functions of
In addition to its functions during muscle regeneration, S1P-mediated pathways in general. Accumulating evidence
Notch signaling is also involved in the maintenance of cell indicates that S1P, being one of the more soluble sphingo-
quiescence in resting health muscle. It was found that ge- lipids, acts through S1P receptors (S1PRs; a group of high-
netic abrogation of Rbpj, the main effector for canonical affinity G protein-coupled receptors) on satellite cells in an
Notch signaling, specifically in satellite cells results in the autocrine/paracrine fashion (76, 122). In addition, abnor-
loss of their quiescent state (356). In Pax7-CT2;Rbpjflox/ mal modulation of S1P activity is also involved in the pa-
mice, Tamoxifen induction and Rbpj depletion in satellite thology of muscular dystrophy (as exemplified in mdx mice)
cells gradually decreased the number of Pax7 satellite (317).
cells, which is accompanied with spontaneous myogenic
differentiation and failure of muscle regeneration upon in- Our current understanding of the functions of bioactive

jury. Interestingly, the spontaneous myogenic differentia- sphingolipids on satellite cells is far from complete. For
tion of the majority of mutant satellite cells in this model example, the role of ceramide, another central player of the
seems to start with G0 (quiescent) satellite cells without sphingolipid signaling pathway, on satellite cell activation/
entry into S phase in vivo. proliferation/differentiation during muscle regeneration is
vastly unknown. Moreover, whether S1P may bind to other
The above findings support the notion that Notch signaling intracellular proteins and exert S1PR-independent actions
is critical for satellite cell activation and proliferation. As remains to be investigated.
Notch signaling can be activated by cell-to-cell contact, it is
2. The myofiber niche
very intriguing to envision that communal satellite cells ex-
isting on the same myofiber can signal each other. This
The myofibers are the primary component of the satellite
community niche effect may serve to determine the number
cell niche due to their direct contact with satellite cells. The
of quiescent satellite cells on a myofiber and/or control the
overarching effect provided by the myofiber for satellite
size of the satellite cell pool during regeneration. In this
cells was revealed through selective killing of myofibers
respect, recent studies have revealed a close relationship
with Marcaine while leaving the basal lamina intact. This
between Notch signaling and Hippo (Salvador/Warts/ resulted in greater numbers of proliferating satellite cells
Hippo) signaling pathways in determining cell proliferation compared with viable myofibers (50). This suggested that
and organ size in Drosophila (77, 339, 412). It would be the myofiber emanates a quiescent signal either by its
interesting to investigate the interactions of these two path- physical association or by releasing chemical compounds
ways in satellite cell activation and proliferation. (50, 53). In accordance with this hypothesis, recent studies
have revealed numerous satellite cell regulatory factors that
C) SPHINGOLIPID SIGNALING. Sphingolipids are a large group
are presented on myofibers or secreted by myofibers. First,
of naturally occurring glycolipids, characterized by their myofibers secrete SDF-1, which serves as ligand to the cell
sphingoid backbone. Although originally recognized as surface receptor CXCR4 on satellite cells (429, 486). SDF-
inert precursors and intermediate products in lipid 1/CXCR4 signaling has been shown to stimulate satellite
metabolism, sphingolipids, particularly ceramide, cer- cell migration (429). In addition, it has been found that the
amide-1-phosphate, sphingosine, and sphingosine-1- transmembrane Notch ligand Delta is upregulated on myo-
phosphate (S1P), have been recently revealed as important fibers after injury, which can activate the Notch signaling
bioactive signaling molecules in regulating cell prolifera- cascade in satellite cells and hence induce their proliferation
tion, migration, death, and senescence (reviewed in Ref. (107). Such an activation signal from myofibers is probably
223). Sphingomyelin is the most abundant component in amplified by the expression of both Notch receptors and
the sphingolipid pathway and also serves as a precursor of Delta ligands on satellite cells, functioning in autocrine and
ceramide, sphingosine, and S1P. It was found that sphingo- juxtacrine fashion (108, 280).
myelin is enriched in plasma membrane of quiescent satel-
lite cells, yet it markedly diminishes after satellite cell acti- In aged muscle, both the caliber and the number of myofi-
vation and reappears in some Pax7/MyoD satellite cells bers decline (202), although the direct effect of these mor-
returning to the quiescent state (369). The dynamics of phological changes is not known. Interestingly, the presence
sphingomyelin are connected with the biosynthesis of mito- of Delta ligands is not sufficiently expressed on aged myo-
genic S1P, which promotes satellite cells to enter the cell fibers, an indication of diminished Notch signaling possibly
cycle on ex vivo cultured myofibers and improves muscle compromising satellite cell activation and muscle regenera-
regeneration (370, 461). On the other hand, pharmacolog- tion (107).

3. ECM and associated factors and in vivo data have revealed that release of nitric oxide
synthase (NOS) from the basal lamina after myofiber
The basal lamina of the myofiber is composed of a network stretch or damage leads to the production of nitric oxide
of ECM that directly contacts the satellite cell and separates (NO), which in turn activates MMPs and release HGF from
it from the muscle interstitium. The basal lamina of skeletal local HSPGs (522, 523, 576). Alternatively, the observed
muscle is composed of type IV collagen, laminin, entactin, rapid upregulation of HGF following muscle injury is due
fibronectin, perlecan, and decorin glycoproteins along with to release of HGF from intact organs, such as the spleen
other proteoglycans (459). These ECM molecules are (513).
mainly synthesized and excreted by interstitial fibroblasts
but can also be produced and remodeled by myoblasts dur- Released HGF and newly synthesized HGF act directly on
ing muscle development and regeneration (278). Satellite satellite cells and myoblasts through the cell surface recep-
cells reside between the basal lamina, composed primarily tor c-Met found on both quiescent and activated satellite
of a type IV collagen network, and the apical sarcolemma cells (13, 116, 179, 521). Multiple studies have demon-
covered in laminin (568). The basal lamina presents a large strated that the activation of HGF/c-Met pathway stimu-
number of binding sites for 7/1-integrins; sites that an- lates quiescent satellite cells to enter the cell cycle, increases
chor the actin cytoskeleton of satellite cells to the ECM myoblasts proliferation, and inhibits myogenic differentia-

(501; reviewed in Ref. 330). This physical tethering is crit- tion (13, 179, 342, 521). Fittingly, HGF isolated from
ical for satellite cell activation as it allows the transduction crushed muscle extracts induces quiescent satellite cell acti-
of extracellular mechanical force into intracellular chemical vation, and an anti-HGF antibody abolished this activity
signals (62; reviewed in Ref. 73). In addition, muscle spe- (521). Furthermore, direct injection of HGF into injured
cific laminin-2 (2/1/1 subunits) and laminin-4 (2/2/
muscle blocked the regeneration process but increased myo-
1) are also associated with myofibers though 7/1-integ-
blast numbers (342, 521). Forced expression of a constitu-
rins and dystroglycan on the surface of myofibers (208;
tive active form of c-Met in C2C12 myoblasts resulted in
reviewed in Ref. 459). Proteoglycans reside on the surface
the inhibition of differentiation (15). HGF inhibits myo-
of satellite cells and function as receptors to bind a suite of
blast differentiation by coordinately repressing transcrip-
secreted, yet inactive growth factor precursors. These pre-
tional activity of MRF/E-protein complexes, increasing
cursors, including HGF (521), basic fibroblast growth fac-
MyoD inhibitor Twist expression, as well as decreasing
tor (bFGF) (141), epidermal growth factor (EGF) (193),
p27kip1 expression (179, 306). The dual function of HGF in
insulin-like growth factor isoforms (IGF-I, IGF-II) (323)
promoting proliferation and inhibiting differentiation in-
and various Wnt glycoproteins (65, 293), originate from
volves sustained activation of MAPK/Erk signaling through
either satellite cells, myofibers, interstitial cells, or serum. In
resting muscle, the sequestering of inactive growth factors binding of Grb2 to phosphorylated c-Met (214, 304, 305).
exists as a local reservoir, to facilitate a rapid response to Moreover, HGF promotes satellite cell migration to the site
muscle injury. These growth factors can be swiftly rendered of injury as demonstrated by the in vitro chemotactic activ-
active by proteolytic enzymes present in serum or intersti- ity of this factor on satellite cells and C2C12 myoblasts (49,
tium, such as thrombin, serine proteases, and matrix met- 512, 551). The function of HGF in muscle regeneration is
alloproteinases (MMPs). This highly coordinated process important during the early phase of repair because over
serves to stimulate satellite cell survival, activation, and time levels of HGF decline and exogenous HGF does not
proliferation upon muscle injury (249, 288, 386, 521, 576). affect muscle regeneration when administrated at later
stages (342, 521). Therefore, these results demonstrate that
A) HGF/SCATTER FACTOR. HGF is a heterodimer of its and HGF is a satellite cell activator, playing a critical role in the
subunits, both of which are processed from a single-chain early stage of muscle regeneration. The activation of satel-
inactive precursor (pro-HGF). HGF is critical for cell lite cells by HGF is due to both transcription activation of
growth, migration, and organ morphogenesis through its HGF in satellite cells and release of HGF from the ECM by
mitogen, motogen, and morphogen activities (reviewed in MMPs, which coordinately function in an autocrine and
Refs. 381, 586). In skeletal muscle, HGF functions in the paracrine fashion to induce the proliferation of satellite
early phase of muscle regeneration and is one of the key cells.
activators of satellite cells (342, 521). In intact muscle, low
levels of HGF mRNA can be detected in satellite cells but B) FIBROBLAST GROWTH FACTORS. Fibroblast growth factors
not in fibroblasts, suggesting an autocrine function of HGF (FGFs) are a large family of mitogens, involved in cell
(13, 484, 521). However, the majority of active and inactive growth, survival, migration, and embryonic development.
forms of HGF are sequestered by heparan sulfate proteogly- Numerous FGFs have been found in skeletal muscle in vivo
cans (HSPGs) within the basal lamina (13, 484, 520, 521). and upon culture and differentiation of myoblasts in vitro
Upon injury, the transcription of HGF is increased in pro- (12, 199, 222, 266). Inhibition of endogenous FGF-1 by
portion to the degree of injury, and an active form of HGF siRNAs led to myogenic differentiation of myoblasts in
is released from the ECM without the need of proteolytic vitro, while exogenous FGF-1, -2, -4, and -6 robustly stim-
cleavage of pro-HGF (484, 520, 521, 525, 569). In vitro ulate the proliferation of rat primary myoblasts in vitro

(266, 483). Of the particular FGF family members, FGF-6 is the downregulation of syndecan-4 mRNA was observed in
of particular interest given its muscle specific expression turkey satellite cells in response to exogenous FGF-2 (548).
and upregulation during muscle regeneration (134, 172). A
study in FGF-6/ mutant mice revealed severe muscle re- C) IGF. IGF-I and IGF-II play important roles in the regula-
generation defects characterized by a reduction in MyoD tion of satellite cell activity (reviewed in Ref. 409). IGF-I has
and Myogenin-expressing cells along with increased colla- pleiotropic functions including anti-inflammation, cell mi-
gen deposition and fibrosis (172). FGF-2 is also likely in- gration, and stimulation of both proliferation and differen-
volved in myoblast proliferation during muscle regenera- tiation in satellite cells. In contrast, IGF-II is believed to only
tion as endogenous FGF-2 was found in the basal lamina promote myogenic differentiation (11, 103, 151, 169, 170,
(113). Moreover, injecting a neutralizing antibody of 547). Elevation of IGF-I signaling within muscle cells in
FGF-2 at the time of injury (297) or injecting exogenous vitro results in muscle hypertrophy with increased DNA
FGF-2 into mdx mice (296) caused a delay in myoblast and protein content in muscle (6, 34, 87, 103, 365). The
proliferation and increased myoblast proliferation, respec- hypertrophic effects of IGF-I are attributed to both the ac-
tively. In addition, FGFs also facilitate muscle regeneration tivation of satellite cell proliferation, which gives rise to
through their well-known function in angiogenesis (295). more myonuclei, and protein synthesis, which increases the
cytoplasmic-to-DNA volume ratio (32, 35, 366). IGF-II ex-

FGF signaling is mediated by virtue of four transmembrane pression and secretion are elevated prior to myoblast differ-
tyrosine kinase receptors known as FGFR1 4, which differ entiation (171), and knock-down of either IGF-I or IGF-II
in their specificity of ligand binding. Of these, FGFR1 and in vitro results in impaired myogenic differentiated (158,
FGFR4 are the most prominent receptors in rat satellite cells 171). Consistently, IGF2/ mutant mice are 40% lighter
in vitro (172). In vitro, FGF-1 can induce the expression of compared with the weight of wild-type mice at birth, and
FGFR1, and this induction effect can be further augmented this defect persists postnatally (133).
by HGF (483). Stable overexpression of FGFR1 increases
myoblast proliferation and delays their differentiation, IGF can function in endocrine, autocrine, and paracrine
whereas overexpression of a dominant negative form of fashions to promote satellite cell proliferation and differen-
FGFR1 leads to the opposite effects (463). In skeletal mus- tiation, but all of these are mediated by IGF-I binding to the
cle, dimerization of FGFs with FGFRs leads to tyrosine IGF-I receptor (IGF1R), which is a ligand-activated recep-
phosphorylation of FGFR and activates the downstream tor tyrosine kinase. In contrast to IGF-I-induced muscle
Ras/MAPK pathway. This is supported by the finding that hypertrophy, IGF1R/ mutant mice display a dystrophic
constitutively expressed active RAS in myoblasts induces phenotype and usually die at birth due to weak respiratory
proliferation and blocks differentiation even in the absence muscles (315). Activation of IGF1R in satellite cells induces
of exogenous FGFs (162). In addition, inhibition of mito- the expression of MRFs (170) and initiates intracellular
gen-activated protein kinase kinase (MAPKK) activity com- signaling cascades involving both mitogenic and myogenic
pletely abolishes the FGF2-dependent inhibition of myo- responses (110, 367). Two primary signaling pathways are
genic differentiation in vitro (561). Therefore, activation of activated by IGF1R. In the first pathway, activated IGF1R
the Ras/MAPK signaling pathway seems to play a central recruits and phosphorylates insulin receptor substrate pro-
role in FGF/FGFR-mediated pro-proliferation and anti-dif- teins (IRSs), leading to the activation of phosphatidylinosi-
ferentiation effects in skeletal muscle cells. tol 3-kinase (PI3K). Activation of PI3K is involved in mul-
tiple cellular processes including an anti-apoptotic effect
In addition to the canonical FGF receptors, HSPGs also mediated by activation of the AKT pathway (502), modu-
serve as low-affinity FGF receptors (reviewed in Ref. 427). lation of intracellular calcium levels by the inositol phos-
Although HSPGs are ubiquitously present on most mam- phate cascade (156), and promoting protein translation (5).
malian cells, both quiescent and activated satellite cells spe- Although evidence supports that IGF-I-dependent satellite
cifically express syndecan-3 and syndecan-4 (113). Further cell proliferation is mediated by the AKT/mTOR pathway
investigations revealed that syndecan-3/ and syndecan- (220), the activation of PI3K/AKT and p38-MAPK path-
4/ mutant mice display distinct panels of phenotypes, ways are also involved in myoblast differentiation (197,
implicating separate roles of these two HSPGs in satellite 539). In the second pathway, IGF1R activates the Ras/Raf/
cell function (115). It is believed that HSPGs interact with extracellular response kinases (ERKs) cascade, which in
both FGFs and FGF receptors to promote ligand recogni- turn activates other protein kinases and several transcrip-
tion (236). In accordance with this, satellite cell activation tion factors (110, 347). The activation of the Ras/Raf/ERK
and proliferation is impaired and MAPK signaling is com- pathway is also required for satellite cell proliferation
pletely abolished in myoblasts derived from syndecan-4/ (110). In addition to the aforementioned pathways, accu-
mutant mice (115). In contrast, hyperplasia of satellite cells mulating evidence indicates that the calcium/calcineurin
and myonuclei and overactivation of MAPK signaling were pathway is also involved in IGF-I signaling-dependent mus-
observed in syndecan-3-mutant mice, which suggests that cle differentiation and hypertrophy (137, 173, 366, 479).
an inhibitory mechanism is missing (115). In light of this, Specifically, it has been revealed that GATA-2-mediated

myofiber hypertrophy depends on IGF-I stimulation of the E) ECM STIFFNESS. Recent studies reveal a previously unappre-
calcineurin-mediated signaling pathway (366). Further evi- ciated role for the stiffness of the ECM in regulating satellite
dence of the pleiotropic functions of IGF-I involves a role cell proliferation and differentiation. Resting healthy
in anti-inflammatation demonstrated by a reduction in skeletal muscles and cultured myotubes possess a similar
chronic inflammation upon IGF-I treatment during muscle elastic stiffness (elastic modulus 12 kPa) (106, 152),
regeneration (357). whereas aged (184, 444) and dystrophic (152) skeletal
muscles are apparently stiffer (elastic modulus 418
Activated satellite cells and cultured myoblasts express in- kPa). These changes of stiffness are presumably due to
sulin-like growth factor binding proteins (IGFBPs), which increased extracellular matrix deposition, in particular
are a family of secreted proteins that specifically bind IGFs collagen deposition by fibroblasts, a result of repeated mus-
and function as carriers during circulation and regulate cle regeneration. The significance of changes in stiffness was
IGF turnover, transport, and half-life (reviewed in Ref. evaluated by assessing the proliferation and differentiation
ability of myoblasts on various in vitro culturing surfaces.
253). Of the five IGFBPs, IGFBP-5 plays a critical role in
Primary myoblast proliferation on polyacrylamide gels
muscle growth and differentiation. IGFBP-5 expression
cross-linked with entactin, type IV collagen, and laminin is
is induced during differentiation and precedes that of
optimal at an elastic modulus equal to 21 kPa, while it is

IGF-II in cultured myoblasts (246, 436). It was found
impaired on softer (3 kPa) or stiffer (80 kPa) culturing sub-
that IGFBP-5 functions to promote myogenic differenti-
strates (61). Similarly, C2C12 myoblasts optimally differ-
ation by switching on an IGF-II-mediated positive-feed- entiate on collagen-coated polyacrylamide gels that mimic
back loop (436). Knockdown of IGFBP-5 impairs myo- the physiological elasticity of skeletal muscle (12 kPa),
genesis and suppresses IGF-II expression (436). whereas either softer (5 kPa) or stiffer (420 kPa) gels greatly
compromise their differentiation efficiency (152). Although
Notably, recent studies demonstrated that alternative splic- the stiffness of the ECM surrounding the satellite cell niche
ing of IGF-I pre-mRNA gives rise to a unique peptide, has not been directly measured yet, these in vitro data draw
termed mechano-growth factor (MGF) (194). MGF pro- attention to a causal relationship between biophysical stim-
motes myoblast proliferation in vitro (26, 578). However, uli and satellite cell function in vivo.
the existence of MGF and its functions in vivo remain con-
troversial (discussed in Ref. 327).
B. The Microenvironment Beyond the
D) MMPS. Matrix metalloproteinases (MMPs) are a family of Immediate Niche
zinc-dependent enzymes that can degrade components of
the extracellular matrix such as collagens, elastin, fibronec- 1. Local milieu
tin, laminin, and proteoglycans. In skeletal muscle, MMPs
play an important role in satellite cell activation, migration, In addition to the immediate niche surrounding satellite
and differentiation during muscle regeneration (reviewed in cells, local interstitial cells, motor neurons, blood vessels,
Ref. 86). Of more than 20 MMPs, MMP-2, -3, -7, and -9 and their associated secretable factors reside within skeletal
were found in skeletal muscle. In particular, MMP-2 and muscle and have the potential to regulate satellite cell func-
MMP-9, which can degrade denatured collagen types (gel- tion and affect muscle regeneration.
atins) and heparan sulfate proteoglycans, have critical func-
A) INTERSTITIAL CELLS. Interstitial cells are the major compo-
tions on ECM remodeling in skeletal muscle regeneration.
nent of the stromal tissue between the basal lamina and
Upon injury, MMP-2 is secreted by satellite cells and re-
epimysial sheath surrounding skeletal muscle. Fibroblasts
generating myofibers, and its activity is elevated in both
comprise a major component of the interstitial stromal cell
degenerative and regenerating stages (167, 178, 270). In
population (51). Fibroblasts secrete growth factors, such as
contrast, MMP-9 is generated by leukocytes and macro-
FGFs, and also contribute to the skeletal muscle ECM by
phages, and its activity drastically decreases after the depositing collagen, laminin, fibronectin, HSPGs, tenascin,
degenerative stage (270). In the degeneration stage, acti- and NCAM (185). Increased levels of fat and connective
vated MMP-2 and MMP-9 degrade collagen IV in the tissue (fibrosis), evidence for increased numbers of adi-
muscle ECM, which allows satellite cells to migrate pocytes and fibroblasts, respectively, are well documented
across the basement membrane to the site of injury (377). for several physiological and pathological conditions, such
In the regeneration stage, it is believed that MMP-2 is as aging, obesity, and muscular dystrophy (38, 66, 195,
involved in remodeling and maintenance of the ECM. 198, 200). It is believed that satellite cells may account for
Recent studies indicate that NO upregulates enzymatic the increase in adipocytes and fibroblasts due to transdiffer-
activity and protein expression levels of MMP-2 (270) entiation along alternative mesenchymal lineages. This no-
and MMP-9, and this activation of MMP-2 is required tion is supported by the observations that myoblasts can
for the release of HGF from the ECM upon satellite cell undergo adipogenic differentiation in vitro (239, 310, 485,
activation (575, 576). 579) and satellite cells on single myofibers can give rise to

both adipocytes and fibroblasts in vitro (23, 66). Recently, coexistence of both myogenic precursors (myoblasts) and
two studies revealed that these intramuscular adipocytes adipogenic/fibrogenic precursors (FAPs) during muscle re-
and fibrocytes can arise from muscle residing fibrocyte/adi- generation. Regeneration is supported by both satellite cells
pocyte progenitors (FAPs) (252, 541). and FAPs, whereas in degenerating muscle, this balance is
disrupted and FAPs differentiate into adipocytes (and pre-
In one study, a population of SM/C-2.6/PDGFR- cells sumably also fibroblasts). These findings also raise several
is able to differentiate into adipocytes in culture (541). In interesting questions including: How do satellite cells re-
vivo, these cells localize to the interstitial space between spond to increased adipocytes and fibroblasts in the afore-
myofibers and muscle bundles. After transplantation into mentioned physiological and pathological conditions? Re-
glycerol-injected fatty degenerating muscle, SM/C-2.6/ cent observations regarding the effect of fibrosis on the
PDGFR- cells can differentiate into adipocytes, a result stiffness of the ECM raise the question as to whether in-
that is not observed in normal regenerating muscle (541). In creased depositions from fibroblasts or adipocytes can alter
another study, a Sca-1/ CD34 or 7-integrin/CD45/ myofiber stiffness and therefore affect the physiological
CD31 cell population was isolated and found to sponta- roles attributed to satellite cells (152; discussed in sect.
neously form both adipocytes and ER-TR7 fibroblasts in IIIA). Finally, it would be interesting to investigate the em-
culture (252). Although the origin of these cells was not bryonic origin and postnatal lineage progression of FAPs,

directly investigated, it was further demonstrated that these particularly their lineage relationship to the CD45/Sca-1
Sca-1/7-integrin cells also express PDGFR-, and count mesenchymal stem cells found in multiple tissues (316, 401,
for the vast majority of PDGFR- cells in skeletal muscle 417, 441, 509, 519). Further study is required to under-
(252). This suggests strong similarities exist between the cell stand whether other regulatory factors are also involved in
populations used in both studies. Consequently, Sca-1/7- the determination of FAP differentiation and whether these
integrin cells also only give rise to adipocytes in degener- factors change in response to various physiological and
ating muscle in vivo, in contrast to their limited adipogenic pathological conditions.
potential in intact muscle and in injured regenerating mus-
cle. Moreover, a single Sca-1/7-integrin cell was able to In addition to FAPs, recent studies identified telocytes (TCs,
differentiate into both adipocytes and fibroblasts in vitro, formerly called interstitial Cajal-like cells or ICLCs) as a
indicating that these cells are bipotent and thus termed new type of cells within muscle interstitium, which are in
FAPs (252). close vicinity of satellite cells, myofibers, nerve endings, and
blood vessels (414). Unlike satellite cells and fibroblasts,
Both studies clearly demonstrate that FAPs do not have skeletal muscle TCs express the cell surface marker c-kit.
myogenic potential either in vitro or in vivo, which makes Transmission electron microscopy (TEM) examination of
them distinct from satellite cells and other muscle-residing TCs in muscle and studies on TCs from other tissues suggest
myogenic cells (252, 541). The distinct adipogenic poten- TCs transmit intercellular signaling by shedding/intaking
tials of FAPs in degenerating and regenerating muscles microvesicles (also called exosomes), which are enriched for
suggest that the differentiation of FAPs is regulated by proteins and RNAs (230, 414, 543). Although their exact
their local microenvironment. Indeed, both groups dem- role in muscle regeneration is still unknown, the finding that
onstrated that FAPs proliferated and transiently in- these cells secrete VEGF suggests telocytes are an important
creased in number in regenerating muscle without differ- player in promoting satellite cells self-renewal, facilitating
entiating into adipocytes or fibroblasts (252, 541). More- vasculogenesis, and preventing fibrosis (132; further dis-
over, when adipogenic FAPs isolated from degenerating cussed in sect. IIIB1C).
muscle were transplanted into regenerating muscle, the
regenerative microenvironment was sufficient to inhibit Another cellular component of skeletal muscle interstitium
adipogenic differentiation (541). These observations indi- is the SP, a population of cells characterized by their expres-
cate that regenerating muscle provides a specialized mi- sion of Abcg2 and hence the ability to efflux Hoechst dye. A
croenvironment, which favors myogenic differentiation and recent study indicated that endothelial cells and interstitial
maintains FAPs in their undifferentiated state. Importantly, cells constitute the major fraction of skeletal muscle SP
the undifferentiated FAPs in such a microenvironment may (146). Ablation of Abcg2 impairs skeletal muscle regenera-
facilitate the myogenic differentiation of satellite cells, tion. In addition, a small percentage of these SP cells have
which is supported by the observation that, in co-culture myogenic potential and may contribute to myogenic regen-
conditions, FAPs increase the commitment of myoblasts to eration in injured muscle (discussed in sect. IID).
terminal differentiation (252). IL-6 signaling was impli-
cated in this process as evidenced by induced IL-6 expres- B) MOTOR NEURONS. It is well known that denervation results
sion in FAPs in response to muscle regeneration (252). in progressive skeletal muscle atrophy. During acute dener-
vation of muscle, the percentage of satellite cells increases
In summary, these intriguing results support the hypothesis during the first week, indicating a proliferation phase simi-
that skeletal muscle provides a balanced environment for lar to muscle injury (468). However, long-term denervation

results in a drastic decline in satellite cell numbers (442, behavior and muscle regeneration. Thus it is conceivable
550), which is at least partially due to decreased mitotic that systematic release of neurotrophic factors after dener-
capability and increased apoptosis of satellite cells. Experi- vation may also exert similar regulatory roles on satellite
ments illustrate that an absence of PCNA (proliferating cell cell activation and differentiation. In addition, denervation
nuclear antigen)-positive satellite cell can be found on myo- can also cause secondary effects on satellite cells by directly
fibers denervated for more than 1 wk. This implies that influencing the physiological properties of myofibers (229).
long-term denervation may cause satellite cells to lose their Moreover, it has been recently found that satellite cells may
capability to enter the mitotic cell cycle (282). Second, sat- control myofiber innervation during muscle regeneration
ellite cells from muscle denervated for 6 and 10 wk dis- by secreting semaphorin 3A, a well-known factor involved
played a twofold increase of apoptosis, compared with con- in axon guidance and growth (524). This finding further
trol cells from normal innervated muscle (248). Although emphasizes the notion that proper muscle regeneration re-
the underlying mechanism of a neural influence on satellite lies on the dynamic interaction of satellite cells with their
cell behavior is still elusive, neurotrophins such as nerve niche.
growth factor (NGF) and brain-derived neurotrophic factor
(BDNF) are involved. In aged muscle, examination of neuromuscular junctions by
EM revealed decreases in nerve terminal area, mitochondria

NGF is expressed in developing muscles (563), and its ex- and synaptic vesicles, along with occasional denervated
pression is downregulated after birth (153). The expression postsynaptic regions (159). These changes, in addition to
of NGF reappears in adult muscle under several pathologi- progressive myofiber atrophy, may potentially disturb sig-
cal conditions such as muscular dystrophy (537) and amyo- nals between myofibers and satellite cells.
trophic lateral sclerosis (283), wherein expression of NGF
was found in regenerating myofibers and connective tissue C) VASCULATURE. Skeletal muscle is nourished by the micro-
fibroblasts within the damaged muscles (99, 537), suggest- vascular network. The importance of this niche component
ing that it may be involved in muscle regeneration (340). is reflected by the fact that most satellite cells are closely
Indeed, ectopic expression of NGF neutralizing antibodies associated with capillaries in intact adult muscle (100, 465).
in vivo causes muscle dystrophy (448). Within skeletal mus- It is also well known that angiogenesis and myogenesis
cle, NGF seems to bind to its low-affinity receptor p75NTR proceed at the same time during muscle regeneration (321).
(138), which is expressed in satellite cells (358) and human Vascular endothelial growth factor (VEGF) plays an impor-
primary myoblasts and myotubes (33). The expression of tant role in satellite cell function and muscle regeneration
both NGF and p75NTR is upregulated during primary myo- (416). It has been reported that overexpression of VEGF by
blast differentiation in vitro, and they function to stimulate adenovirus can stimulate satellite cell proliferation and im-
morphological changes involved in myoblast fusion (138). prove myofiber regeneration in vivo (20). A recent study
revealed that in coculture, endothelial cells promote myo-
Similar to NGF, developing muscles express high levels of blasts proliferation by secreting a panel of growth factors,
BDNF, whereas in adult myofibers it is not detectable (201, such as IGF-I, HGF, FGF, platelet-derived growth fac-
358). BDNF is present in most adult satellite cells, and its tor-BB (PDGF-BB), and VEGF (100). In addition, it was
expression is correlated with Pax3 expression (358). In cul- found that periendothelial cells (smooth muscle cells and
tured primary myoblasts, the expression of BDNF is de- endomysial fibroblasts) promote a subset of myoblasts (pre-
creased dramatically during myogenic differentiation; in sumably reserve cells) to return to the quiescent state (100).
concordance, a reduction in endogenous BDNF leads to This procedure mimics the self-renewal of satellite cells dur-
early myogenic differentiation, while addition of exogenous ing muscle regeneration. Indeed, recent studies demon-
BDNF can reverse this phenotype (358). In vivo, BDNF/ strated that the Tie-2 receptor is preferentially expressed by
satellite cells are decreased and hence compromise muscle quiescent satellite cells and angiopoietin-1/Tie-2 signaling
regeneration (102). These observations suggest that the acts through ERK1/2 pathway to promote the reentry to
function of BDNF in adult skeletal muscle is to maintain quiescence and thus self-renewal of a subset of satellite cells
satellite cells in their quiescent state and prevent their myo- (3, 100). Based on these observations, it was proposed that
genic differentiation (358). This is consistent with the ob- during muscle regeneration, while vessels are not stabilized,
servation that neural electrical activity stimulates the acti- endothelial cells and myogenic precursors interact with
vation of satellite cells (reviewed in Ref. 470) and represses each other to promote both myogenesis and angiogenesis.
the expression of BDNF (358). Since the TrkB receptor of Once homeostasis of muscle is achieved, the proximity of
BDNF was not detected in skeletal muscle, BDNF signaling satellite cells and periendothelial cells permits angiopoi-
is proposed to occur via the p75NTR in a similar fashion to etin-1, which is secreted by periendothelial cells, to bind
NGF. Tie-2 receptors on satellite cells to simultaneously stabilize
vessels and promote satellite cell quiescence (4, 100). In
Taken together, these data indicate that neurotrophic fac- addition to endothelial cells, satellite cells and myoblasts,
tors function in an autocrine fashion to regulate satellite cell differentiating myofibers also generate VEGF within skele-

tal muscle (70, 92, 189). VEGF can function in an autocrine B) IL-6. IL-6 is a ubiquitous pleiotropic cytokine, which can
fashion through VEGF receptors present on various myo- be produced by many cell types, such as hematopoietic cells,
genic cells to stimulate migration, prevent apoptosis, and fibroblasts, and vascular endothelial cells. Although IL-6 is
promote differentiation (92, 189). In addition, VEGF stim- primarily produced following an immune response, con-
ulation can reportedly activate the Akt pathway and pro- vincing evidence demonstrates that IL-6 is also involved in
mote myofiber hypertrophy (70, 514). satellite cell-mediated muscle hypertrophy and regenera-
tion. Chronic systematic elevation of IL-6 leads to muscle
In aged muscle, it was observed that while myofibers lose atrophy in aging and disease states (29, 212; reviewed in
their close contact with the microvascular network, there is Ref. 154). Likewise, transgenic mice overexpressing IL-6
a corresponding VEGF level decrease (451). In addition, display a muscle wasting (cachexia) phenotype (538). It is
endothelial nitric oxide synthase (eNOS) secreted by endo- also well documented that exercise causes an increase in
thelial cells is also decreased in aged muscle (580; reviewed IL-6 levels within muscle (533; reviewed in Ref. 403). Dur-
in Ref. 67). ing regeneration, satellite cells, myofibers, and neutrophils
are the principal sources of IL-6, the expression of which is
Taken together, recent studies have begun to unveil inter- regulated by calcineurin-NFAT, NF-B, AP-1, IL-1, and
NO signaling pathways (74, 333, 583; reviewed in Ref.

actions between satellite cells and cells within the microvas-
culature, experiments that imply a potentially profound 403).
functional role necessitating the close proximity of satellite
cells to the microvasculature. Future studies are needed to The IL-6 receptor (IL-6R) is expressed on the myofiber
further elucidate these interactions, particularly those of sarcolemma and is responsive to exercise (268). Muscle-
periendothelial cells, during muscle regeneration. derived IL-6 can act in an autocrine fashion by binding to
the IL-6R on the sarcolemma and activate the JAK/STAT3
signaling pathway (480; reviewed in Refs. 403, 430). Bind-
2. Systemic milieu
ing of IL-6 to the receptor IL-6R leads to JAK2 phosphor-
ylation and subsequent STAT3 phosphorylation. Phos-
A) IMMUNE CELLS. Only a small number of immune cells reside
phorylated STAT3 dimerizes and translocates to the nu-
within intact skeletal muscle. During the early stages of cleus where it acts as a transcription factor for target gene
muscle injury, immune cells are recruited and play impor- activation.
tant roles in the regeneration process (reviewed in Ref. 532).
Upon injury, immune cells rapidly infiltrate the muscle to It has been shown that IL-6 can also induce satellite cell
remove necrotic tissue and secrete soluble factors that serve proliferation (80). Recently, it was demonstrated that
to activate satellite cells (reviewed in Ref. 530). As such, IL-6 is involved in satellite cell-mediated muscle hyper-
immune cells constitute a transient local environment for trophy (480). Although early studies demonstrated that
satellite cells. Depletion of macrophages and monocytes muscle regeneration in IL-6/ null mice was compara-
impairs subsequent muscle regeneration (206). Satellite ble to that of wild type (556), a recent study reported a
cells and immune cells attract one another through chemo- blunted hypertrophic response and less contribution of
kines (chemoattraction) (440). Satellite cells have been satellite cell myonuclei to regenerating myofibers (480).
demonstrated to secrete a panel of pro-inflammatory cyto- Furthermore, it was shown that the proliferation of sat-
kines, such as IL-1, IL-6, and TNF-, to facilitate immune ellite cells from IL-6/ mice was impaired both in vivo
cell infiltration and function (reviewed in Ref. 92). In turn, and in vitro, which is due to the attenuation of STAT3
immune cells secrete a wealth of diffusible factors, such as signaling (480).
growth factors, IL-6, globular adiponectin, ECM compo-
nents, and ECM remodeling MMPs. These diffusible fac- C) ANDROGENS. The musculature of men and woman differs
tors generate ECM chemoattractive fragments, help satel- in mass, fiber size, and various other physiological prop-
lite cells escape from the basal lamina of myofibers, and erties. These differences are in part due to the anabolic
promote satellite cell proliferation. In addition, cell-to-cell actions of circulating androgens, e.g., testosterone, on
contact between immune cells and satellite cells protects muscle size and muscle strength (reviewed in Refs. 97,
satellite cells from apoptosis (503). 228). Androgens bind to androgen receptors (AR) and
lead to the dimerization and nuclear translocation of AR.
Aged muscle displays a functional deficit in the immune In the nucleus, AR homodimers bind to the DNA motifs
cells surrounding the satellite cell niche. In vitro studies or androgen response elements (AREs) and activate tran-
indicate that the capabilities of free radical generation, scriptional target genes.
phagocytosis, and chemotaxis are decreased in aged im-
mune cells (25). The perturbation between satellite cells and Satellite cells express androgen receptors and are recep-
immune cells impedes satellite cell activation and migra- tive to androgen signaling (143); however, the endoge-
tion. nous androgens acting on satellite cells have yet to be

determined. Exogenous testosterone increases satellite of HGF from the ECM (575, 576). MMP-2 was demon-
cell numbers by promoting satellite cell activation and strated to be involved in this process (575). In addition, it
proliferation (255, 494). This function is predicted to was also suggested that NO may regulate satellite cell mi-
involve the induction of Notch signaling in satellite cells gration (104) and prevent fibrosis by inhibiting transform-
(494). Furthermore, androgen administration causes in- ing growth factor- signaling during muscle regeneration
creased myonuclei and muscle hypertrophy in a dose- (126).
dependent manner (254, 493, 495). Multiple mecha-
nisms have been implicated in androgen-induced muscle
hypertrophy. First, androgen administration has been IV. CONCLUDING REMARKS
shown to elevate local IGF-I levels (165, 307) through a AND PERSPECTIVES
postulated induction of IGF1R expression on satellite
cells (529). Androgen administration can also elevate in- Compelling evidence indicates that adult satellite cells rep-
tracellular calcium and inositol 1,4,5-trisphosphate (IP3) resent a heterogeneous population of stem cells and com-
levels, which induces phosphorylation of ERK1/2 and mitted myogenic progenitors in skeletal muscle. At the pop-
contributes to affect the IGF pathway (157). Addition- ulation level, the stem cell characteristics of satellite cells are
ally, androgen may promote muscle hypertrophy by well represented by their remarkable and sustained ability

counteracting the catabolic effect of glucocorticoid hor- to support skeletal muscle regeneration. At the individual
mones and promote the myogenic differentiation (48, level, satellite cells vary in their self-renewal, proliferation,
496). and myogenic differentiation potential. These intrinsic dif-
ferences of satellite cells likely reflect the distinct needs of
During aging, systemic levels of androgens decline, which is 1) maintaining a sustainable reservoir of stem cells, 2) pro-
concomitant with a loss in muscle mass and a gain in fat ducing sufficient numbers of myogenic cells, and 3) gener-
mass (228, 544). ating, during the course of muscle regeneration, functional
contractile muscular structures. Throughout regeneration,
D) NITRIC OXIDE. NO is a diffusible small molecule, which can the hierarchical and collaborative behaviors of satellite cells
freely pass through cell membranes. It can be produced by are influenced by changes in their niche. These changes
nitric oxide synthase (NOS) in diverse cell types, including include diverse molecules, cells, and structures that consti-
epithelial cells, endothelial cells, fibroblasts, hepatocytes, tute a dynamic niche continually influencing the multiple
macrophages, and skeletal muscle cells (60). Currently tasks set forth for satellite cells.
three NOS isoforms exist: endothelial NOS (eNOS), neuro-
nal NOS (nNOS), and inducible NOS (iNOS) (394). Satellite cells are an ideal cellular model system to study
adult stem cells and tissue regeneration. Extensive studies
NO has profound functions in intact muscle as well as dur- over the last three decades have accumulated much knowl-
ing muscle regeneration (reviewed in Ref. 505). In skeletal edge and insights. Satellite cells are currently not applicable
muscle, nNOS is constitutively expressed within the sarco- to regenerative medicine due to difficulties in their isolation
lemma of myofibers (275). Loss of nNOS from the sarco- and loss of stemness ex vivo. However, satellite cell-based
lemma (e.g., as a result of a dystrophin deficiency) leads to cell therapy would greatly benefit from future studies in
inflammation and myofiber lysis, implicating a protective lineage progression to better delineate satellite cell hierar-
function for NO in skeletal muscle (89). iNOS levels are chy along with physiologically relevant interactions be-
extremely low in intact muscle, yet drastically induced by tween satellite cells and other myogenic cells. Moreover,
macrophages and myofibers in response to muscle injury such issues may be resolved following the maturation of
(449; reviewed in Ref. 262). In the degenerating phase, NO, techniques involving the generation of iPS or other types of
generated by macrophages and myofibers, promotes the ES-like multipotent cells. If so, the broad interest of future
lysis of necrotic myofibers by macrophages while reducing studies should focus on identification of the intrinsic and
other inflammation-induced damage (375; reviewed in Ref. extrinsic regulatory mechanisms that govern satellite cell
505). During regeneration, NO induces satellite cell activa- commitment and differentiation throughout the muscle re-
tion, as evidenced by the inhibitory effect of L-arginine generation. Future advances in system biology and bioengi-
methyl ester (L-NAME), a NOS inhibitor, on satellite cell neering may hopefully harness these previous achievements
activation (16). NOS inhibition prevents the binding of towards developing therapeutic approaches for sarcopenia
HGF to the c-Met receptor on satellite cells, whereas treat- and muscle dystrophic diseases.
ment with L-arginine, the NOS substrate, resulted in an
increase in satellite cell activation. Accordingly, iNOS/ ACKNOWLEDGMENTS
mice display delayed satellite cell activation following mus-
cle injury, although injured muscles were still able to regen- We credit L. Bucklin for the human leg anatomy image used
erate (16). The function of NO-dependent satellite cell ac- in FIGURE 3 and Alexander Grayston for critical review of
tivation stems from the ability of NO to promote the release the manuscript.

Address for reprint requests and other correspondence: 17. Angelini C, Di Mauro S, Margreth A. Relationship of serum enzyme changes to muscle
damage in vitamin E deficiency of the rabbit. Sperimentale 118: 349 369, 1968.
M. A. Rudnicki, Ottawa Hospital Research Institute, 501
Smyth Rd., Ottawa, Ontario, Canada K1H 8L6 (e-mail: 18. Armand O, Boutineau AM, Mauger A, Pautou MP, Kieny M. Origin of satellite cells in
mrudnicki@ohri.ca). avian skeletal muscles. Arch Anat Microsc Morphol Exp 72: 163181, 1983.
19. Armstrong RB. Initial events in exercise-induced muscular injury. Med Sci Sports Ex-
ercise 22: 429 435, 1990.
DISCLOSURES
20. Arsic N, Zacchigna S, Zentilin L, Ramirez-Correa G, Pattarini L, Salvi A, Sinagra G,
Giacca M. Vascular endothelial growth factor stimulates skeletal muscle regeneration
No conflicts of interest, financial or otherwise, are declared in vivo. Mol Ther 10: 844 854, 2004.
by the authors. 21. Artavanis-Tsakonas S, Rand MD, Lake RJ. Notch signaling: cell fate control and signal
integration in development. Science 284: 770 776, 1999.
22. Asakura A, Hirai H, Kablar B, Morita S, Ishibashi J, Piras BA, Christ AJ, Verma M,
REFERENCES Vineretsky KA, Rudnicki MA. Increased survival of muscle stem cells lacking the MyoD
gene after transplantation into regenerating skeletal muscle. Proc Natl Acad Sci USA
1. Abedi M, Greer DA, Colvin GA, Demers DA, Dooner MS, Harpel JA, Weier HU, 104: 1655216557, 2007.
Lambert JF, Quesenberry PJ. Robust conversion of marrow cells to skeletal muscle
with formation of marrow-derived muscle cell colonies: a multifactorial process. Exp 23. Asakura A, Komaki M, Rudnicki M. Muscle satellite cells are multipotential stem cells

Hematol 32: 426 434, 2004. that exhibit myogenic, osteogenic, adipogenic differentiation. Differentiation 68: 245
253, 2001.
2. Abiola M, Favier M, Christodoulou-Vafeiadou E, Pichard AL, Martelly I, Guillet-Deniau
I. Activation of Wnt/beta-catenin signaling increases insulin sensitivity through a recip- 24. Asakura A, Seale P, Girgis-Gabardo A, Rudnicki MA. Myogenic specification of side
rocal regulation of Wnt10b and SREBP-1c in skeletal muscle cells. PLoS One 4: e8509, population cells in skeletal muscle. J Cell Biol 159: 123134, 2002.
2009.
25. Ashcroft GS, Mills SJ, Ashworth JJ. Ageing and wound healing. Biogerontology 3: 337
3. Abou-Khalil R, Le Grand F, Pallafacchina G, Valable S, Authier FJ, Rudnicki MA, Gh- 345, 2002.
erardi RK, Germain S, Chretien F, Sotiropoulos A, Lafuste P, Montarras D, Chazaud B.
Autocrine and paracrine angiopoietin 1/Tie-2 signaling promotes muscle satellite cell 26. Ates K, Yang SY, Orrell RW, Sinanan AC, Simons P, Solomon A, Beech S, Goldspink G,
self-renewal. Cell Stem Cell 5: 298 309, 2009. Lewis MP. The IGF-I splice variant MGF increases progenitor cells in ALS, dystrophic,
and normal muscle. FEBS Lett 581: 27272732, 2007.
4. Abou-Khalil R, Mounier R, Chazaud B. Regulation of myogenic stem cell behavior by
vessel cells: the menage a trois of satellite cells, periendothelial cells and endothelial 27. Bachrach E, Li S, Perez AL, Schienda J, Liadaki K, Volinski J, Flint A, Chamberlain J,
cells. Cell Cycle 9: 892 896, 2010. Kunkel LM. Systemic delivery of human microdystrophin to regenerating mouse dys-
trophic muscle by muscle progenitor cells. Proc Natl Acad Sci USA 101: 35813586,
5. Adams GR. Autocrine and/or paracrine insulin-like growth factor-I activity in skeletal 2004.
muscle. Clin Orthop Relat Res S188 196, 2002.
28. Baldwin KM, Haddad F. Effects of different activity and inactivity paradigms on myosin
6. Adams GR, McCue SA. Localized infusion of IGF-I results in skeletal muscle hypertro- heavy chain gene expression in striated muscle. J Appl Physiol 90: 345357, 2001.
phy in rats. J Appl Physiol 84: 1716 1722, 1998.
29. Baltgalvis KA, Berger FG, Pena MM, Davis JM, Muga SJ, Carson JA. Interleukin-6 and
7. Alderton JM, Steinhardt RA. How calcium influx through calcium leak channels is cachexia in ApcMin/ mice. Am J Physiol Regul Integr Comp Physiol 294: R393R401,
responsible for the elevated levels of calcium-dependent proteolysis in dystrophic 2008.
myotubes. Trends Cardiovasc Med 10: 268 272, 2000.
30. Bansal D, Miyake K, Vogel SS, Groh S, Chen CC, Williamson R, McNeil PL, Campbell
8. Alfaro LA, Dick SA, Siegel AL, Anonuevo AS, McNagny KM, Megeney LA, Cornelison KP. Defective membrane repair in dysferlin-deficient muscular dystrophy. Nature
DD, Rossi FM. CD34 promotes satellite cell motility and entry into proliferation to 423: 168 172, 2003.
facilitate efficient skeletal muscle regeneration. Stem Cells 29: 2030 2041, 2011.
31. Barberi T, Bradbury M, Dincer Z, Panagiotakos G, Socci ND, Studer L. Derivation of
9. Allbrook DB, Han MF, Hellmuth AE. Population of muscle satellite cells in relation to engraftable skeletal myoblasts from human embryonic stem cells. Nat Med 13: 642
age and mitotic activity. Pathology 3: 223243, 1971.
648, 2007.
10. Allen RE, Boxhorn LK. Inhibition of skeletal muscle satellite cell differentiation by
32. Bark TH, McNurlan MA, Lang CH, Garlick PJ. Increased protein synthesis after acute
transforming growth factor-beta. J Cell Physiol 133: 567572, 1987.
IGF-I or insulin infusion is localized to muscle in mice. Am J Physiol Endocrinol Metab
11. Allen RE, Boxhorn LK. Regulation of skeletal muscle satellite cell proliferation and 275: E118 E123, 1998.
differentiation by transforming growth factor-beta, insulin-like growth factor I, and
33. Baron P, Scarpini E, Meola G, Santilli I, Conti G, Pleasure D, Scarlato G. Expression of
fibroblast growth factor. J Cell Physiol 138: 311315, 1989.
the low-affinity NGF receptor during human muscle development, regeneration, and
12. Allen RE, Dodson MV, Luiten LS. Regulation of skeletal muscle satellite cell prolifer- in tissue culture. Muscle Nerve 17: 276 284, 1994.
ation by bovine pituitary fibroblast growth factor. Exp Cell Res 152: 154 160, 1984.
34. Barton-Davis ER, Shoturma DI, Musaro A, Rosenthal N, Sweeney HL. Viral mediated
13. Allen RE, Sheehan SM, Taylor RG, Kendall TL, Rice GM. Hepatocyte growth factor expression of insulin-like growth factor I blocks the aging-related loss of skeletal
activates quiescent skeletal muscle satellite cells in vitro. J Cell Physiol 165: 307312, muscle function. Proc Natl Acad Sci USA 95: 1560315607, 1998.
1995.
35. Barton-Davis ER, Shoturma DI, Sweeney HL. Contribution of satellite cells to IGF-I
14. Allouh MZ, Yablonka-Reuveni Z, Rosser BW. Pax7 reveals a greater frequency and induced hypertrophy of skeletal muscle. Acta Physiol Scand 167: 301305, 1999.
concentration of satellite cells at the ends of growing skeletal muscle fibers. J His-
tochem Cytochem 56: 77 87, 2008. 36. Bashir R, Britton S, Strachan T, Keers S, Vafiadaki E, Lako M, Richard I, Marchand S,
Bourg N, Argov Z, Sadeh M, Mahjneh I, Marconi G, Passos-Bueno MR, Moreira Ede S,
15. Anastasi S, Giordano S, Sthandier O, Gambarotta G, Maione R, Comoglio P, Amati P. Zatz M, Beckmann JS, Bushby K. A gene related to Caenorhabditis elegans spermato-
A natural hepatocyte growth factor/scatter factor autocrine loop in myoblast cells and genesis factor fer-1 is mutated in limb-girdle muscular dystrophy type 2B. Nat Genet
the effect of the constitutive Met kinase activation on myogenic differentiation. J Cell 20: 37 42, 1998.
Biol 137: 10571068, 1997.
37. Beauchamp JR, Heslop L, Yu DS, Tajbakhsh S, Kelly RG, Wernig A, Buckingham ME,
16. Anderson JE. A role for nitric oxide in muscle repair: nitric oxide-mediated activation Partridge TA, Zammit PS. Expression of CD34 and Myf5 defines the majority of
of muscle satellite cells. Mol Biol Cell 11: 1859 1874, 2000. quiescent adult skeletal muscle satellite cells. J Cell Biol 151: 12211234, 2000.

38. Beggs ML, Nagarajan R, Taylor-Jones JM, Nolen G, Macnicol M, Peterson CA. Alter- 61. Boonen KJ, Rosaria-Chak KY, Baaijens FP, van der Schaft DW, Post MJ. Essential
ations in the TGFbeta signaling pathway in myogenic progenitors with age. Aging Cell environmental cues from the satellite cell niche: optimizing proliferation and differ-
3: 353361, 2004. entiation. Am J Physiol Cell Physiol 296: C1338 C1345, 2009.
39. Belcastro AN, Shewchuk LD, Raj DA. Exercise-induced muscle injury: a calpain hy- 62. Boppart MD, Burkin DJ, Kaufman SJ. Alpha7beta1-integrin regulates mechanotrans-
pothesis. Mol Cell Biochem 179: 135145, 1998. duction and prevents skeletal muscle injury. Am J Physiol Cell Physiol 290: C1660
C1665, 2006.
40. Ben-Yair R, Kalcheim C. Lineage analysis of the avian dermomyotome sheet reveals
the existence of single cells with both dermal and muscle progenitor fates. Develop- 63. Bosnakovski D, Xu Z, Li W, Thet S, Cleaver O, Perlingeiro RC, Kyba M. Prospective
ment 132: 689 701, 2005. isolation of skeletal muscle stem cells with a Pax7 reporter. Stem Cells 26: 3194 3204,
2008.
41. Benchaouir R, Meregalli M, Farini A, DAntona G, Belicchi M, Goyenvalle A, Battistelli
M, Bresolin N, Bottinelli R, Garcia L, Torrente Y. Restoration of human dystrophin 64. Bourke DL, Ontell M. Branched myofibers in long-term whole muscle transplants: a
following transplantation of exon-skipping-engineered DMD patient stem cells into quantitative study. Anat Rec 209: 281288, 1984.
dystrophic mice. Cell Stem Cell 1: 646 657, 2007.
65. Brack AS, Conboy IM, Conboy MJ, Shen J, Rando TA. A temporal switch from notch
42. Benezra R, Davis RL, Lassar A, Tapscott S, Thayer M, Lockshon D, Weintraub H. Id: to Wnt signaling in muscle stem cells is necessary for normal adult myogenesis. Cell
a negative regulator of helix-loop-helix DNA binding proteins. Control of terminal Stem Cell 2: 50 59, 2008.
myogenic differentiation. Ann NY Acad Sci 599: 111, 1990.
66. Brack AS, Conboy MJ, Roy S, Lee M, Kuo CJ, Keller C, Rando TA. Increased Wnt
43. Benezra R, Davis RL, Lockshon D, Turner DL, Weintraub H. The protein Id: a nega- signaling during aging alters muscle stem cell fate and increases fibrosis. Science 317:
tive regulator of helix-loop-helix DNA binding proteins. Cell 61: 49 59, 1990.

807 810, 2007.
44. Bergstrom DA, Penn BH, Strand A, Perry RL, Rudnicki MA, Tapscott SJ. Promoter- 67. Brandes RP, Fleming I, Busse R. Endothelial aging. Cardiovasc Res 66: 286 294, 2005.
specific regulation of MyoD binding and signal transduction cooperate to pattern gene
expression. Mol Cell 9: 587 600, 2002. 68. Brazelton TR, Nystrom M, Blau HM. Significant differences among skeletal muscles in
the incorporation of bone marrow-derived cells. Dev Biol 262: 64 74, 2003.
45. Berkes CA, Tapscott SJ. MyoD and the transcriptional control of myogenesis. Semin
Cell Dev Biol 16: 585595, 2005. 69. Brockes JP, Kumar A. Plasticity and reprogramming of differentiated cells in amphibian
regeneration. Nat Rev Mol Cell Biol 3: 566 574, 2002.
46. Besson V, Smeriglio P, Wegener A, Relaix F, Nait Oumesmar B, Sassoon DA, Marazzi
G. PW1 gene/paternally expressed gene 3 (PW1/Peg3) identifies multiple adult stem 70. Bryan BA, Walshe TE, Mitchell DC, Havumaki JS, Saint-Geniez M, Maharaj AS, Mal-
and progenitor cell populations. Proc Natl Acad Sci USA 108: 11470 11475, 2011. donado AE, DAmore PA. Coordinated vascular endothelial growth factor expression
and signaling during skeletal myogenic differentiation. Mol Biol Cell 19: 994 1006,
47. Bhagavati S, Xu W. Generation of skeletal muscle from transplanted embryonic stem 2008.
cells in dystrophic mice. Biochem Biophys Res Commun 333: 644 649, 2005.
71. Buckingham M. Myogenic progenitor cells and skeletal myogenesis in vertebrates.
48. Bhasin S, Taylor WE, Singh R, Artaza J, Sinha-Hikim I, Jasuja R, Choi H, Gonzalez- Curr Opin Genet Dev 16: 525532, 2006.
Cadavid NF. The mechanisms of androgen effects on body composition: mesenchy-
mal pluripotent cell as the target of androgen action. J Gerontol A Biol Sci Med Sci 58: 72. Buckingham M, Bajard L, Chang T, Daubas P, Hadchouel J, Meilhac S, Montarras D,
M1103M1110, 2003. Rocancourt D, Relaix F. The formation of skeletal muscle: from somite to limb. J Anat
202: 59 68, 2003.
49. Bischoff R. Chemotaxis of skeletal muscle satellite cells. Dev Dyn 208: 505515, 1997.
73. Burkin DJ, Kaufman SJ. The alpha7beta1 integrin in muscle development and disease.
50. Bischoff R. Interaction between satellite cells and skeletal muscle fibers. Development
Cell Tissue Res 296: 183190, 1999.
109: 943952, 1990.
74. Cahill CM, Rogers JT. Interleukin (IL) 1beta induction of IL-6 is mediated by a novel
51. Bischoff R. Regeneration of single skeletal muscle fibers in vitro. Anat Rec 182: 215
phosphatidylinositol 3-kinase-dependent AKT/IkappaB kinase alpha pathway target-
235, 1975.
ing activator protein-1. J Biol Chem 283: 25900 25912, 2008.
52. Bischoff R. The satellite cell and muscle regeneration. Myology 97118, 1994.
75. Cairns J. Mutation selection and the natural history of cancer. Nature 255: 197200,
53. Bischoff R. A satellite cell mitogen from crushed adult muscle. Dev Biol 115: 140 147, 1975.
1986.
76. Calise S, Blescia S, Cencetti F, Bernacchioni C, Donati C, Bruni P. Sphingosine 1-phos-
54. Bittner RE, Schofer C, Weipoltshammer K, Ivanova S, Streubel B, Hauser E, Freilinger phate stimulates proliferation and migration of satellite cells: role of S1P receptors.
M, Hoger H, Elbe-Burger A, Wachtler F. Recruitment of bone-marrow-derived cells Biochim Biophys Acta 1823: 439 450, 2012.
by skeletal and cardiac muscle in adult dystrophic mdx mice. Anat Embryol 199:
77. Camargo FD, Gokhale S, Johnnidis JB, Fu D, Bell GW, Jaenisch R, Brummelkamp TR.
391396, 1999.
YAP1 increases organ size and expands undifferentiated progenitor cells. Curr Biol 17:
55. Bjerknes M, Cheng H. Gastrointestinal stem cells. II. Intestinal stem cells. Am J Physiol 2054 2060, 2007.
Gastrointest Liver Physiol 289: G381G387, 2005.
78. Camargo FD, Green R, Capetanaki Y, Jackson KA, Goodell MA. Single hematopoietic
56. Blais A, Tsikitis M, Acosta-Alvear D, Sharan R, Kluger Y, Dynlacht BD. An initial stem cells generate skeletal muscle through myeloid intermediates. Nat Med 9: 1520
blueprint for myogenic differentiation. Genes Dev 19: 553569, 2005. 1527, 2003.
57. Blaivas M, Carlson BM. Muscle fiber branching difference between grafts in old and 79. Campion DR. The muscle satellite cell: a review. Int Rev Cytol 87: 225251, 1984.
young rats. Mech Ageing Dev 60: 4353, 1991.
80. Cantini M, Carraro U. Macrophage-released factor stimulates selectively myogenic
58. Blaveri K, Heslop L, Yu DS, Rosenblatt JD, Gross JG, Partridge TA, Morgan JE. cells in primary muscle culture. J Neuropathol Exp Neurol 54: 121128, 1995.
Patterns of repair of dystrophic mouse muscle: studies on isolated fibers. Dev Dyn 216:
244 256, 1999. 81. Cantini M, Giurisato E, Radu C, Tiozzo S, Pampinella F, Senigaglia D, Zaniolo G,
Mazzoleni F, Vitiello L. Macrophage-secreted myogenic factors: a promising tool for
59. Bockhold KJ, Rosenblatt JD, Partridge TA. Aging normal and dystrophic mouse mus- greatly enhancing the proliferative capacity of myoblasts in vitro and in vivo. Neurol Sci
cle: analysis of myogenicity in cultures of living single fibers. Muscle Nerve 21: 173183, 23: 189 194, 2002.
1998.
82. Cao B, Zheng B, Jankowski RJ, Kimura S, Ikezawa M, Deasy B, Cummins J, Epperly M,
60. Bogdan C. Nitric oxide and the regulation of gene expression. Trends Cell Biol 11: Qu-Petersen Z, Huard J. Muscle stem cells differentiate into haematopoietic lineages
66 75, 2001. but retain myogenic potential. Nat Cell Biol 5: 640 646, 2003.

83. Cao Y, Kumar RM, Penn BH, Berkes CA, Kooperberg C, Boyer LA, Young RA, 104. Collins-Hooper H, Woolley TE, Dyson L, Patel A, Potter P, Baker RE, Gaffney EA,
Tapscott SJ. Global and gene-specific analyses show distinct roles for Myod and Myog Maini PK, Dash PR, Patel K. Age-related changes in speed and mechanism of adult
at a common set of promoters. EMBO J 25: 502511, 2006. skeletal muscle stem cell migration. Stem Cells 30: 11821195, 2012.
84. Cao Y, Yao Z, Sarkar D, Lawrence M, Sanchez GJ, Parker MH, MacQuarrie KL, 105. Collins CA, Olsen I, Zammit PS, Heslop L, Petrie A, Partridge TA, Morgan JE. Stem
Davison J, Morgan MT, Ruzzo WL, Gentleman RC, Tapscott SJ. Genome-wide MyoD cell function, self-renewal, and behavioral heterogeneity of cells from the adult muscle
binding in skeletal muscle cells: a potential for broad cellular reprogramming. Dev Cell satellite cell niche. Cell 122: 289 301, 2005.
18: 662 674, 2010.
106. Collinsworth AM, Zhang S, Kraus WE, Truskey GA. Apparent elastic modulus and
85. Caplan AI. All MSCs are pericytes? Cell Stem Cell 3: 229 230, 2008. hysteresis of skeletal muscle cells throughout differentiation. Am J Physiol Cell Physiol
283: C1219 C1227, 2002.
86. Carmeli E, Moas M, Reznick AZ, Coleman R. Matrix metalloproteinases and skeletal
muscle: a brief review. Muscle Nerve 29: 191197, 2004. 107. Conboy IM, Conboy MJ, Smythe GM, Rando TA. Notch-mediated restoration of
regenerative potential to aged muscle. Science 302: 15751577, 2003.
87. Chakravarthy MV, Davis BS, Booth FW. IGF-I restores satellite cell proliferative po-
108. Conboy IM, Rando TA. The regulation of Notch signaling controls satellite cell acti-
tential in immobilized old skeletal muscle. J Appl Physiol 89: 13651379, 2000.
vation and cell fate determination in postnatal myogenesis. Dev Cell 3: 397 409, 2002.
88. Chang H, Yoshimoto M, Umeda K, Iwasa T, Mizuno Y, Fukada S, Yamamoto H,
109. Conboy MJ, Karasov AO, Rando TA. High incidence of non-random template strand
Motohashi N, Miyagoe-Suzuki Y, Takeda S, Heike T, Nakahata T. Generation of
segregation and asymmetric fate determination in dividing stem cells and their prog-
transplantable, functional satellite-like cells from mouse embryonic stem cells. FASEB
eny. PLoS Biol 5: e102, 2007.
J 23: 19071919, 2009.

110. Coolican SA, Samuel DS, Ewton DZ, McWade FJ, Florini JR. The mitogenic and
89. Chao DS, Gorospe JR, Brenman JE, Rafael JA, Peters MF, Froehner SC, Hoffman EP,
myogenic actions of insulin-like growth factors utilize distinct signaling pathways. J Biol
Chamberlain JS, Bredt DS. Selective loss of sarcolemmal nitric oxide synthase in
Chem 272: 6653 6662, 1997.
Becker muscular dystrophy. J Exp Med 184: 609 618, 1996.
111. Cooper RN, Tajbakhsh S, Mouly V, Cossu G, Buckingham M, Butler-Browne GS. In
90. Charge SB, Brack AS, Hughes SM. Aging-related satellite cell differentiation defect vivo satellite cell activation via Myf5 and MyoD in regenerating mouse skeletal muscle.
occurs prematurely after Ski-induced muscle hypertrophy. Am J Physiol Cell Physiol J Cell Sci 112: 28952901, 1999.
283: C1228 C1241, 2002.
112. Corbel SY, Lee A, Yi L, Duenas J, Brazelton TR, Blau HM, Rossi FM. Contribution of
91. Chazaud B, Brigitte M, Yacoub-Youssef H, Arnold L, Gherardi R, Sonnet C, Lafuste P, hematopoietic stem cells to skeletal muscle. Nat Med 9: 1528 1532, 2003.
Chretien F. Dual and beneficial roles of macrophages during skeletal muscle regen-
eration. Exerc Sport Sci Rev 37: 18 22, 2009. 113. Cornelison DD, Filla MS, Stanley HM, Rapraeger AC, Olwin BB. Syndecan-3 and
syndecan-4 specifically mark skeletal muscle satellite cells and are implicated in satel-
92. Chazaud B, Sonnet C, Lafuste P, Bassez G, Rimaniol AC, Poron F, Authier FJ, Dreyfus lite cell maintenance and muscle regeneration. Dev Biol 239: 79 94, 2001.
PA, Gherardi RK. Satellite cells attract monocytes and use macrophages as a support
to escape apoptosis and enhance muscle growth. J Cell Biol 163: 11331143, 2003. 114. Cornelison DD, Olwin BB, Rudnicki MA, Wold BJ. MyoD(/) satellite cells in single-
fiber culture are differentiation defective and MRF4 deficient. Dev Biol 224: 122137,
93. Chen JF, Mandel EM, Thomson JM, Wu Q, Callis TE, Hammond SM, Conlon FL, Wang 2000.
DZ. The role of microRNA-1 and microRNA-133 in skeletal muscle proliferation and
differentiation. Nature Genet 38: 228 233, 2006. 115. Cornelison DD, Wilcox-Adelman SA, Goetinck PF, Rauvala H, Rapraeger AC, Olwin
BB. Essential and separable roles for Syndecan-3 and Syndecan-4 in skeletal muscle
94. Chen JF, Tao Y, Li J, Deng Z, Yan Z, Xiao X, Wang DZ. microRNA-1 and microRNA- development and regeneration. Genes Dev 18: 22312236, 2004.
206 regulate skeletal muscle satellite cell proliferation and differentiation by repress-
116. Cornelison DD, Wold BJ. Single-cell analysis of regulatory gene expression in quies-
ing Pax7. J Cell Biol 190: 867 879, 2010.
cent and activated mouse skeletal muscle satellite cells. Dev Biol 191: 270 283, 1997.
95. Chen X, Mao Z, Liu S, Liu H, Wang X, Wu H, Wu Y, Zhao T, Fan W, Li Y, Yew DT,
117. Cox DM, Du M, Marback M, Yang EC, Chan J, Siu KW, McDermott JC. Phosphory-
Kindler PM, Li L, He Q, Qian L, Fan M. Dedifferentiation of adult human myoblasts
lation motifs regulating the stability and function of myocyte enhancer factor 2A. J Biol
induced by ciliary neurotrophic factor in vitro. Mol Biol Cell 16: 3140 3151, 2005.
Chem 278: 1529715303, 2003.
96. Chen Y, Lin G, Slack JM. Control of muscle regeneration in the Xenopus tadpole tail by
118. Crisan M, Yap S, Casteilla L, Chen CW, Corselli M, Park TS, Andriolo G, Sun B, Zheng
Pax7. Development 133: 23032313, 2006.
B, Zhang L, Norotte C, Teng PN, Traas J, Schugar R, Deasy BM, Badylak S, Buhring HJ,
97. Chen Y, Zajac JD, MacLean HE. Androgen regulation of satellite cell function. J Endo- Giacobino JP, Lazzari L, Huard J, Peault B. A perivascular origin for mesenchymal stem
cells in multiple human organs. Cell Stem Cell 3: 301313, 2008.
crinol 186: 2131, 2005.
119. Crist CG, Montarras D, Pallafacchina G, Rocancourt D, Cumano A, Conway SJ,
98. Cheung TH, Quach NL, Charville GW, Liu L, Park L, Edalati A, Yoo B, Hoang P, Rando
Buckingham M. Muscle stem cell behavior is modified by microRNA-27 regulation of
TA. Maintenance of muscle stem-cell quiescence by microRNA-489. Nature 482:
Pax3 expression. Proc Natl Acad Sci USA 106: 1338313387, 2009.
524 528, 2012.
120. Csete M, Walikonis J, Slawny N, Wei Y, Korsnes S, Doyle JC, Wold B. Oxygen-
99. Chevrel G, Hohlfeld R, Sendtner M. The role of neurotrophins in muscle under
mediated regulation of skeletal muscle satellite cell proliferation and adipogenesis in
physiological and pathological conditions. Muscle Nerve 33: 462 476, 2006.
culture. J Cell Physiol 189: 189 196, 2001.
100. Christov C, Chretien F, Abou-Khalil R, Bassez G, Vallet G, Authier FJ, Bassaglia Y, 121. dAlbis A, Lenfant-Guyot M, Janmot C, Chanoine C, Weinman J, Gallien CL. Regula-
Shinin V, Tajbakhsh S, Chazaud B, Gherardi RK. Muscle satellite cells and endothelial tion by thyroid hormones of terminal differentiation in the skeletal dorsal muscle. I.
cells: close neighbors and privileged partners. Mol Biol Cell 18: 13971409, 2007. Neonate mouse. Dev Biol 123: 2532, 1987.
101. Cinnamon Y, Ben-Yair R, Kalcheim C. Differential effects of N-cadherin-mediated 122. Danieli-Betto D, Peron S, Germinario E, Zanin M, Sorci G, Franzoso S, Sandona D,
adhesion on the development of myotomal waves. Development 133: 11011112, Betto R. Sphingosine 1-phosphate signaling is involved in skeletal muscle regeneration.
2006. Am J Physiol Cell Physiol 298: C550 C558, 2010.
102. Clow C, Jasmin BJ. Skeletal muscle-derived BDNF regulates satellite cell differentia- 123. Darabi R, Arpke RW, Irion S, Dimos JT, Grskovic M, Kyba M, Perlingeiro RC. Human
tion and muscle regeneration. Mol Biol Cell 2010. ES- and iPS-derived myogenic progenitors restore dystrophin and improve contrac-
tility upon transplantation in dystrophic mice. Cell Stem Cell 10: 610 619, 2012.
103. Coleman ME, DeMayo F, Yin KC, Lee HM, Geske R, Montgomery C, Schwartz RJ.
Myogenic vector expression of insulin-like growth factor I stimulates muscle cell 124. Darabi R, Gehlbach K, Bachoo RM, Kamath S, Osawa M, Kamm KE, Kyba M, Per-
differentiation and myofiber hypertrophy in transgenic mice. J Biol Chem 270: 12109 lingeiro RC. Functional skeletal muscle regeneration from differentiating embryonic
12116, 1995. stem cells. Nat Med 14: 134 143, 2008.

125. Darabi R, Santos FN, Filareto A, Pan W, Koene R, Rudnicki MA, Kyba M, Perlingeiro 144. Doumit ME, Merkel RA. Conditions for isolation and culture of porcine myogenic
RC. Assessment of the myogenic stem cell compartment following transplantation of satellite cells. Tissue Cell 24: 253262, 1992.
Pax3/Pax7-induced embryonic stem cell-derived progenitors. Stem Cells 29: 777
790, 2011. 145. Dourdin N, Balcerzak D, Brustis JJ, Poussard S, Cottin P, Ducastaing A. Potential
m-calpain substrates during myoblast fusion. Exp Cell Res 246: 433 442, 1999.
126. Darmani H, Crossan J, McLellan SD, Meek D, Adam C. Expression of nitric oxide
synthase and transforming growth factor-beta in crush-injured tendon and synovium. 146. Doyle MJ, Zhou S, Tanaka KK, Pisconti A, Farina NH, Sorrentino BP, Olwin BB. Abcg2
Mediators Inflamm 13: 299 305, 2004. labels multiple cell types in skeletal muscle and participates in muscle regeneration. J
Cell Biol 195: 147163, 2011.
127. Day K, Shefer G, Richardson JB, Enikolopov G, Yablonka-Reuveni Z. Nestin-GFP
reporter expression defines the quiescent state of skeletal muscle satellite cells. Dev 147. Doyonnas R, LaBarge MA, Sacco A, Charlton C, Blau HM. Hematopoietic contribu-
Biol 304: 246 259, 2007. tion to skeletal muscle regeneration by myelomonocytic precursors. Proc Natl Acad
Sci USA 101: 1350713512, 2004.
128. Day K, Shefer G, Shearer A, Yablonka-Reuveni Z. The depletion of skeletal muscle
satellite cells with age is concomitant with reduced capacity of single progenitors to 148. Dreyfus PA, Chretien F, Chazaud B, Kirova Y, Caramelle P, Garcia L, Butler-Browne
produce reserve progeny. Dev Biol 340: 330 343, 2010. G, Gherardi RK. Adult bone marrow-derived stem cells in muscle connective tissue
and satellite cell niches. Am J Pathol 164: 773779, 2004.
129. De Angelis L, Berghella L, Coletta M, Lattanzi L, Zanchi M, Cusella-De Angelis MG,
Ponzetto C, Cossu G. Skeletal myogenic progenitors originating from embryonic 149. Duckmanton A, Kumar A, Chang YT, Brockes JP. A single-cell analysis of myogenic
dorsal aorta coexpress endothelial and myogenic markers and contribute to postnatal dedifferentiation induced by small molecules. Chem Biol 12: 11171126, 2005.
muscle growth and regeneration. J Cell Biol 147: 869 878, 1999.
150. Enesco M, Puddy D. Increase in the number of nuclei and weight in skeletal muscle of

130. De Castro Rodrigues A, Andreo JC, de Mattos Rodrigues SP. Myonuclei and satellite rats of various ages. Am J Anat 114: 235244, 1964.
cells in denervated rat muscles: an electron microscopy study. Microsurgery 26: 396
398, 2006. 151. Engert JC, Berglund EB, Rosenthal N. Proliferation precedes differentiation in IGF-I-
stimulated myogenesis. J Cell Biol 135: 431 440, 1996.
131. De Strooper B, Annaert W. Where Notch and Wnt signaling meet. The presenilin hub.
J Cell Biol 152: F1720, 2001. 152. Engler AJ, Griffin MA, Sen S, Bonnemann CG, Sweeney HL, Discher DE. Myotubes
differentiate optimally on substrates with tissue-like stiffness: pathological implica-
132. Deasy BM, Feduska JM, Payne TR, Li Y, Ambrosio F, Huard J. Effect of VEGF on the tions for soft or stiff microenvironments. J Cell Biol 166: 877 887, 2004.
regenerative capacity of muscle stem cells in dystrophic skeletal muscle. Mol Ther J Am
Soc Gene Ther 17: 1788 1798, 2009. 153. Ernfors P, Wetmore C, Eriksdotter-Nilsson M, Bygdeman M, Stromberg I, Olson L,
Persson H. The nerve growth factor receptor gene is expressed in both neuronal and
133. DeChiara TM, Efstratiadis A, Robertson EJ. A growth-deficiency phenotype in non-neuronal tissues in the human fetus. Int J Dev Neurosci 9: 57 66, 1991.
heterozygous mice carrying an insulin-like growth factor II gene disrupted by target-
ing. Nature 345: 78 80, 1990. 154. Ershler WB, Keller ET. Age-associated increased interleukin-6 gene expression, late-
life diseases, and frailty. Annu Rev Med 51: 245270, 2000.
134. deLapeyriere O, Ollendorff V, Planche J, Ott MO, Pizette S, Coulier F, Birnbaum D.
Expression of the Fgf6 gene is restricted to developing skeletal muscle in the mouse 155. Esner M, Meilhac SM, Relaix F, Nicolas JF, Cossu G, Buckingham ME. Smooth muscle
embryo. Development 118: 601 611, 1993. of the dorsal aorta shares a common clonal origin with skeletal muscle of the myo-
tome. Development 133: 737749, 2006.
135. Dellavalle A, Maroli G, Covarello D, Azzoni E, Innocenzi A, Perani L, Antonini S,
Sambasivan R, Brunelli S, Tajbakhsh S, Cossu G. Pericytes resident in postnatal skel- 156. Espinosa A, Estrada M, Jaimovich E. IGF-I and insulin induce different intracellular
etal muscle differentiate into muscle fibres and generate satellite cells. Nature Com- calcium signals in skeletal muscle cells. J Endocrinol 182: 339 352, 2004.
mun 2: 499, 2011.
157. Estrada M, Espinosa A, Muller M, Jaimovich E. Testosterone stimulates intracellular
136. Dellavalle A, Sampaolesi M, Tonlorenzi R, Tagliafico E, Sacchetti B, Perani L, Innocenzi calcium release and mitogen-activated protein kinases via a G protein-coupled recep-
A, Galvez BG, Messina G, Morosetti R, Li S, Belicchi M, Peretti G, Chamberlain JS, tor in skeletal muscle cells. Endocrinology 144: 3586 3597, 2003.
Wright WE, Torrente Y, Ferrari S, Bianco P, Cossu G. Pericytes of human skeletal
muscle are myogenic precursors distinct from satellite cells. Nat Cell Biol 9: 255267, 158. Ewton DZ, Falen SL, Florini JR. The type II insulin-like growth factor (IGF) receptor
2007. has low affinity for IGF-I analogs: pleiotypic actions of IGFs on myoblasts are appar-
ently mediated by the type I receptor. Endocrinology 120: 115123, 1987.
137. Delling U, Tureckova J, Lim HW, De Windt LJ, Rotwein P, Molkentin JD. A calcineurin-
NFATc3-dependent pathway regulates skeletal muscle differentiation and slow my- 159. Fahim MA, Robbins N. Ultrastructural studies of young and old mouse neuromuscular
osin heavy-chain expression. Mol Cell Biol 20: 6600 6611, 2000. junctions. J Neurocytol 11: 641 656, 1982.
138. Deponti D, Buono R, Catanzaro G, De Palma C, Longhi R, Meneveri R, Bresolin N, 160. Fan Y, Maley M, Beilharz M, Grounds M. Rapid death of injected myoblasts in myoblast
Bassi MT, Cossu G, Clementi E, Brunelli S. The low-affinity receptor for neurotro- transfer therapy. Muscle Nerve 19: 853 860, 1996.
phins p75NTR plays a key role for satellite cell function in muscle repair acting via
161. Farrington-Rock C, Crofts NJ, Doherty MJ, Ashton BA, Griffin-Jones C, Canfield AE.
RhoA. Mol Biol Cell 20: 3620 3627, 2009.
Chondrogenic and adipogenic potential of microvascular pericytes. Circulation 110:
139. Dey BK, Gagan J, Dutta A. miR-206 and -486 induce myoblast differentiation by 2226 2232, 2004.
downregulating Pax7. Mol Cell Biol 31: 203214, 2011.
162. Fedorov YV, Rosenthal RS, Olwin BB. Oncogenic Ras-induced proliferation requires
140. Dezawa M, Ishikawa H, Itokazu Y, Yoshihara T, Hoshino M, Takeda S, Ide C, autocrine fibroblast growth factor 2 signaling in skeletal muscle cells. J Cell Biol 152:
Nabeshima Y. Bone marrow stromal cells generate muscle cells and repair muscle 13011305, 2001.
degeneration. Science 309: 314 317, 2005.
163. Feng J, Mantesso A, De Bari C, Nishiyama A, Sharpe PT. Dual origin of mesenchymal
141. DiMario J, Buffinger N, Yamada S, Strohman RC. Fibroblast growth factor in the stem cells contributing to organ growth and repair. Proc Natl Acad Sci USA 108:
extracellular matrix of dystrophic (mdx) mouse muscle. Science 244: 688 690, 1989. 6503 6508, 2011.
142. Doherty MJ, Ashton BA, Walsh S, Beresford JN, Grant ME, Canfield AE. Vascular 164. Fernando P, Kelly JF, Balazsi K, Slack RS, Megeney LA. Caspase 3 activity is required
pericytes express osteogenic potential in vitro and in vivo. J Bone Miner Res 13: for skeletal muscle differentiation. Proc Natl Acad Sci USA 99: 1102511030, 2002.
828 838, 1998.
165. Ferrando AA, Sheffield-Moore M, Yeckel CW, Gilkison C, Jiang J, Achacosa A, Lieber-
143. Doumit ME, Cook DR, Merkel RA. Testosterone up-regulates androgen receptors man SA, Tipton K, Wolfe RR, Urban RJ. Testosterone administration to older men
and decreases differentiation of porcine myogenic satellite cells in vitro. Endocrinology improves muscle function: molecular and physiological mechanisms. Am J Physiol En-
137: 13851394, 1996. docrinol Metab 282: E601E607, 2002.

166. Ferrari G, Cusella-De Angelis G, Coletta M, Paolucci E, Stornaiuolo A, Cossu G, 187. Gayraud-Morel B, Chretien F, Flamant P, Gomes D, Zammit PS, Tajbakhsh S. A role
Mavilio F. Muscle regeneration by bone marrow-derived myogenic progenitors. Sci- for the myogenic determination gene Myf5 in adult regenerative myogenesis. Dev Biol
ence 279: 1528 1530, 1998. 312: 1328, 2007.
167. Ferre PJ, Liaubet L, Concordet D, SanCristobal M, Uro-Coste E, Tosser-Klopp G, 188. Gensch N, Borchardt T, Schneider A, Riethmacher D, Braun T. Different autonomous
Bonnet A, Toutain PL, Hatey F, Lefebvre HP. Longitudinal analysis of gene expression myogenic cell populations revealed by ablation of Myf5-expressing cells during mouse
in porcine skeletal muscle after post-injection local injury. Pharm Res 24: 1480 1489, embryogenesis. Development 135: 15971604, 2008.
2007.
189. Germani A, Di Carlo A, Mangoni A, Straino S, Giacinti C, Turrini P, Biglioli P, Capo-
168. Fielding RA, Manfredi TJ, Ding W, Fiatarone MA, Evans WJ, Cannon JG. Acute phase grossi MC. Vascular endothelial growth factor modulates skeletal myoblast function.
response in exercise. III. Neutrophil and IL-1 beta accumulation in skeletal muscle. Am Am J Pathol 163: 14171428, 2003.
J Physiol Regul Integr Comp Physiol 265: R166 R172, 1993.
190. Gibson MC, Schultz E. The distribution of satellite cells and their relationship to
169. Florini JR, Ewton DZ, Coolican SA. Growth hormone and the insulin-like growth
specific fiber types in soleus and extensor digitorum longus muscles. Anat Rec 202:
factor system in myogenesis. Endocr Rev 17: 481517, 1996.
329 337, 1982.
170. Florini JR, Ewton DZ, Roof SL. Insulin-like growth factor-I stimulates terminal myo-
191. Gillespie MA, Le Grand F, Scime A, Kuang S, von Maltzahn J, Seale V, Cuenda A, Ranish
genic differentiation by induction of myogenin gene expression. Mol Endocrinol 5:
JA, Rudnicki MA. p38--dependent gene silencing restricts entry into the myogenic
718 724, 1991.
differentiation program. J Cell Biol 187: 9911005, 2009.
171. Florini JR, Magri KA, Ewton DZ, James PL, Grindstaff K, Rotwein PS. Spontaneous
192. Gnocchi VF, White RB, Ono Y, Ellis JA, Zammit PS. Further characterisation of the
differentiation of skeletal myoblasts is dependent upon autocrine secretion of insulin-

like growth factor-II. J Biol Chem 266: 1591715923, 1991. molecular signature of quiescent and activated mouse muscle satellite cells. PLoS One
4: e5205, 2009.
172. Floss T, Arnold HH, Braun T. A role for FGF-6 in skeletal muscle regeneration. Genes
Dev 11: 2040 2051, 1997. 193. Golding JP, Calderbank E, Partridge TA, Beauchamp JR. Skeletal muscle stem cells
express anti-apoptotic ErbB receptors during activation from quiescence. Exp Cell Res
173. Friday BB, Horsley V, Pavlath GK. Calcineurin activity is required for the initiation of 313: 341356, 2007.
skeletal muscle differentiation. J Cell Biol 149: 657 666, 2000.
194. Goldspink G. Research on mechano growth factor: its potential for optimising physical
174. Fuchs E. Finding ones niche in the skin. Cell Stem Cell 4: 499 502, 2009. training as well as misuse in doping. Br J Sports Med 39: 787788, 2005.
175. Fuchtbauer EM, Westphal H. MyoD and myogenin are coexpressed in regenerating 195. Goldspink G, Fernandes K, Williams PE, Wells DJ. Age-related changes in collagen
skeletal muscle of the mouse. Dev Dyn 193: 34 39, 1992. gene expression in the muscles of mdx dystrophic and normal mice. Neuromuscul
Disord 4: 183191, 1994.
176. Fukada S. Molecular regulation of muscle stem cells by quiescence genes. Yakugaku
zasshi J Pharmaceutical Soc Japan 131: 1329 1332, 2011. 196. Goljanek-Whysall K, Sweetman D, Abu-Elmagd M, Chapnik E, Dalmay T, Hornstein
E, Munsterberg A. MicroRNA regulation of the paired-box transcription factor Pax3
177. Fukada S, Uezumi A, Ikemoto M, Masuda S, Segawa M, Tanimura N, Yamamoto H,
confers robustness to developmental timing of myogenesis. Proc Natl Acad Sci USA
Miyagoe-Suzuki Y, Takeda S. Molecular signature of quiescent satellite cells in adult
skeletal muscle. Stem Cells 25: 2448 2459, 2007. 108: 11936 11941, 2011.
178. Fukushima K, Nakamura A, Ueda H, Yuasa K, Yoshida K, Takeda S, Ikeda S. Activation 197. Gonzalez I, Tripathi G, Carter EJ, Cobb LJ, Salih DA, Lovett FA, Holding C, Pell JM.
and localization of matrix metalloproteinase-2 and -9 in the skeletal muscle of the Akt2, a novel functional link between p38 mitogen-activated protein kinase and phos-
muscular dystrophy dog (CXMDJ). BMC Musculoskelet Disord 8: 54, 2007. phatidylinositol 3-kinase pathways in myogenesis. Mol Cell Biol 24: 36073622, 2004.
179. Gal-Levi R, Leshem Y, Aoki S, Nakamura T, Halevy O. Hepatocyte growth factor 198. Goodpaster BH, Wolf D. Skeletal muscle lipid accumulation in obesity, insulin resis-
plays a dual role in regulating skeletal muscle satellite cell proliferation and differenti- tance, and type 2 diabetes. Pediatr Diabetes 5: 219 226, 2004.
ation. Biochim Biophys Acta 1402: 39 51, 1998.
199. Grass S, Arnold HH, Braun T. Alterations in somite patterning of Myf-5-deficient
180. Galbiati F, Volonte D, Engelman JA, Scherer PE, Lisanti MP. Targeted down-regula- mice: a possible role for FGF-4 and FGF-6. Development 122: 141150, 1996.
tion of caveolin-3 is sufficient to inhibit myotube formation in differentiating C2C12
myoblasts. Transient activation of p38 mitogen-activated protein kinase is required 200. Greco AV, Mingrone G, Giancaterini A, Manco M, Morroni M, Cinti S, Granzotto M,
for induction of caveolin-3 expression and subsequent myotube formation. J Biol Chem Vettor R, Camastra S, Ferrannini E. Insulin resistance in morbid obesity: reversal with
274: 3031530321, 1999. intramyocellular fat depletion. Diabetes 51: 144 151, 2002.
181. Galbiati F, Volonte D, Minetti C, Chu JB, Lisanti MP. Phenotypic behavior of caveo- 201. Griesbeck O, Parsadanian AS, Sendtner M, Thoenen H. Expression of neurotrophins
lin-3 mutations that cause autosomal dominant limb girdle muscular dystrophy in skeletal muscle: quantitative comparison and significance for motoneuron survival
(LGMD-1C). Retention of LGMD-1C caveolin-3 mutants within the Golgi complex. J and maintenance of function. J Neurosci Res 42: 2133, 1995.
Biol Chem 274: 2563225641, 1999.
202. Grimby G, Saltin B. The ageing muscle. Clin Physiol 3: 209 218, 1983.
182. Galvez BG, Sampaolesi M, Brunelli S, Covarello D, Gavina M, Rossi B, Constantin G,
Torrente Y, Cossu G. Complete repair of dystrophic skeletal muscle by mesoangio- 203. Gros J, Manceau M, Thome V, Marcelle C. A common somitic origin for embryonic
blasts with enhanced migration ability. J Cell Biol 174: 231243, 2006. muscle progenitors and satellite cells. Nature 435: 954 958, 2005.
183. Gao C, Chen YG. Dishevelled: the hub of Wnt signaling. Cell Signal 22: 717727, 2010. 204. Gros J, Scaal M, Marcelle C. A two-step mechanism for myotome formation in chick.
Dev Cell 6: 875 882, 2004.
184. Gao Y, Kostrominova TY, Faulkner JA, Wineman AS. Age-related changes in the
mechanical properties of the epimysium in skeletal muscles of rats. J Biomech 41: 205. Gros J, Serralbo O, Marcelle C. WNT11 acts as a directional cue to organize the
465 469, 2008. elongation of early muscle fibres. Nature 457: 589 593, 2009.
185. Gatchalian CL, Schachner M, Sanes JR. Fibroblasts that proliferate near denervated 206. Grounds MD. Phagocytosis of necrotic muscle in muscle isografts is influenced by the
synaptic sites in skeletal muscle synthesize the adhesive molecules tenascin(J1), N- strain, age, and sex of host mice. J Pathol 153: 71 82, 1987.
CAM, fibronectin, and a heparan sulfate proteoglycan. J Cell Biol 108: 18731890,
1989. 207. Grounds MD, Garrett KL, Lai MC, Wright WE, Beilharz MW. Identification of skeletal
muscle precursor cells in vivo by use of MyoD1 and myogenin probes. Cell Tissue Res
186. Gauthier-Rouviere C, Vandromme M, Tuil D, Lautredou N, Morris M, Soulez M, Kahn 267: 99 104, 1992.
A, Fernandez A, Lamb N. Expression and activity of serum response factor is required
for expression of the muscle-determining factor MyoD in both dividing and differen- 208. Gullberg D, Tiger CF, Velling T. Laminins during muscle development and in muscular
tiating mouse C2C12 myoblasts. Mol Biol Cell 7: 719 729, 1996. dystrophies. Cell Mol Life Sci 56: 442 460, 1999.

209. Guo K, Wang J, Andres V, Smith RC, Walsh K. MyoD-induced expression of p21 230. Hinescu ME, Gherghiceanu M, Suciu L, Popescu LM. Telocytes in pleura: two- and
inhibits cyclin-dependent kinase activity upon myocyte terminal differentiation. Mol three-dimensional imaging by transmission electron microscopy. Cell Tissue Res 343:
Cell Biol 15: 38233829, 1995. 389 397, 2011.
210. Gussoni E, Soneoka Y, Strickland CD, Buzney EA, Khan MK, Flint AF, Kunkel LM, 231. Hirai H, Verma M, Watanabe S, Tastad C, Asakura Y, Asakura A. MyoD regulates
Mulligan RC. Dystrophin expression in the mdx mouse restored by stem cell trans- apoptosis of myoblasts through microRNA-mediated down-regulation of Pax3. J Cell
plantation. Nature 401: 390 394, 1999. Biol 191: 347365, 2010.
211. Guttinger M, Tafi E, Battaglia M, Coletta M, Cossu G. Allogeneic mesoangioblasts give 232. Hjiantoniou E, Anayasa M, Nicolaou P, Bantounas I, Saito M, Iseki S, Uney JB, Phylac-
rise to alpha-sarcoglycan expressing fibers when transplanted into dystrophic mice. tou LA. Twist induces reversal of myotube formation. Differ Res Biol Diversity 76:
Exp Cell Res 312: 38723879, 2006. 182192, 2008.
212. Haddad F, Zaldivar F, Cooper DM, Adams GR. IL-6-induced skeletal muscle atrophy. 233. Hollemann D, Budka H, Loscher WN, Yanagida G, Fischer MB, Wanschitz JV. Endo-
J Appl Physiol 98: 911917, 2005. thelial and myogenic differentiation of hematopoietic progenitor cells in inflammatory
myopathies. J Neuropathol Exp Neurol 67: 711719, 2008.
213. Haldar M, Karan G, Tvrdik P, Capecchi MR. Two cell lineages, myf5 and myf5-
independent, participate in mouse skeletal myogenesis. Dev Cell 14: 437 445, 2008. 234. Hollenberg SM, Cheng PF, Weintraub H. Use of a conditional MyoD transcription
factor in studies of MyoD trans-activation and muscle determination. Proc Natl Acad
214. Halevy O, Cantley LC. Differential regulation of the phosphoinositide 3-kinase and Sci USA 90: 8028 8032, 1993.
MAP kinase pathways by hepatocyte growth factor vs. insulin-like growth factor-I in
myogenic cells. Exp Cell Res 297: 224 234, 2004. 235. Holterman CE, Le Grand F, Kuang S, Seale P, Rudnicki MA. Megf10 regulates the

progression of the satellite cell myogenic program. J Cell Biol 179: 911922, 2007.
215. Halevy O, Novitch BG, Spicer DB, Skapek SX, Rhee J, Hannon GJ, Beach D, Lassar
AB. Correlation of terminal cell cycle arrest of skeletal muscle with induction of p21 236. Horowitz A, Tkachenko E, Simons M. Fibroblast growth factor-specific modulation of
by MyoD. Science 267: 1018 1021, 1995. cellular response by syndecan-4. J Cell Biol 157: 715725, 2002.
216. Halevy O, Piestun Y, Allouh MZ, Rosser BW, Rinkevich Y, Reshef R, Rozenboim I, 237. Horsley V, Friday BB, Matteson S, Kegley KM, Gephart J, Pavlath GK. Regulation of the
Wleklinski-Lee M, Yablonka-Reuveni Z. Pattern of Pax7 expression during myogen- growth of multinucleated muscle cells by an NFATC2-dependent pathway. J Cell Biol
esis in the posthatch chicken establishes a model for satellite cell differentiation and 153: 329 338, 2001.
renewal. Dev Dyn 231: 489 502, 2004.
238. Horsley V, Pavlath GK. Forming a multinucleated cell: molecules that regulate myo-
217. Hall-Craggs EC, Seyan HS. Histochemical changes in innervated and denervated skel- blast fusion. Cells Tissues Organs 176: 6778, 2004.
etal muscle fibers following treatment with bupivacaine (marcain). Exp Neurol 46:
239. Hu E, Tontonoz P, Spiegelman BM. Transdifferentiation of myoblasts by the adipo-
345354, 1975.
genic transcription factors PPAR gamma and C/EBP alpha. Proc Natl Acad Sci USA 92:
218. Hamer PW, McGeachie JM, Davies MJ, Grounds MD. Evans Blue Dye as an in vivo 9856 9860, 1995.
marker of myofibre damage: optimising parameters for detecting initial myofibre
240. Huckins C. The spermatogonial stem cell population in adult rats. I. Their morphol-
membrane permeability. J Anat 200: 69 79, 2002.
ogy, proliferation and maturation. Anat Rec 169: 533557, 1971.
219. Hammond CL, Hinits Y, Osborn DP, Minchin JE, Tettamanti G, Hughes SM. Signals
241. Hughes SM, Blau HM. Migration of myoblasts across basal lamina during skeletal
and myogenic regulatory factors restrict pax3 and pax7 expression to dermomyo-
muscle development. Nature 345: 350 353, 1990.
tome-like tissue in zebrafish. Dev Biol 302: 504 521, 2007.
242. Hutcheson DA, Zhao J, Merrell A, Haldar M, Kardon G. Embryonic and fetal limb
220. Han B, Tong J, Zhu MJ, Ma C, Du M. Insulin-like growth factor-1 (IGF-1) and leucine
myogenic cells are derived from developmentally distinct progenitors and have dif-
activate pig myogenic satellite cells through mammalian target of rapamycin (mTOR)
ferent requirements for beta-catenin. Genes Dev 23: 9971013, 2009.
pathway. Mol Reprod Dev 75: 810 817, 2008.
243. Ikezawa M, Cao B, Qu Z, Peng H, Xiao X, Pruchnic R, Kimura S, Miike T, Huard J.
221. Han J, Jiang Y, Li Z, Kravchenko VV, Ulevitch RJ. Activation of the transcription factor
Dystrophin delivery in dystrophin-deficient DMDmdx skeletal muscle by isogenic
MEF2C by the MAP kinase p38 in inflammation. Nature 386: 296 299, 1997.
muscle-derived stem cell transplantation. Hum Gene Ther 14: 15351546, 2003.
222. Hannon K, Kudla AJ, McAvoy MJ, Clase KL, Olwin BB. Differentially expressed fibro-
244. Irintchev A, Zeschnigk M, Starzinski-Powitz A, Wernig A. Expression pattern of M-
blast growth factors regulate skeletal muscle development through autocrine and
cadherin in normal, denervated, and regenerating mouse muscles. Dev Dyn 199:
paracrine mechanisms. J Cell Biol 132: 11511159, 1996.
326 337, 1994.
223. Hannun YA, Obeid LM. Principles of bioactive lipid signalling: lessons from sphingo-
245. Jackson KA, Mi T, Goodell MA. Hematopoietic potential of stem cells isolated from
lipids. Nat Rev Mol Cell Biol 9: 139 150, 2008.
murine skeletal muscle. Proc Natl Acad Sci USA 96: 1448214486, 1999.
224. Hansen-Smith FM, Picou D, Golden MH. Muscle satellite cells in malnourished and 246. James PL, Jones SB, Busby WH Jr, Clemmons DR, Rotwein P. A highly conserved
nutritionally rehabilitated children. J Neurol Sci 41: 207221, 1979. insulin-like growth factor-binding protein (IGFBP-5) is expressed during myoblast
differentiation. J Biol Chem 268: 2230522312, 1993.
225. Harel I, Nathan E, Tirosh-Finkel L, Zigdon H, Guimaraes-Camboa N, Evans SM,
Tzahor E. Distinct origins and genetic programs of head muscle satellite cells. Dev Cell 247. Jankowski RJ, Huard J. Establishing reliable criteria for isolating myogenic cell fractions
16: 822 832, 2009. with stem cell properties and enhanced regenerative capacity. Blood Cells Mol Dis 32:
24 33, 2004.
226. He L, Papoutsi M, Huang R, Tomarev SI, Christ B, Kurz H, Wilting J. Three different
fates of cells migrating from somites into the limb bud. Anat Embryol 207: 29 34, 248. Jejurikar SS, Marcelo CL, Kuzon WM Jr. Skeletal muscle denervation increases satellite
2003. cell susceptibility to apoptosis. Plast Reconstr Surg 110: 160 168, 2002.
227. Hellmuth AE, Allbrook DB. Muscle satellite cell numbers during the postnatal period. 249. Jenniskens GJ, Veerkamp JH, van Kuppevelt TH. Heparan sulfates in skeletal muscle
J Anat 110: 503, 1971. development and physiology. J Cell Physiol 206: 283294, 2006.
228. Herbst KL, Bhasin S. Testosterone action on skeletal muscle. Curr Opin Clin Nutr 250. Jirmanova I, Thesleff S. Ultrastructural study of experimental muscle degeneration
Metab Care 7: 271277, 2004. and regeneration in the adult rat. Z Zellforsch Mikrosk Anat 131: 7797, 1972.
229. Hermanson JW, Moschella MC, Ontell M. Effect of neonatal denervation-reinnerva- 251. Jockusch H, Voigt S. Migration of adult myogenic precursor cells as revealed by
tion on the functional capacity of a 129ReJ dy/dy murine dystrophic muscle. Exp Neurol GFP/nLacZ labelling of mouse transplantation chimeras. J Cell Sci 116: 16111616,
102: 210 216, 1988. 2003.

252. Joe AW, Yi L, Natarajan A, Le Grand F, So L, Wang J, Rudnicki MA, Rossi FM. Muscle 273. Kitzmann M, Carnac G, Vandromme M, Primig M, Lamb NJ, Fernandez A. The muscle
injury activates resident fibro/adipogenic progenitors that facilitate myogenesis. Nat regulatory factors MyoD and myf-5 undergo distinct cell cycle-specific expression in
Cell Biol 12: 153163, 2010. muscle cells. J Cell Biol 142: 14471459, 1998.
253. Jones JI, Clemmons DR. Insulin-like growth factors and their binding proteins: biolog- 274. Knudsen KA, Horwitz AF. Tandem events in myoblast fusion. Dev Biol 58: 328 338,
ical actions. Endocr Rev 16: 334, 1995. 1977.
254. Joubert Y, Tobin C. Satellite cell proliferation and increase in the number of myonuclei 275. Kobzik L, Reid MB, Bredt DS, Stamler JS. Nitric oxide in skeletal muscle. Nature 372:
induced by testosterone in the levator ani muscle of the adult female rat. Dev Biol 131: 546 548, 1994.
550 557, 1989.
276. Konigsberg IR. Clonal analysis of myogenesis. Science 140: 12731284, 1963.
255. Joubert Y, Tobin C. Testosterone treatment results in quiescent satellite cells being
activated and recruited into cell cycle in rat levator ani muscle. Dev Biol 169: 286 294, 277. Konigsberg UR, Lipton BH, Konigsberg IR. The regenerative response of single ma-
1995. ture muscle fibers isolated in vitro. Dev Biol 45: 260 275, 1975.
256. Kablar B, Asakura A, Krastel K, Ying C, May LL, Goldhamer DJ, Rudnicki MA. MyoD 278. Kovanen V. Intramuscular extracellular matrix: complex environment of muscle cells.
and Myf-5 define the specification of musculature of distinct embryonic origin. Exerc Sport Sci Rev 30: 20 25, 2002.
Biochem Cell Biol 76: 1079 1091, 1998.
279. Kuang S, Charge SB, Seale P, Huh M, Rudnicki MA. Distinct roles for Pax7 and Pax3 in
257. Kablar B, Krastel K, Tajbakhsh S, Rudnicki MA. Myf5 and MyoD activation define adult regenerative myogenesis. J Cell Biol 172: 103113, 2006.
independent myogenic compartments during embryonic development. Dev Biol 258:
280. Kuang S, Kuroda K, Le Grand F, Rudnicki MA. Asymmetric self-renewal and commit-

307318, 2003.
ment of satellite stem cells in muscle. Cell 129: 999 1010, 2007.
258. Kablar B, Krastel K, Ying C, Asakura A, Tapscott SJ, Rudnicki MA. MyoD and Myf-5
281. Kurosu H, Ogawa Y, Miyoshi M, Yamamoto M, Nandi A, Rosenblatt KP, Baum MG,
differentially regulate the development of limb versus trunk skeletal muscle. Develop-
Schiavi S, Hu MC, Moe OW, Kuro-o M. Regulation of fibroblast growth factor-23
ment 124: 4729 4738, 1997.
signaling by klotho. J Biol Chem 281: 6120 6123, 2006.
259. Kablar B, Krastel K, Ying C, Tapscott SJ, Goldhamer DJ, Rudnicki MA. Myogenic
282. Kuschel R, Yablonka-Reuveni Z, Bornemann A. Satellite cells on isolated myofibers
determination occurs independently in somites and limb buds. Dev Biol 206: 219 231,
from normal and denervated adult rat muscle. J Histochem Cytochem 47: 13751384,
1999.
1999.
260. Kablar B, Rudnicki MA. Skeletal muscle development in the mouse embryo. Histol
283. Kust BM, Copray JC, Brouwer N, Troost D, Boddeke HW. Elevated levels of neu-
Histopathol 15: 649 656, 2000.
rotrophins in human biceps brachii tissue of amyotrophic lateral sclerosis. Exp Neurol
261. Kalcheim C, Ben-Yair R. Cell rearrangements during development of the somite and 177: 419 427, 2002.
its derivatives. Curr Opin Genet Dev 15: 371380, 2005.
284. Kutcher ME, Herman IM. The pericyte: cellular regulator of microvascular blood flow.
262. Kaminski HJ, Andrade FH. Nitric oxide: biologic effects on muscle and role in muscle Microvasc Res 77: 235246, 2009.
diseases. Neuromuscul Disord 11: 517524, 2001.
285. LHonore A, Lamb NJ, Vandromme M, Turowski P, Carnac G, Fernandez A. MyoD
263. Kanisicak O, Mendez JJ, Yamamoto S, Yamamoto M, Goldhamer DJ. Progenitors of distal regulatory region contains an SRF binding CArG element required for MyoD
skeletal muscle satellite cells express the muscle determination gene, MyoD. Dev Biol expression in skeletal myoblasts and during muscle regeneration. Mol Biol Cell 14:
332: 131141, 2009. 21512162, 2003.
264. Kardon G, Campbell JK, Tabin CJ. Local extrinsic signals determine muscle and 286. LHonore A, Rana V, Arsic N, Franckhauser C, Lamb NJ, Fernandez A. Identification
endothelial cell fate and patterning in the vertebrate limb. Dev Cell 3: 533545, of a new hybrid serum response factor and myocyte enhancer factor 2-binding ele-
2002. ment in MyoD enhancer required for MyoD expression during myogenesis. Mol Biol
Cell 18: 19922001, 2007.
265. Kassar-Duchossoy L, Giacone E, Gayraud-Morel B, Jory A, Gomes D, Tajbakhsh S.
Pax3/Pax7 mark a novel population of primitive myogenic cells during development. 287. LaBarge MA, Blau HM. Biological progression from adult bone marrow to mononu-
Genes Dev 19: 1426 1431, 2005. cleate muscle stem cell to multinucleate muscle fiber in response to injury. Cell 111:
589 601, 2002.
266. Kastner S, Elias MC, Rivera AJ, Yablonka-Reuveni Z. Gene expression patterns of the
fibroblast growth factors and their receptors during myogenesis of rat satellite cells. J 288. Langsdorf A, Do AT, Kusche-Gullberg M, Emerson CP Jr, Ai X. Sulfs are regulators of
Histochem Cytochem 48: 1079 1096, 2000. growth factor signaling for satellite cell differentiation and muscle regeneration. Dev
Biol 311: 464 477, 2007.
267. Kazuki Y, Hiratsuka M, Takiguchi M, Osaki M, Kajitani N, Hoshiya H, Hiramatsu K,
Yoshino T, Kazuki K, Ishihara C, Takehara S, Higaki K, Nakagawa M, Takahashi K, 289. Lansdorp PM. Immortal strands? Give me a break. Cell 129: 1244 1247, 2007.
Yamanaka S, Oshimura M. Complete genetic correction of ips cells from Duchenne
muscular dystrophy. Mol Ther 18: 386 393, 2010. 290. Larsen BD, Rampalli S, Burns LE, Brunette S, Dilworth FJ, Megeney LA. Caspase
3/caspase-activated DNase promote cell differentiation by inducing DNA strand
268. Keller P, Penkowa M, Keller C, Steensberg A, Fischer CP, Giralt M, Hidalgo J, Ped- breaks. Proc Natl Acad Sci USA 107: 4230 4235, 2010.
ersen BK. Interleukin-6 receptor expression in contracting human skeletal muscle:
regulating role of IL-6. FASEB J 19: 11811183, 2005. 291. Lassar AB, Davis RL, Wright WE, Kadesch T, Murre C, Voronova A, Baltimore D,
Weintraub H. Functional activity of myogenic HLH proteins requires hetero-oli-
269. Kelly AM. Perisynaptic satellite cells in the developing and mature rat soleus muscle. gomerization with E12/E47-like proteins in vivo. Cell 66: 305315, 1991.
Anat Rec 190: 891903, 1978.
292. Laterza OF, Lim L, Garrett-Engele PW, Vlasakova K, Muniappa N, Tanaka WK, John-
270. Kherif S, Lafuma C, Dehaupas M, Lachkar S, Fournier JG, Verdiere-Sahuque M, son JM, Sina JF, Fare TL, Sistare FD, Glaab WE. Plasma MicroRNAs as sensitive and
Fardeau M, Alameddine HS. Expression of matrix metalloproteinases 2 and 9 in specific biomarkers of tissue injury. Clin Chem 55: 19771983, 2009.
regenerating skeletal muscle: a study in experimentally injured and mdx muscles. Dev
Biol 205: 158 170, 1999. 293. Le Grand F, Jones AE, Seale V, Scime A, Rudnicki MA. Wnt7a activates the planar cell
polarity pathway to drive the symmetric expansion of satellite stem cells. Cell Stem
271. Kim CH, Neiswender H, Baik EJ, Xiong WC, Mei L. Beta-catenin interacts with MyoD Cell 4: 535547, 2009.
and regulates its transcription activity. Mol Cell Biol 28: 29412951, 2008.
294. Lee JY, Qu-Petersen Z, Cao B, Kimura S, Jankowski R, Cummins J, Usas A, Gates C,
272. Kitamoto T, Hanaoka K. Notch3 null mutation in mice causes muscle hyperplasia by Robbins P, Wernig A, Huard J. Clonal isolation of muscle-derived cells capable of
repetitive muscle regeneration. Stem Cells 28: 22052216, 2010. enhancing muscle regeneration and bone healing. J Cell Biol 150: 10851100, 2000.

295. Lefaucheur JP, Gjata B, Lafont H, Sebille A. Angiogenic and inflammatory responses 315. Liu JP, Baker J, Perkins AS, Robertson EJ, Efstratiadis A. Mice carrying null mutations
following skeletal muscle injury are altered by immune neutralization of endogenous of the genes encoding insulin-like growth factor I (Igf-1) and type 1 IGF receptor
basic fibroblast growth factor, insulin-like growth factor-1 and transforming growth (Igf1r). Cell 75: 59 72, 1993.
factor-beta 1. J Neuroimmunol 70: 37 44, 1996.
316. Liu Y, Gao L, Zuba-Surma EK, Peng X, Kucia M, Ratajczak MZ, Wang W, Enzmann V,
296. Lefaucheur JP, Sebille A. Basic fibroblast growth factor promotes in vivo muscle Kaplan HJ, Dean DC. Identification of small Sca-1(), Lin(), and CD45() multipo-
regeneration in murine muscular dystrophy. Neurosci Lett 202: 121124, 1995. tential cells in the neonatal murine retina. Exp Hematol 37: 1096 1107, 2009.
297. Lefaucheur JP, Sebille A. Muscle regeneration following injury can be modified in vivo 317. Loh KC, Leong WI, Carlson ME, Oskouian B, Kumar A, Fyrst H, Zhang M, Proia RL,
by immune neutralization of basic fibroblast growth factor, transforming growth fac- Hoffman EP, Saba JD. Sphingosine-1-phosphate enhances satellite cell activation in
tor beta 1 or insulin-like growth factor I. J Neuroimmunol 57: 8591, 1995. dystrophic muscles through a S1PR2/STAT3 signaling pathway. PLoS One 7: e37218,
2012.
298. Lemercier C, To RQ, Carrasco RA, Konieczny SF. The basic helix-loop-helix tran-
scription factor Mist1 functions as a transcriptional repressor of myoD. EMBO J 17: 318. Lu A, Cummins JH, Pollett JB, Cao B, Sun B, Rudnicki MA, Huard J. Isolation of
14121422, 1998. myogenic progenitor populations from Pax7-deficient skeletal muscle based on ad-
hesion characteristics. Gene Ther 15: 1116 1125, 2008.
299. Lepper C, Conway SJ, Fan CM. Adult satellite cells and embryonic muscle progenitors
have distinct genetic requirements. Nature 460: 627 631, 2009. 319. Lu J, McKinsey TA, Zhang CL, Olson EN. Regulation of skeletal myogenesis by asso-
ciation of the MEF2 transcription factor with class II histone deacetylases. Mol Cell 6:
300. Lepper C, Fan CM. Inducible lineage tracing of Pax7-descendant cells reveals embry- 233244, 2000.
onic origin of adult satellite cells. Genesis 48: 424 436, 2010.
320. Luo D, Renault VM, Rando TA. The regulation of Notch signaling in muscle stem cell

301. Lepper C, Partridge TA, Fan CM. An absolute requirement for Pax7-positive satellite activation and postnatal myogenesis. Semin Cell Dev Biol 16: 612 622, 2005.
cells in acute injury-induced skeletal muscle regeneration. Development 138: 3639
3646, 2011. 321. Luque E, Pena J, Martin P, Jimena I, Vaamonde R. Capillary supply during development
of individual regenerating muscle fibers. Anat Histol Embryol 24: 87 89, 1995.
302. Leri A, Kajstura J, Anversa P, Frishman WH. Myocardial regeneration and stem cell
repair. Curr Probl Cardiol 33: 91153, 2008. 322. Ma DK, Bonaguidi MA, Ming GL, Song H. Adult neural stem cells in the mammalian
central nervous system. Cell Res 19: 672 682, 2009.
303. Lescaudron L, Peltekian E, Fontaine-Perus J, Paulin D, Zampieri M, Garcia L, Parrish
E. Blood borne macrophages are essential for the triggering of muscle regeneration 323. Machida S, Booth FW. Insulin-like growth factor 1 and muscle growth: implication for
following muscle transplant. Neuromuscul Disord 9: 72 80, 1999. satellite cell proliferation. Proc Nutr Soc 63: 337340, 2004.
304. Leshem Y, Gitelman I, Ponzetto C, Halevy O. Preferential binding of Grb2 or phos- 324. Mackey AL, Kjaer M, Charifi N, Henriksson J, Bojsen-Moller J, Holm L, Kadi F. As-
phatidylinositol 3-kinase to the met receptor has opposite effects on HGF-induced sessment of satellite cell number and activity status in human skeletal muscle biopsies.
myoblast proliferation. Exp Cell Res 274: 288 298, 2002. Muscle Nerve 40: 455 465, 2009.
305. Leshem Y, Halevy O. Phosphorylation of pRb is required for HGF-induced muscle cell 325. Mal A, Sturniolo M, Schiltz RL, Ghosh MK, Harter ML. A role for histone deacetylase
proliferation and is p27kip1-dependent. J Cell Physiol 191: 173182, 2002. HDAC1 in modulating the transcriptional activity of MyoD: inhibition of the myogenic
program. EMBO J 20: 1739 1753, 2001.
306. Leshem Y, Spicer DB, Gal-Levi R, Halevy O. Hepatocyte growth factor (HGF) inhibits
skeletal muscle cell differentiation: a role for the bHLH protein twist and the cdk 326. Mansouri A, Stoykova A, Torres M, Gruss P. Dysgenesis of cephalic neural crest
inhibitor p27. J Cell Physiol 184: 101109, 2000. derivatives in Pax7/ mutant mice. Development 122: 831 838, 1996.
307. Lewis MI, Horvitz GD, Clemmons DR, Fournier M. Role of IGF-I and IGF-binding 327. Matheny RW Jr, Nindl BC, Adamo ML. Minireview: Mechano-growth factor: a puta-
proteins within diaphragm muscle in modulating the effects of nandrolone. Am J Physiol tive product of IGF-I gene expression involved in tissue repair and regeneration.
Endocrinol Metab 282: E483E490, 2002. Endocrinology 151: 865 875, 2010.
308. Li L, Heller-Harrison R, Czech M, Olson EN. Cyclic AMP-dependent protein kinase 328. Matsuda R, Nishikawa A, Tanaka H. Visualization of dystrophic muscle fibers in mdx
inhibits the activity of myogenic helix-loop-helix proteins. Mol Cell Biol 12: 4478 mouse by vital staining with Evans blue: evidence of apoptosis in dystrophin-deficient
4485, 1992. muscle. J Biochem 118: 959 964, 1995.
309. Li L, Zhou J, James G, Heller-Harrison R, Czech MP, Olson EN. FGF inactivates 329. Mauro A. Satellite cell of skeletal muscle fibers. J Biophys Biochem Cytol 9: 493 495,
myogenic helix-loop-helix proteins through phosphorylation of a conserved protein 1961.
kinase C site in their DNA-binding domains. Cell 71: 11811194, 1992.
330. Mayer U. Integrins: redundant or important players in skeletal muscle? J Biol Chem
310. Li Y, Foster W, Deasy BM, Chan Y, Prisk V, Tang Y, Cummins J, Huard J. Transforming 278: 1458714590, 2003.
growth factor-beta1 induces the differentiation of myogenic cells into fibrotic cells in
331. McGann CJ, Odelberg SJ, Keating MT. Mammalian myotube dedifferentiation induced
injured skeletal muscle: a key event in muscle fibrogenesis. Am J Pathol 164: 1007 by newt regeneration extract. Proc Natl Acad Sci USA 98: 13699 13704, 2001.
1019, 2004.
332. McGeachie JK, Grounds MD. Initiation and duration of muscle precursor replication
311. Lindstrom M, Pedrosa-Domellof F, Thornell LE. Satellite cell heterogeneity with after mild and severe injury to skeletal muscle of mice. An autoradiographic study. Cell
respect to expression of MyoD, myogenin, Dlk1 and c-Met in human skeletal muscle: Tissue Res 248: 125130, 1987.
application to a cohort of power lifters and sedentary men. Histochem Cell Biol 134:
371385, 2010. 333. McKay BR, De Lisio M, Johnston AP, OReilly CE, Phillips SM, Tarnopolsky MA, Parise
G. Association of interleukin-6 signalling with the muscle stem cell response following
312. Lipton BH, Konigsberg IR. A fine-structural analysis of the fusion of myogenic cells. J muscle-lengthening contractions in humans. PLoS One 4: e6027, 2009.
Cell Biol 53: 348 364, 1972.
334. McLoon LK, Wirtschafter J. Activated satellite cells in extraocular muscles of normal
313. Liu H, Fergusson MM, Castilho RM, Liu J, Cao L, Chen J, Malide D, Rovira II, Schimel adult monkeys and humans. Invest Ophthalmol Vis Sci 44: 19271932, 2003.
D, Kuo CJ, Gutkind JS, Hwang PM, Finkel T. Augmented Wnt signaling in a mammalian
model of accelerated aging. Science 317: 803 806, 2007. 335. Meech R, Gomez M, Woolley C, Barro M, Hulin JA, Walcott EC, Delgado J, Makar-
enkova HP. The homeobox transcription factor Barx2 regulates plasticity of young
314. Liu J, Aoki M, Illa I, Wu C, Fardeau M, Angelini C, Serrano C, Urtizberea JA, Hentati F, primary myofibers. PLoS One 5: e11612, 2010.
Hamida MB, Bohlega S, Culper EJ, Amato AA, Bossie K, Oeltjen J, Bejaoui K, McK-
enna-Yasek D, Hosler BA, Schurr E, Arahata K, de Jong PJ, Brown RH Jr. Dysferlin, a 336. Meech R, Gonzalez KN, Barro M, Gromova A, Zhuang L, Hulin JA, Makarenkova HP.
novel skeletal muscle gene, is mutated in Miyoshi myopathy and limb girdle muscular Barx2 is expressed in satellite cells and is required for normal muscle growth and
dystrophy. Nat Genet 20: 3136, 1998. regeneration. Stem Cells 30: 253265, 2012.

337. Meeson AP, Hawke TJ, Graham S, Jiang N, Elterman J, Hutcheson K, Dimaio JM, 357. Mourkioti F, Rosenthal N. IGF-1, inflammation and stem cells: interactions during
Gallardo TD, Garry DJ. Cellular and molecular regulation of skeletal muscle side muscle regeneration. Trends Immunol 26: 535542, 2005.
population cells. Stem Cells 22: 13051320, 2004.
358. Mousavi K, Jasmin BJ. BDNF is expressed in skeletal muscle satellite cells and inhibits
338. Megeney LA, Kablar B, Garrett K, Anderson JE, Rudnicki MA. MyoD is required for myogenic differentiation. J Neurosci 26: 5739 5749, 2006.
myogenic stem cell function in adult skeletal muscle. Genes Dev 10: 11731183, 1996.
359. Mu X, Peng H, Pan H, Huard J, Li Y. Study of muscle cell dedifferentiation after skeletal
339. Meignin C, Alvarez-Garcia I, Davis I, Palacios IM. The salvador-warts-hippo pathway muscle injury of mice with a Cre-Lox system. PLoS One 6: e16699, 2011.
is required for epithelial proliferation and axis specification in Drosophila. Curr Biol 17:
18711878, 2007. 360. Mulvaney DR, Marple DN, Merkel RA. Proliferation of skeletal muscle satellite cells
after castration and administration of testosterone propionate. Proc Soc Exp Biol Med
340. Menetrey J, Kasemkijwattana C, Day CS, Bosch P, Vogt M, Fu FH, Moreland MS, 188: 40 45, 1988.
Huard J. Growth factors improve muscle healing in vivo. J Bone Joint Surg Br 82:
131137, 2000. 361. Murphy MM, Lawson JA, Mathew SJ, Hutcheson DA, Kardon G. Satellite cells, con-
nective tissue fibroblasts and their interactions are crucial for muscle regeneration.
341. Merly F, Lescaudron L, Rouaud T, Crossin F, Gardahaut MF. Macrophages enhance Development 138: 36253637, 2011.
muscle satellite cell proliferation and delay their differentiation. Muscle Nerve 22:
724 732, 1999. 362. Murre C, McCaw PS, Baltimore D. A new DNA binding and dimerization motif in
immunoglobulin enhancer binding, daughterless, MyoD, and myc proteins. Cell 56:
342. Miller KJ, Thaloor D, Matteson S, Pavlath GK. Hepatocyte growth factor affects 777783, 1989.
satellite cell activation and differentiation in regenerating skeletal muscle. Am J Physiol
Cell Physiol 278: C174 C181, 2000. 363. Murre C, McCaw PS, Vaessin H, Caudy M, Jan LY, Jan YN, Cabrera CV, Buskin JN,

Hauschka SD, Lassar AB. Interactions between heterologous helix-loop-helix pro-
343. Minasi MG, Riminucci M, De Angelis L, Borello U, Berarducci B, Innocenzi A, Caprioli teins generate complexes that bind specifically to a common DNA sequence. Cell 58:
A, Sirabella D, Baiocchi M, De Maria R, Boratto R, Jaffredo T, Broccoli V, Bianco P, 537544, 1989.
Cossu G. The meso-angioblast: a multipotent, self-renewing cell that originates from
the dorsal aorta and differentiates into most mesodermal tissues. Development 129: 364. Musaro A, Barberi L. Isolation and culture of mouse satellite cells. Methods Mol Biol
27732783, 2002. 633: 101111, 2010.
344. Minetti C, Sotgia F, Bruno C, Scartezzini P, Broda P, Bado M, Masetti E, Mazzocco M, 365. Musaro A, McCullagh K, Paul A, Houghton L, Dobrowolny G, Molinaro M, Barton ER,
Egeo A, Donati MA, Volonte D, Galbiati F, Cordone G, Bricarelli FD, Lisanti MP, Zara Sweeney HL, Rosenthal N. Localized Igf-1 transgene expression sustains hypertrophy
F. Mutations in the caveolin-3 gene cause autosomal dominant limb-girdle muscular and regeneration in senescent skeletal muscle. Nat Genet 27: 195200, 2001.
dystrophy. Nat Genet 18: 365368, 1998.
366. Musaro A, McCullagh KJ, Naya FJ, Olson EN, Rosenthal N. IGF-1 induces skeletal
345. Mitchell KJ, Pannerec A, Cadot B, Parlakian A, Besson V, Gomes ER, Marazzi G, myocyte hypertrophy through calcineurin in association with GATA-2 and NF-ATc1.
Sassoon DA. Identification and characterization of a non-satellite cell muscle resident Nature 400: 581585, 1999.
progenitor during postnatal development. Nat Cell Biol 12: 257266, 2010.
367. Musaro A, Rosenthal N. Maturation of the myogenic program is induced by postmi-
346. Mizuno Y, Chang H, Umeda K, Niwa A, Iwasa T, Awaya T, Fukada SI, Yamamoto H, totic expression of insulin-like growth factor I. Mol Cell Biol 19: 31153124, 1999.
Yamanaka S, Nakahata T, Heike T. Generation of skeletal muscle stem/progenitor
cells from murine induced pluripotent stem cells. FASEB J 2010. 368. Muskiewicz KR, Frank NY, Flint AF, Gussoni E. Myogenic potential of muscle side and
main population cells after intravenous injection into sub-lethally irradiated mdx mice.
347. Moelling K, Schad K, Bosse M, Zimmermann S, Schweneker M. Regulation of Raf-Akt J Histochem Cytochem 53: 861 873, 2005.
Cross-talk. J Biol Chem 277: 31099 31106, 2002.
369. Nagata Y, Kobayashi H, Umeda M, Ohta N, Kawashima S, Zammit PS, Matsuda R.
348. Mokalled MH, Johnson AN, Creemers EE, Olson EN. MASTR directs MyoD-depen- Sphingomyelin levels in the plasma membrane correlate with the activation state of
dent satellite cell differentiation during skeletal muscle regeneration. Genes Dev 26: muscle satellite cells. J Histochem Cytochem 54: 375384, 2006.
190 202, 2012.
370. Nagata Y, Partridge TA, Matsuda R, Zammit PS. Entry of muscle satellite cells into the
349. Montarras D, Lindon C, Pinset C, Domeyne P. Cultured myf5 null and myoD null cell cycle requires sphingolipid signaling. J Cell Biol 174: 245253, 2006.
muscle precursor cells display distinct growth defects. Biol Cell 92: 565572, 2000.
371. Nakagawa M, Koyanagi M, Tanabe K, Takahashi K, Ichisaka T, Aoi T, Okita K,
350. Montarras D, Morgan J, Collins C, Relaix F, Zaffran S, Cumano A, Partridge T, Buck- Mochiduki Y, Takizawa N, Yamanaka S. Generation of induced pluripotent stem cells
ingham M. Direct isolation of satellite cells for skeletal muscle regeneration. Science without Myc from mouse and human fibroblasts. Nat Biotechnol 26: 101106, 2008.
309: 2064 2067, 2005.
372. Negroni E, Riederer I, Chaouch S, Belicchi M, Razini P, Di Santo J, Torrente Y,
351. Moresi V, Pristera A, Scicchitano BM, Molinaro M, Teodori L, Sassoon D, Adamo S, Butler-Browne GS, Mouly V. In vivo myogenic potential of human CD133 muscle-
Coletti D. Tumor necrosis factor-alpha inhibition of skeletal muscle regeneration is derived stem cells: a quantitative study. Mol Ther 17: 17711778, 2009.
mediated by a caspase-dependent stem cell response. Stem Cells 26: 9971008, 2008.
373. Nelson WJ, Nusse R. Convergence of Wnt, beta-catenin, and cadherin pathways.
352. Morosetti R, Mirabella M, Gliubizzi C, Broccolini A, De Angelis L, Tagliafico E, Sam- Science 303: 14831487, 2004.
paolesi M, Gidaro T, Papacci M, Roncaglia E, Rutella S, Ferrari S, Tonali PA, Ricci E,
Cossu G. MyoD expression restores defective myogenic differentiation of human 374. Nguyen HT, Frasch M. MicroRNAs in muscle differentiation: lessons from Drosophila
mesoangioblasts from inclusion-body myositis muscle. Proc Natl Acad Sci USA 103: and beyond. Curr Opin Genet Dev 16: 533539, 2006.
1699517000, 2006.
375. Nguyen HX, Tidball JG. Interactions between neutrophils and macrophages promote
353. Morrison JI, Loof S, He P, Simon A. Salamander limb regeneration involves the acti- macrophage killing of rat muscle cells in vitro. J Physiol 547: 125132, 2003.
vation of a multipotent skeletal muscle satellite cell population. J Cell Biol 172: 433
440, 2006. 376. Nicolas N, Marazzi G, Kelley K, Sassoon D. Embryonic deregulation of muscle stress
signaling pathways leads to altered postnatal stem cell behavior and a failure in post-
354. Morrison SJ, Kimble J. Asymmetric and symmetric stem-cell divisions in development natal muscle growth. Dev Biol 281: 171183, 2005.
and cancer. Nature 441: 1068 1074, 2006.
377. Nishimura T, Nakamura K, Kishioka Y, Kato-Mori Y, Wakamatsu J, Hattori A. Inhibi-
355. Moss FP, Leblond CP. Nature of dividing nuclei in skeletal muscle of growing rats. J tion of matrix metalloproteinases suppresses the migration of skeletal muscle cells. J
Cell Biol 44: 459 462, 1970. Muscle Res Cell Motil 29: 37 44, 2008.
356. Mourikis P, Sambasivan R, Castel D, Rocheteau P, Bizzarro V, Tajbakhsh S. A critical 378. Novitch BG, Mulligan GJ, Jacks T, Lassar AB. Skeletal muscle cells lacking the retino-
requirement for notch signaling in maintenance of the quiescent skeletal muscle stem blastoma protein display defects in muscle gene expression and accumulate in S and
cell state. Stem Cells 30: 243252, 2012. G2 phases of the cell cycle. J Cell Biol 135: 441 456, 1996.

379. Odelberg SJ, Kollhoff A, Keating MT. Dedifferentiation of mammalian myotubes in- 401. Pasquinelli G, Pacilli A, Alviano F, Foroni L, Ricci F, Valente S, Orrico C, Lanzoni G,
duced by msx1. Cell 103: 1099 1109, 2000. Buzzi M, Luigi Tazzari P, Pagliaro P, Stella A, Paolo Bagnara G. Multidistrict human
mesenchymal vascular cells: pluripotency and stemness characteristics. Cytotherapy
380. Ohlstein B, Kai T, Decotto E, Spradling A. The stem cell niche: theme and variations. 12: 275287, 2010.
Curr Opin Cell Biol 16: 693 699, 2004.
402. Patruno M, Caliaro F, Martinello T, Mascarello F. Expression of the paired box domain
381. Ohnishi T, Daikuhara Y. Hepatocyte growth factor/scatter factor in development, Pax7 protein in myogenic cells isolated from the porcine semitendinosus muscle after
inflammation and carcinogenesis: its expression and role in oral tissues. Arch Oral Biol birth. Tissue Cell 40: 1 6, 2008.
48: 797 804, 2003.
403. Pedersen BK, Febbraio MA. Muscle as an endocrine organ: focus on muscle-derived
382. Ojima K, Uezumi A, Miyoshi H, Masuda S, Morita Y, Fukase A, Hattori A, Nakauchi H,
interleukin-6. Physiol Rev 88: 1379 1406, 2008.
Miyagoe-Suzuki Y, Takeda S. Mac-1(low) early myeloid cells in the bone marrow-
derived SP fraction migrate into injured skeletal muscle and participate in muscle 404. Peng H, Huard J. Muscle-derived stem cells for musculoskeletal tissue regeneration
regeneration. Biochem Biophys Res Commun 321: 1050 1061, 2004. and repair. Transpl Immunol 12: 311319, 2004.
383. Okada S, Nonaka I, Chou SM. Muscle fiber type differentiation and satellite cell 405. Penn BH, Bergstrom DA, Dilworth FJ, Bengal E, Tapscott SJ. A MyoD-generated
populations in normally grown and neonatally denervated muscles in the rat. Acta feed-forward circuit temporally patterns gene expression during skeletal muscle dif-
Neuropathol 65: 90 98, 1984. ferentiation. Genes Dev 18: 2348 2353, 2004.
384. Okita K, Ichisaka T, Yamanaka S. Generation of germline-competent induced pluri- 406. Peppiatt CM, Howarth C, Mobbs P, Attwell D. Bidirectional control of CNS capillary
potent stem cells. Nature 448: 313317, 2007. diameter by pericytes. Nature 443: 700 704, 2006.

385. Olguin HC, Yang Z, Tapscott SJ, Olwin BB. Reciprocal inhibition between Pax7 and 407. Perez-Ruiz A, Ono Y, Gnocchi VF, Zammit PS. beta-Catenin promotes self-renewal
muscle regulatory factors modulates myogenic cell fate determination. J Cell Biol 177: of skeletal-muscle satellite cells. J Cell Sci 121: 13731382, 2008.
769 779, 2007.
408. Petropoulos H, Skerjanc IS. Beta-catenin is essential and sufficient for skeletal myo-
386. Olwin BB, Rapraeger A. Repression of myogenic differentiation by aFGF, bFGF, and genesis in P19 cells. J Biol Chem 277: 1539315399, 2002.
K-FGF is dependent on cellular heparan sulfate. J Cell Biol 118: 631 639, 1992.
409. Philippou A, Halapas A, Maridaki M, Koutsilieris M. Type I insulin-like growth factor
387. Ono Y, Boldrin L, Knopp P, Morgan JE, Zammit PS. Muscle satellite cells are a
receptor signaling in skeletal muscle regeneration and hypertrophy. J Musculoskelet
functionally heterogeneous population in both somite-derived and branchiomeric
Neuronal Interact 7: 208 218, 2007.
muscles. Dev Biol 337: 29 41, 2010.
410. Phillips WD, Bennett MR. Elimination of distributed synaptic acetylcholine receptor
388. Ono Y, Masuda S, Nam HS, Benezra R, Miyagoe-Suzuki Y, Takeda S. Slow-dividing
clusters on developing avian fast-twitch muscle fibres accompanies loss of polyneu-
satellite cells retain long-term self-renewal ability in adult muscle. J Cell Sci 125:
ronal innervation. J Neurocytol 16: 785797, 1987.
1309 1317, 2012.
411. Pietsch J. The effects of colchicine on regeneration of mouse skeletal muscle. Anat Rec
389. Orimo S, Hiyamuta E, Arahata K, Sugita H. Analysis of inflammatory cells and com-
167172, 1961.
plement C3 in bupivacaine-induced myonecrosis. Muscle Nerve 14: 515520, 1991.
412. Polesello C, Tapon N. Salvador-warts-hippo signaling promotes Drosophila posterior
390. Ornatsky OI, Cox DM, Tangirala P, Andreucci JJ, Quinn ZA, Wrana JL, Prywes R, Yu
follicle cell maturation downstream of notch. Curr Biol 17: 1864 1870, 2007.
YT, McDermott JC. Post-translational control of the MEF2A transcriptional regula-
tory protein. Nucleic Acids Res 27: 2646 2654, 1999. 413. Polesskaya A, Seale P, Rudnicki MA. Wnt signaling induces the myogenic specification
of resident CD45 adult stem cells during muscle regeneration. Cell 113: 841 852,
391. Otto A, Schmidt C, Luke G, Allen S, Valasek P, Muntoni F, Lawrence-Watt D, Patel K.
2003.
Canonical Wnt signalling induces satellite-cell proliferation during adult skeletal mus-
cle regeneration. J Cell Sci 121: 2939 2950, 2008. 414. Popescu LM, Manole E, Serboiu CS, Manole CG, Suciu LC, Gherghiceanu M, Popescu
BO. Identification of telocytes in skeletal muscle interstitium: implication for muscle
392. Otto A, Schmidt C, Patel K. Pax3 and Pax7 expression and regulation in the avian
embryo. Anat Embryol 211: 293310, 2006. regeneration. J Cell Mol Med 15: 1379 1392, 2011.
393. Oustanina S, Hause G, Braun T. Pax7 directs postnatal renewal and propagation of 415. Pouget C, Pottin K, Jaffredo T. Sclerotomal origin of vascular smooth muscle cells and
myogenic satellite cells but not their specification. EMBO J 23: 3430 3439, 2004. pericytes in the embryo. Dev Biol 315: 437 447, 2008.
394. Pacher P, Beckman JS, Liaudet L. Nitric oxide and peroxynitrite in health and disease. 416. Prior BM, Lloyd PG, Yang HT, Terjung RL. Exercise-induced vascular remodeling.
Physiol Rev 87: 315 424, 2007. Exerc Sport Sci Rev 31: 26 33, 2003.
395. Pajcini KV, Corbel SY, Sage J, Pomerantz JH, Blau HM. Transient inactivation of Rb and 417. Prockop DJ. Marrow stromal cells as stem cells for nonhematopoietic tissues. Science
ARF yields regenerative cells from postmitotic mammalian muscle. Cell Stem Cell 7: 276: 7174, 1997.
198 213, 2010.
418. Przybylski RJ, Blumberg JM. Ultrastructural aspects of myogenesis in the chick. Lab
396. Palacio J, Galdiz JB, Alvarez FJ, Orozco-Levi M, Lloreta J, Gea J. Procion orange tracer Invest 15: 836 863, 1966.
dye technique vs. identification of intrafibrillar fibronectin in the assessment of sar-
419. Puri PL, Avantaggiati ML, Balsano C, Sang N, Graessmann A, Giordano A, Levrero M.
colemmal damage. Eur J Clin Invest 32: 443 447, 2002.
p300 is required for MyoD-dependent cell cycle arrest and muscle-specific gene
397. Paliwal P, Conboy IM. Inhibitors of tyrosine phosphatases and apoptosis reprogram transcription. EMBO J 16: 369 383, 1997.
lineage-marked differentiated muscle to myogenic progenitor cells. Chem Biol 18:
420. Puri PL, Sartorelli V. Regulation of muscle regulatory factors by DNA-binding, inter-
11531166, 2011.
acting proteins, and post-transcriptional modifications. J Cell Physiol 185: 155173,
398. Pallafacchina G, Francois S, Regnault B, Czarny B, Dive V, Cumano A, Montarras D, 2000.
Buckingham M. An adult tissue-specific stem cell in its niche: a gene profiling analysis
of in vivo quiescent and activated muscle satellite cells. Stem Cell Res 4: 7791, 2010. 421. Qu-Petersen Z, Deasy B, Jankowski R, Ikezawa M, Cummins J, Pruchnic R, Myt-
inger J, Cao B, Gates C, Wernig A, Huard J. Identification of a novel population of
399. Palumbo R, Sampaolesi M, De Marchis F, Tonlorenzi R, Colombetti S, Mondino A, muscle stem cells in mice: potential for muscle regeneration. J Cell Biol 157: 851 864,
Cossu G, Bianchi ME. Extracellular HMGB1, a signal of tissue damage, induces me- 2002.
soangioblast migration and proliferation. J Cell Biol 164: 441 449, 2004.
422. Qu Z, Balkir L, van Deutekom JC, Robbins PD, Pruchnic R, Huard J. Development of
400. Parise G, McKinnell IW, Rudnicki MA. Muscle satellite cell and atypical myogenic approaches to improve cell survival in myoblast transfer therapy. J Cell Biol 142:
progenitor response following exercise. Muscle Nerve 37: 611 619, 2008. 12571267, 1998.

423. Quinlan JG, Lyden SP, Cambier DM, Johnson SR, Michaels SE, Denman DL. Radiation 445. Rosen GD, Sanes JR, LaChance R, Cunningham JM, Roman J, Dean DC. Roles for the
inhibition of mdx mouse muscle regeneration: dose and age factors. Muscle Nerve 18: integrin VLA-4 and its counter receptor VCAM-1 in myogenesis. Cell 69: 11071119,
201206, 1995. 1992.
424. Rampalli S, Li L, Mak E, Ge K, Brand M, Tapscott SJ, Dilworth FJ. p38 MAPK signaling 446. Rosenblatt JD, Lunt AI, Parry DJ, Partridge TA. Culturing satellite cells from living
regulates recruitment of Ash2L-containing methyltransferase complexes to specific single muscle fiber explants. In Vitro Cell Dev Biol Anim 31: 773779, 1995.
genes during differentiation. Nat Struct Mol Biol 14: 1150 1156, 2007.
447. Rosu-Myles M, Stewart E, Trowbridge J, Ito CY, Zandstra P, Bhatia M. A unique
425. Rando TA, Blau HM. Primary mouse myoblast purification, characterization, and population of bone marrow cells migrates to skeletal muscle via hepatocyte growth
transplantation for cell-mediated gene therapy. J Cell Biol 125: 12751287, 1994. factor/c-met axis. J Cell Sci 118: 4343 4352, 2005.
426. Rantanen J, Hurme T, Lukka R, Heino J, Kalimo H. Satellite cell proliferation and the 448. Ruberti F, Capsoni S, Comparini A, Di Daniel E, Franzot J, Gonfloni S, Rossi G, Berardi
expression of myogenin and desmin in regenerating skeletal muscle: evidence for two N, Cattaneo A. Phenotypic knockout of nerve growth factor in adult transgenic mice
different populations of satellite cells. Lab Invest 72: 341347, 1995. reveals severe deficits in basal forebrain cholinergic neurons, cell death in the spleen,
and skeletal muscle dystrophy. J Neurosci 20: 2589 2601, 2000.
427. Rapraeger AC. Syndecan-regulated receptor signaling. J Cell Biol 149: 995998, 2000.
449. Rubinstein I, Abassi Z, Coleman R, Milman F, Winaver J, Better OS. Involvement of
428. Rash JE, Fambrough D. Ultrastructural and electrophysiological correlates of cell
nitric oxide system in experimental muscle crush injury. J Clin Invest 101: 13251333,
coupling and cytoplasmic fusion during myogenesis in vitro. Dev Biol 30: 166 186,
1998.
1973.
450. Rudnicki MA, Le Grand F, McKinnell I, Kuang S. The molecular regulation of muscle
429. Ratajczak MZ, Majka M, Kucia M, Drukala J, Pietrzkowski Z, Peiper S, Janowska-

stem cell function. Cold Spring Harb Symp Quant Biol 73: 323331, 2008.
Wieczorek A. Expression of functional CXCR4 by muscle satellite cells and secretion
of SDF-1 by muscle-derived fibroblasts is associated with the presence of both muscle 451. Ryan NA, Zwetsloot KA, Westerkamp LM, Hickner RC, Pofahl WE, Gavin TP. Lower
progenitors in bone marrow and hematopoietic stem/progenitor cells in muscles. skeletal muscle capillarization and VEGF expression in aged vs. young men. J Appl
Stem Cells 21: 363371, 2003. Physiol 100: 178 185, 2006.
430. Rawlings JS, Rosler KM, Harrison DA. The JAK/STAT signaling pathway. J Cell Sci 117: 452. Sabourin LA, Girgis-Gabardo A, Seale P, Asakura A, Rudnicki MA. Reduced differen-
12811283, 2004. tiation potential of primary MyoD/ myogenic cells derived from adult skeletal
muscle. J Cell Biol 144: 631 643, 1999.
431. Relaix F, Montarras D, Zaffran S, Gayraud-Morel B, Rocancourt D, Tajbakhsh S,
Mansouri A, Cumano A, Buckingham M. Pax3 and Pax7 have distinct and overlapping 453. Sabourin LA, Rudnicki MA. The molecular regulation of myogenesis. Clin Genet 57:
functions in adult muscle progenitor cells. J Cell Biol 172: 91102, 2006. 16 25, 2000.
432. Relaix F, Polimeni M, Rocancourt D, Ponzetto C, Schafer BW, Buckingham M. The 454. Sacco A, Doyonnas R, Kraft P, Vitorovic S, Blau HM. Self-renewal and expansion of
transcriptional activator PAX3-FKHR rescues the defects of Pax3 mutant mice but single transplanted muscle stem cells. Nature 456: 502506, 2008.
induces a myogenic gain-of-function phenotype with ligand-independent activation of
Met signaling in vivo. Genes Dev 17: 2950 2965, 2003. 455. Sakurai H, Okawa Y, Inami Y, Nishio N, Isobe K. Paraxial mesodermal progenitors
derived from mouse embryonic stem cells contribute to muscle regeneration via
433. Relaix F, Rocancourt D, Mansouri A, Buckingham M. Divergent functions of murine
differentiation into muscle satellite cells. Stem Cells 26: 18651873, 2008.
Pax3 and Pax7 in limb muscle development. Genes Dev 18: 1088 1105, 2004.
456. Sambasivan R, Gayraud-Morel B, Dumas G, Cimper C, Paisant S, Kelly RG, Tajbakhsh
434. Relaix F, Rocancourt D, Mansouri A, Buckingham M. A Pax3/Pax7-dependent popu-
S. Distinct regulatory cascades govern extraocular and pharyngeal arch muscle pro-
lation of skeletal muscle progenitor cells. Nature 435: 948 953, 2005.
genitor cell fates. Dev Cell 16: 810 821, 2009.
435. Relaix F, Weng X, Marazzi G, Yang E, Copeland N, Jenkins N, Spence SE, Sassoon D.
457. Sambasivan R, Yao R, Kissenpfennig A, Van Wittenberghe L, Paldi A, Gayraud-Morel
Pw1, a novel zinc finger gene implicated in the myogenic and neuronal lineages. Dev
B, Guenou H, Malissen B, Tajbakhsh S, Galy A. Pax7-expressing satellite cells are
Biol 177: 383396, 1996.
indispensable for adult skeletal muscle regeneration. Development 138: 36473656,
436. Ren H, Yin P, Duan C. IGFBP-5 regulates muscle cell differentiation by binding to 2011.
IGF-II and switching on the IGF-II auto-regulation loop. J Cell Biol 182: 979 991, 2008.
458. Sampaolesi M, Torrente Y, Innocenzi A, Tonlorenzi R, DAntona G, Pellegrino MA,
437. Reznik M. Thymidine-3H uptake by satellite cells of regenerating skeletal muscle. J Cell Barresi R, Bresolin N, De Angelis MG, Campbell KP, Bottinelli R, Cossu G. Cell
Biol 40: 568 571, 1969. therapy of alpha-sarcoglycan null dystrophic mice through intra-arterial delivery of
mesoangioblasts. Science 301: 487 492, 2003.
438. Riuzzi F, Sorci G, Sagheddu R, Donato R. HMGB1-RAGE regulates muscle satellite cell
homeostasis through p38-MAPK- and myogenin-dependent repression of Pax7 tran- 459. Sanes JR. The basement membrane/basal lamina of skeletal muscle. J Biol Chem 278:
scription. J Cell Sci 125: 1440 1454, 2012. 1260112604, 2003.
439. Rivier F, Alkan O, Flint AF, Muskiewicz K, Allen PD, Leboulch P, Gussoni E. Role of 460. Santa Maria L, Rojas CV, Minguell JJ. Signals from damaged but not undamaged skeletal
bone marrow cell trafficking in replenishing skeletal muscle SP and MP cell popula- muscle induce myogenic differentiation of rat bone-marrow-derived mesenchymal
tions. J Cell Sci 117: 1979 1988, 2004. stem cells. Exp Cell Res 300: 418 426, 2004.
440. Robertson TA, Maley MA, Grounds MD, Papadimitriou JM. The role of macrophages 461. Sassoli C, Formigli L, Bini F, Tani A, Squecco R, Battistini C, Zecchi-Orlandini S,
in skeletal muscle regeneration with particular reference to chemotaxis. Exp Cell Res Francini F, Meacci E. Effects of S1P on skeletal muscle repair/regeneration during
207: 321331, 1993. eccentric contraction. J Cell Mol Med 15: 2498 2511, 2011.
441. Rodeheffer MS, Birsoy K, Friedman JM. Identification of white adipocyte progenitor 462. Scaal M, Christ B. Formation and differentiation of the avian dermomyotome. Anat
cells in vivo. Cell 135: 240 249, 2008. Embryol 208: 411 424, 2004.
442. Rodrigues Ade C, Schmalbruch H. Satellite cells and myonuclei in long-term dener- 463. Scata KA, Bernard DW, Fox J, Swain JL. FGF receptor availability regulates skeletal
vated rat muscles. Anat Rec 243: 430 437, 1995. myogenesis. Exp Cell Res 250: 10 21, 1999.
443. Rosania GR, Chang YT, Perez O, Sutherlin D, Dong H, Lockhart DJ, Schultz PG. 464. Schienda J, Engleka KA, Jun S, Hansen MS, Epstein JA, Tabin CJ, Kunkel LM, Kardon G.
Myoseverin, a microtubule-binding molecule with novel cellular effects. Nature Bio- Somitic origin of limb muscle satellite and side population cells. Proc Natl Acad Sci USA
technol 18: 304 308, 2000. 103: 945950, 2006.
444. Rosant C, Nagel MD, Perot C. Aging affects passive stiffness and spindle function of 465. Schmalbruch H. The morphology of regeneration of skeletal muscles in the rat. Tissue
the rat soleus muscle. Exp Gerontol 42: 301308, 2007. Cell 8: 673 692, 1976.

466. Schmalbruch H, Hellhammer U. The number of nuclei in adult rat muscles with special 489. Shinin V, Gayraud-Morel B, Gomes D, Tajbakhsh S. Asymmetric division and coseg-
reference to satellite cells. Anat Rec 189: 169 175, 1977. regation of template DNA strands in adult muscle satellite cells. Nat Cell Biol 8:
677 687, 2006.
467. Schmalbruch H, Lewis DM. Dynamics of nuclei of muscle fibers and connective tissue
cells in normal and denervated rat muscles. Muscle Nerve 23: 617 626, 2000. 490. Siegel AL, Atchison K, Fisher KE, Davis GE, Cornelison DD. 3D timelapse analysis of
muscle satellite cell motility. Stem Cells 27: 25272538, 2009.
468. Schultz E. Changes in the satellite cells of growing muscle following denervation. Anat
Rec 190: 299 311, 1978. 491. Simone C, Forcales SV, Hill DA, Imbalzano AN, Latella L, Puri PL. p38 pathway targets
SWI-SNF chromatin-remodeling complex to muscle-specific loci. Nat Genet 36: 738
469. Schultz E. A quantitative study of the satellite cell population in postnatal mouse 743, 2004.
lumbrical muscle. Anat Rec 180: 589 595, 1974.
492. Simons M, Mlodzik M. Planar cell polarity signaling: from fly development to human
470. Schultz E. Satellite cell behavior during skeletal muscle growth and regeneration. Med disease. Annu Rev Genet 42: 517540, 2008.
Sci Sports Exerc 21: S181186, 1989.
493. Sinha-Hikim I, Artaza J, Woodhouse L, Gonzalez-Cadavid N, Singh AB, Lee MI, Storer
471. Schultz E. Satellite cell proliferative compartments in growing skeletal muscles. Dev TW, Casaburi R, Shen R, Bhasin S. Testosterone-induced increase in muscle size in
Biol 175: 84 94, 1996. healthy young men is associated with muscle fiber hypertrophy. Am J Physiol Endocrinol
Metab 283: E154 E164, 2002.
472. Schultz E, Gibson MC, Champion T. Satellite cells are mitotically quiescent in mature
mouse muscle: an EM and radioautographic study. J Exp Zool 206: 451 456, 1978. 494. Sinha-Hikim I, Cornford M, Gaytan H, Lee ML, Bhasin S. Effects of testosterone
supplementation on skeletal muscle fiber hypertrophy and satellite cells in communi-
473. Schultz E, Jaryszak DL, Valliere CR. Response of satellite cells to focal skeletal muscle
ty-dwelling older men. J Clin Endocrinol Metab 91: 3024 3033, 2006.

injury. Muscle Nerve 8: 217222, 1985.
495. Sinha-Hikim I, Roth SM, Lee MI, Bhasin S. Testosterone-induced muscle hypertrophy
474. Schwander M, Leu M, Stumm M, Dorchies OM, Ruegg UT, Schittny J, Muller U. Beta1 is associated with an increase in satellite cell number in healthy, young men. Am J
integrins regulate myoblast fusion and sarcomere assembly. Dev Cell 4: 673 685, Physiol Endocrinol Metab 285: E197E205, 2003.
2003.
496. Sinha-Hikim I, Taylor WE, Gonzalez-Cadavid NF, Zheng W, Bhasin S. Androgen
475. Sciorati C, Galvez BG, Brunelli S, Tagliafico E, Ferrari S, Cossu G, Clementi E. Ex vivo receptor in human skeletal muscle and cultured muscle satellite cells: up-regulation by
treatment with nitric oxide increases mesoangioblast therapeutic efficacy in muscular androgen treatment. J Clin Endocrinol Metab 89: 52455255, 2004.
dystrophy. J Cell Sci 119: 5114 5123, 2006.
497. Smith CK 2nd, Janney MJ, Allen RE. Temporal expression of myogenic regulatory
476. Seale P, Ishibashi J, Holterman C, Rudnicki MA. Muscle satellite cell-specific genes genes during activation, proliferation, differentiation of rat skeletal muscle satellite
identified by genetic profiling of MyoD-deficient myogenic cell. Dev Biol 275: 287300, cells. J Cell Physiol 159: 379 385, 1994.
2004.
498. Snow MH. An autoradiographic study of satellite cell differentiation into regenerating
477. Seale P, Ishibashi J, Scime A, Rudnicki MA. Pax7 is necessary and sufficient for the myotubes following transplantation of muscles in young rats. Cell Tissue Res 186:
myogenic specification of CD45:Sca1 stem cells from injured muscle. PLoS Biol 2: 535540, 1978.
E130, 2004.
499. Snow MH. Myogenic cell formation in regenerating rat skeletal muscle injured by
478. Seale P, Sabourin LA, Girgis-Gabardo A, Mansouri A, Gruss P, Rudnicki MA. Pax7 mincing. II. An autoradiographic study. Anat Rec 188: 201217, 1977.
is required for the specification of myogenic satellite cells. Cell 102: 777786,
2000. 500. Snow MH. A quantitative ultrastructural analysis of satellite cells in denervated fast and
slow muscles of the mouse. Anat Rec 207: 593 604, 1983.
479. Semsarian C, Wu MJ, Ju YK, Marciniec T, Yeoh T, Allen DG, Harvey RP, Graham RM.
Skeletal muscle hypertrophy is mediated by a Ca2-dependent calcineurin signalling 501. Song WK, Wang W, Foster RF, Bielser DA, Kaufman SJ. H36-alpha 7 is a novel integrin
pathway. Nature 400: 576 581, 1999. alpha chain that is developmentally regulated during skeletal myogenesis. J Cell Biol
117: 643 657, 1992.
480. Serrano AL, Baeza-Raja B, Perdiguero E, Jardi M, Munoz-Canoves P. Interleukin-6 is
an essential regulator of satellite cell-mediated skeletal muscle hypertrophy. Cell 502. Song YH, Li Y, Du J, Mitch WE, Rosenthal N, Delafontaine P. Muscle-specific expres-
Metab 7: 33 44, 2008. sion of IGF-1 blocks angiotensin II-induced skeletal muscle wasting. J Clin Invest 115:
451 458, 2005.
481. Shafiq SA, Gorycki MA, Mauro A. Mitosis during postnatal growth in skeletal and
cardiac muscle of the rat. J Anat 103: 135141, 1968. 503. Sonnet C, Lafuste P, Arnold L, Brigitte M, Poron F, Authier FJ, Chretien F, Gherardi
RK, Chazaud B. Human macrophages rescue myoblasts and myotubes from apoptosis
482. Shea KL, Xiang W, LaPorta VS, Licht JD, Keller C, Basson MA, Brack AS. Sprouty1 through a set of adhesion molecular systems. J Cell Sci 119: 24972507, 2006.
regulates reversible quiescence of a self-renewing adult muscle stem cell pool during
regeneration. Cell Stem Cell 6: 117129, 2010. 504. Spicer DB, Rhee J, Cheung WL, Lassar AB. Inhibition of myogenic bHLH and MEF2
transcription factors by the bHLH protein Twist. Science 272: 1476 1480, 1996.
483. Sheehan SM, Allen RE. Skeletal muscle satellite cell proliferation in response to mem-
bers of the fibroblast growth factor family and hepatocyte growth factor. J Cell Physiol 505. Stamler JS, Meissner G. Physiology of nitric oxide in skeletal muscle. Physiol Rev 81:
181: 499 506, 1999. 209 237, 2001.
484. Sheehan SM, Tatsumi R, Temm-Grove CJ, Allen RE. HGF is an autocrine growth 506. Stark DA, Karvas RM, Siegel AL, Cornelison DD. Eph/ephrin interactions modulate
factor for skeletal muscle satellite cells in vitro. Muscle Nerve 23: 239 245, 2000. muscle satellite cell motility and patterning. Development 138: 5279 5289, 2011.
485. Shefer G, Wleklinski-Lee M, Yablonka-Reuveni Z. Skeletal muscle satellite cells can 507. Starkey JD, Yamamoto M, Yamamoto S, Goldhamer DJ. Skeletal muscle satellite cells
spontaneously enter an alternative mesenchymal pathway. J Cell Sci 117: 53935404, are committed to myogenesis and do not spontaneously adopt nonmyogenic fates. J
2004. Histochem Cytochem 59: 33 46, 2011.
486. Sherwood RI, Christensen JL, Conboy IM, Conboy MJ, Rando TA, Weissman IL, 508. Steinhardt RA, Bi G, Alderton JM. Cell membrane resealing by a vesicular mechanism
Wagers AJ. Isolation of adult mouse myogenic progenitors: functional heterogeneity similar to neurotransmitter release. Science 263: 390 393, 1994.
of cells within and engrafting skeletal muscle. Cell 119: 543554, 2004.
509. Summer R, Fitzsimmons K, Dwyer D, Murphy J, Fine A. Isolation of an adult mouse
487. Sherwood RI, Christensen JL, Weissman IL, Wagers AJ. Determinants of skeletal lung mesenchymal progenitor cell population. Am J Respir Cell Mol Biol 37: 152159,
muscle contributions from circulating cells, bone marrow cells, and hematopoietic 2007.
stem cells. Stem Cells 22: 12921304, 2004.
510. Sun D, Martinez CO, Ochoa O, Ruiz-Willhite L, Bonilla JR, Centonze VE, Waite LL,
488. Shi D, Reinecke H, Murry CE, Torok-Storb B. Myogenic fusion of human bone mar- Michalek JE, McManus LM, Shireman PK. Bone marrow-derived cell regulation of
row stromal cells, but not hematopoietic cells. Blood 104: 290 294, 2004. skeletal muscle regeneration. FASEB J 23: 382395, 2009.

511. Sun H, Li L, Vercherat C, Gulbagci NT, Acharjee S, Li J, Chung TK, Thin TH, Taneja R. 532. Tidball JG, Villalta SA. Regulatory interactions between muscle and the immune sys-
Stra13 regulates satellite cell activation by antagonizing Notch signaling. J Cell Biol 177: tem during muscle regeneration. Am J Physiol Regul Integr Comp Physiol 2010.
647 657, 2007.
533. Tomiya A, Aizawa T, Nagatomi R, Sensui H, Kokubun S. Myofibers express IL-6 after
512. Suzuki J, Yamazaki Y, Li G, Kaziro Y, Koide H. Involvement of Ras and Ral in chemot- eccentric exercise. Am J Sports Med 32: 503508, 2004.
actic migration of skeletal myoblasts. Mol Cell Biol 20: 4658 4665, 2000.
534. Torrente Y, Belicchi M, Marchesi C, Dantona G, Cogiamanian F, Pisati F, Gavina M,
513. Suzuki S, Yamanouchi K, Soeta C, Katakai Y, Harada R, Naito K, Tojo H. Skeletal Giordano R, Tonlorenzi R, Fagiolari G, Lamperti C, Porretti L, Lopa R, Sampaolesi M,
muscle injury induces hepatocyte growth factor expression in spleen. Biochem Biophys Vicentini L, Grimoldi N, Tiberio F, Songa V, Baratta P, Prelle A, Forzenigo L, Guglieri
Res Commun 292: 709 714, 2002. M, Pansarasa O, Rinaldi C, Mouly V, Butler-Browne GS, Comi GP, Biondetti P,
Moggio M, Gaini SM, Stocchetti N, Priori A, DAngelo MG, Turconi A, Bottinelli R,
514. Takahashi A, Kureishi Y, Yang J, Luo Z, Guo K, Mukhopadhyay D, Ivashchenko Y,
Cossu G, Rebulla P, Bresolin N. Autologous transplantation of muscle-derived
Branellec D, Walsh K. Myogenic Akt signaling regulates blood vessel recruitment
CD133 stem cells in Duchenne muscle patients. Cell Transplant 16: 563577, 2007.
during myofiber growth. Mol Cell Biol 22: 4803 4814, 2002.
535. Torrente Y, Belicchi M, Sampaolesi M, Pisati F, Meregalli M, DAntona G, Tonlorenzi
515. Takahashi K, Tanabe K, Ohnuki M, Narita M, Ichisaka T, Tomoda K, Yamanaka S.
R, Porretti L, Gavina M, Mamchaoui K, Pellegrino MA, Furling D, Mouly V, Butler-
Induction of pluripotent stem cells from adult human fibroblasts by defined factors.
Browne GS, Bottinelli R, Cossu G, Bresolin N. Human circulating AC133() stem
Cell 131: 861 872, 2007.
cells restore dystrophin expression and ameliorate function in dystrophic skeletal
516. Takahashi K, Yamanaka S. Induction of pluripotent stem cells from mouse embryonic muscle. J Clin Invest 114: 182195, 2004.
and adult fibroblast cultures by defined factors. Cell 126: 663 676, 2006.
536. Torrente Y, Tremblay JP, Pisati F, Belicchi M, Rossi B, Sironi M, Fortunato F, El Fahime

517. Tamaki T, Akatsuka A, Yoshimura S, Roy RR, Edgerton VR. New fiber formation in the M, DAngelo MG, Caron NJ, Constantin G, Paulin D, Scarlato G, Bresolin N. Intra-
interstitial spaces of rat skeletal muscle during postnatal growth. J Histochem Cy- arterial injection of muscle-derived CD34()Sca-1() stem cells restores dystrophin
tochem 50: 10971111, 2002. in mdx mice. J Cell Biol 152: 335348, 2001.
518. Tanaka KK, Hall JK, Troy AA, Cornelison DD, Majka SM, Olwin BB. Syndecan-4- 537. Toti P, Villanova M, Vatti R, Schuerfeld K, Stumpo M, Barbagli L, Malandrini A, Costan-
expressing muscle progenitor cells in the SP engraft as satellite cells during muscle tini M. Nerve growth factor expression in human dystrophic muscles. Muscle Nerve
regeneration. Cell Stem Cell 4: 217225, 2009. 27: 370 373, 2003.
519. Tang W, Zeve D, Suh JM, Bosnakovski D, Kyba M, Hammer RE, Tallquist MD, Graff 538. Tsujinaka T, Ebisui C, Fujita J, Kishibuchi M, Morimoto T, Ogawa A, Katsume A,
JM. White fat progenitor cells reside in the adipose vasculature. Science 322: 583586, Ohsugi Y, Kominami E, Monden M. Muscle undergoes atrophy in association with
2008. increase of lysosomal cathepsin activity in interleukin-6 transgenic mouse. Biochem
Biophys Res Commun 207: 168 174, 1995.
520. Tatsumi R, Allen RE. Active hepatocyte growth factor is present in skeletal muscle
extracellular matrix. Muscle Nerve 30: 654 658, 2004. 539. Tureckova J, Wilson EM, Cappalonga JL, Rotwein P. Insulin-like growth factor-medi-
ated muscle differentiation: collaboration between phosphatidylinositol 3-kinase-Akt-
521. Tatsumi R, Anderson JE, Nevoret CJ, Halevy O, Allen RE. HGF/SF is present in normal signaling pathways and myogenin. J Biol Chem 276: 39264 39270, 2001.
adult skeletal muscle and is capable of activating satellite cells. Dev Biol 194: 114 128,
1998. 540. Tzahor E. Heart and craniofacial muscle development: a new developmental theme of
distinct myogenic fields. Dev Biol 327: 273279, 2009.
522. Tatsumi R, Hattori A, Ikeuchi Y, Anderson JE, Allen RE. Release of hepatocyte growth
factor from mechanically stretched skeletal muscle satellite cells and role of pH and 541. Uezumi A, Fukada S, Yamamoto N, Takeda S, Tsuchida K. Mesenchymal progenitors
nitric oxide. Mol Biol Cell 13: 2909 2918, 2002. distinct from satellite cells contribute to ectopic fat cell formation in skeletal muscle.
Nat Cell Biol 12: 143152, 2010.
523. Tatsumi R, Liu X, Pulido A, Morales M, Sakata T, Dial S, Hattori A, Ikeuchi Y, Allen RE.
Satellite cell activation in stretched skeletal muscle and the role of nitric oxide and 542. Ustanina S, Carvajal J, Rigby P, Braun T. The myogenic factor Myf5 supports efficient
hepatocyte growth factor. Am J Physiol Cell Physiol 290: C1487C1494, 2006. skeletal muscle regeneration by enabling transient myoblast amplification. Stem Cells
25: 2006 2016, 2007.
524. Tatsumi R, Sankoda Y, Anderson JE, Sato Y, Mizunoya W, Shimizu N, Suzuki T,
Yamada M, Rhoads RP Jr, Ikeuchi Y, Allen RE. Possible implication of satellite cells in 543. Valadi H, Ekstrom K, Bossios A, Sjostrand M, Lee JJ, Lotvall JO. Exosome-mediated
regenerative motoneuritogenesis: HGF upregulates neural chemorepellent Sema3A transfer of mRNAs and microRNAs is a novel mechanism of genetic exchange be-
during myogenic differentiation. Am J Physiol Cell Physiol 297: C238 C252, 2009. tween cells. Nature Cell Biol 9: 654 659, 2007.
525. Tatsumi R, Sheehan SM, Iwasaki H, Hattori A, Allen RE. Mechanical stretch induces 544. Van den Beld AW, de Jong FH, Grobbee DE, Pols HA, Lamberts SW. Measures of
activation of skeletal muscle satellite cells in vitro. Exp Cell Res 267: 107114, 2001.
bioavailable serum testosterone and estradiol and their relationships with muscle
526. Taulli R, Bersani F, Foglizzo V, Linari A, Vigna E, Ladanyi M, Tuschl T, Ponzetto C. The strength, bone density, and body composition in elderly men. J Clin Endocrinol Metab
muscle-specific microRNA miR-206 blocks human rhabdomyosarcoma growth in 85: 3276 3282, 2000.
xenotransplanted mice by promoting myogenic differentiation. J Clin Invest 119:
545. Van Rooij E, Quiat D, Johnson BA, Sutherland LB, Qi X, Richardson JA, Kelm RJ Jr,
2366 2378, 2009.
Olson EN. A family of microRNAs encoded by myosin genes governs myosin expres-
527. Taylor-Jones JM, McGehee RE, Rando TA, Lecka-Czernik B, Lipschitz DA, Peterson sion and muscle performance. Dev Cell 17: 662 673, 2009.
CA. Activation of an adipogenic program in adult myoblasts with age. Mech Ageing Dev
546. Van Rooij E, Sutherland LB, Qi X, Richardson JA, Hill J, Olson EN. Control of stress-
123: 649 661, 2002.
dependent cardiac growth and gene expression by a microRNA. Science 316: 575
528. Theise ND. Gastrointestinal stem cells. III. Emergent themes of liver stem cell biology: 579, 2007.
niche, quiescence, self-renewal, and plasticity. Am J Physiol Gastrointest Liver Physiol
547. Vandenburgh HH, Karlisch P, Shansky J, Feldstein R. Insulin and IGF-I induce pro-
290: G189 G193, 2006.
nounced hypertrophy of skeletal myofibers in tissue culture. Am J Physiol Cell Physiol
529. Thompson SH, Boxhorn LK, Kong WY, Allen RE. Trenbolone alters the responsive- 260: C475C484, 1991.
ness of skeletal muscle satellite cells to fibroblast growth factor and insulin-like growth
factor I. Endocrinology 124: 2110 2117, 1989. 548. Velleman SG, Li X, Coy CS, McFarland DC. The effect of fibroblast growth factor 2 on
the in vitro expression of syndecan-4 and glypican-1 in turkey satellite cells. Poult Sci
530. Tidball JG. Inflammatory cell response to acute muscle injury. Med Sci Sports Exerc 27: 87: 1834 1840, 2008.
10221032, 1995.
549. Vertino AM, Taylor-Jones JM, Longo KA, Bearden ED, Lane TF, McGehee RE Jr,
531. Tidball JG, Daniel TL. Myotendinous junctions of tonic muscle cells: structure and MacDougald OA, Peterson CA. Wnt10b deficiency promotes coexpression of myo-
loading. Cell Tissue Res 245: 315322, 1986. genic and adipogenic programs in myoblasts. Mol Biol Cell 16: 2039 2048, 2005.

550. Viguie CA, Lu DX, Huang SK, Rengen H, Carlson BM. Quantitative study of the effects 572. Yablonka-Reuveni Z, Rivera AJ. Temporal expression of regulatory and structural
of long-term denervation on the extensor digitorum longus muscle of the rat. Anat Rec muscle proteins during myogenesis of satellite cells on isolated adult rat fibers. Dev Biol
248: 346 354, 1997. 164: 588 603, 1994.
551. Villena J, Brandan E. Dermatan sulfate exerts an enhanced growth factor response on 573. Yablonka-Reuveni Z, Rudnicki MA, Rivera AJ, Primig M, Anderson JE, Natanson P. The
skeletal muscle satellite cell proliferation and migration. J Cell Physiol 198: 169 178, transition from proliferation to differentiation is delayed in satellite cells from mice
2004. lacking MyoD. Dev Biol 210: 440 455, 1999.
552. Volonte D, Liu Y, Galbiati F. The modulation of caveolin-1 expression controls satel- 574. Yaffe D. Cellular aspects of muscle differentiation in vitro. Curr Top Dev Biol 4: 3777,
lite cell activation during muscle repair. FASEB J 19: 237239, 2005. 1969.
553. Wakelam MJ. The fusion of myoblasts. Biochem J 228: 112, 1985. 575. Yamada M, Sankoda Y, Tatsumi R, Mizunoya W, Ikeuchi Y, Sunagawa K, Allen RE.
554. Walker BE. An investigation of skeletal muscle regeneration with radioautography. Matrix metalloproteinase-2 mediates stretch-induced activation of skeletal muscle
Anat Rec 350, 1960. satellite cells in a nitric oxide-dependent manner. Int J Biochem Cell Biol 40: 2183
2191, 2008.
555. Walsh K. Coordinate regulation of cell cycle and apoptosis during myogenesis. Prog
Cell Cycle Res 3: 5358, 1997. 576. Yamada M, Tatsumi R, Kikuiri T, Okamoto S, Nonoshita S, Mizunoya W, Ikeuchi Y,
Shimokawa H, Sunagawa K, Allen RE. Matrix metalloproteinases are involved in me-
556. Warren GL, Hulderman T, Jensen N, McKinstry M, Mishra M, Luster MI, Simeonova chanical stretch-induced activation of skeletal muscle satellite cells. Muscle Nerve 34:
PP. Physiological role of tumor necrosis factor alpha in traumatic muscle injury. FASEB 313319, 2006.
J 16: 1630 1632, 2002.

577. Yan D, Dong Xda E, Chen X, Wang L, Lu C, Wang J, Qu J, Tu L. MicroRNA-1/206
557. Watt DJ, Morgan JE, Clifford MA, Partridge TA. The movement of muscle precursor targets c-Met and inhibits rhabdomyosarcoma development. J Biol Chem 284: 29596
cells between adjacent regenerating muscles in the mouse. Anat Embryol 175: 527 29604, 2009.
536, 1987.
578. Yang SY, Goldspink G. Different roles of the IGF-I Ec peptide (MGF) and mature IGF-I
558. Wehrman TS, von Degenfeld G, Krutzik PO, Nolan GP, Blau HM. Luminescent in myoblast proliferation and differentiation. FEBS Lett 522: 156 160, 2002.
imaging of beta-galactosidase activity in living subjects using sequential reporter-en-
zyme luminescence. Nat Methods 3: 295301, 2006. 579. Yeow K, Phillips B, Dani C, Cabane C, Amri EZ, Derijard B. Inhibition of myogenesis
enables adipogenic trans-differentiation in the C2C12 myogenic cell line. FEBS Lett
559. Weinberg RA. The retinoblastoma protein and cell cycle control. Cell 81: 323330,
506: 157162, 2001.
1995.
580. Yildiz O. Vascular smooth muscle and endothelial functions in aging. Ann NY Acad Sci
560. Wen Y, Bi P, Liu W, Asakura A, Keller C, Kuang S. Constitutive notch activation
1100: 353360, 2007.
upregulates pax7 and promotes the self-renewal of skeletal muscle satellite cells. Mol
Cell Biol 32: 2300 2311, 2012. 581. Yoshimoto M, Chang H, Shiota M, Kobayashi H, Umeda K, Kawakami A, Heike T,
561. Weyman CM, Wolfman A. Mitogen-activated protein kinase kinase (MEK) activity is Nakahata T. Two different roles of purified CD45c-KitSca-1Lin cells after
required for inhibition of skeletal muscle differentiation by insulin-like growth factor 1 transplantation in muscles. Stem Cells 23: 610 618, 2005.
or fibroblast growth factor 2. Endocrinology 139: 1794 1800, 1998.
582. Yu J, Vodyanik MA, Smuga-Otto K, Antosiewicz-Bourget J, Frane JL, Tian S, Nie J,
562. Whalen RG, Harris JB, Butler-Browne GS, Sesodia S. Expression of myosin isoforms Jonsdottir GA, Ruotti V, Stewart R, Slukvin II, Thomson JA. Induced pluripotent
during notexin-induced regeneration of rat soleus muscles. Dev Biol 141: 2440, 1990. stem cell lines derived from human somatic cells. Science 318: 19171920, 2007.
563. Wheeler EF, Bothwell M. Spatiotemporal patterns of expression of NGF and the 583. Yu Y, Ge N, Xie M, Sun W, Burlingame S, Pass AK, Nuchtern JG, Zhang D, Fu S,
low-affinity NGF receptor in rat embryos suggest functional roles in tissue morpho- Schneider MD, Fan J, Yang J. Phosphorylation of Thr-178 and Thr-184 in the TAK1
genesis and myogenesis. J Neurosci 12: 930 945, 1992. T-loop is required for interleukin (IL)-1-mediated optimal NFkappaB and AP-1
activation as well as IL-6 gene expression. J Biol Chem 283: 2449724505, 2008.
564. White JD, Scaffidi A, Davies M, McGeachie J, Rudnicki MA, Grounds MD. Myotube
formation is delayed but not prevented in MyoD-deficient skeletal muscle: studies in 584. Zammit PS, Golding JP, Nagata Y, Hudon V, Partridge TA, Beauchamp JR. Muscle
regenerating whole muscle grafts of adult mice. J Histochem Cytochem 48: 15311544, 2000. satellite cells adopt divergent fates: a mechanism for self-renewal? J Cell Biol 166:
347357, 2004.
565. Williams AH, Liu N, van Rooij E, Olson EN. MicroRNA control of muscle develop-
ment and disease. Curr Opin Cell Biol 21: 461 469, 2009. 585. Zammit PS, Heslop L, Hudon V, Rosenblatt JD, Tajbakhsh S, Buckingham ME, Beau-
champ JR, Partridge TA. Kinetics of myoblast proliferation show that resident satellite
566. Wilson A, Trumpp A. Bone-marrow haematopoietic-stem-cell niches. Nat Rev Immu-
cells are competent to fully regenerate skeletal muscle fibers. Exp Cell Res 281: 39
nol 6: 93106, 2006.
49, 2002.
567. Wokke JH, Van den Oord CJ, Leppink GJ, Jennekens FG. Perisynaptic satellite cells in
586. Zarnegar R, Michalopoulos GK. The many faces of hepatocyte growth factor: from
human external intercostal muscle: a quantitative and qualitative study. Anat Rec 223:
hepatopoiesis to hematopoiesis. J Cell Biol 129: 11771180, 1995.
174 180, 1989.
568. Woodley DT, Rao CN, Hassell JR, Liotta LA, Martin GR, Kleinman HK. Interactions of 587. Zhang JM, Wei Q, Zhao X, Paterson BM. Coupling of the cell cycle and myogenesis
basement membrane components. Biochim Biophys Acta 761: 278 283, 1983. through the cyclin D1-dependent interaction of MyoD with cdk4. EMBO J 18: 926
933, 1999.
569. Wozniak AC, Anderson JE. Nitric oxide-dependence of satellite stem cell activation
and quiescence on normal skeletal muscle fibers. Dev Dyn 236: 240 250, 2007. 588. Zhang P, Wong C, Liu D, Finegold M, Harper JW, Elledge SJ. p21(CIP1) and p57(KIP2)
control muscle differentiation at the myogenin step. Genes Dev 13: 213224, 1999.
570. Wu Z, Luby-Phelps K, Bugde A, Molyneux LA, Denard B, Li WH, Suel GM, Garbers
DL. Capacity for stochastic self-renewal and differentiation in mammalian spermato- 589. Zhao M, New L, Kravchenko VV, Kato Y, Gram H, di Padova F, Olson EN, Ulevitch RJ,
gonial stem cells. J Cell Biol 187: 513524, 2009. Han J. Regulation of the MEF2 family of transcription factors by p38. Mol Cell Biol 19:
2130, 1999.
571. Wu Z, Woodring PJ, Bhakta KS, Tamura K, Wen F, Feramisco JR, Karin M, Wang JY,
Puri PL. p38 and extracellular signal-regulated kinases regulate the myogenic program 590. Zhong W, Chia W. Neurogenesis and asymmetric cell division. Curr Opin Neurobiol 18:
at multiple steps. Mol Cell Biol 20: 39513964, 2000. 4 11, 2008.

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Physiol Rev 93: 23 67, 2013

SATELLITE CELLS AND THE MUSCLE STEM CELL

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B Satellite Stem Cell

Symmetric division Asymmetric division

Symmetric division Symmetric division

Satellite Myogenic Cell

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Signaling within the Immediate Niche

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Signaling within the Local Milieu

Signaling within the Systemic Milieu

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