Aging Changes in Satellite Cells and Their Functions

Current Aging Science, 2011, 4, 279-297 279
1874-6098/11 $58.00+.00 2011 Bentham Science Publishers

Aging Changes in Satellite Cells and Their Functions
Robert S. Hikida*
Ohio Musculoskeletal and Neurological Institute (OMNI), Department of Biomedical Sciences, Ohio University, College
of Osteopathic Medicine Athens, OH 45701, USA
Abstract: Vertebrate skeletal muscle fibers have two traits that make them unique: the fibers are multinucleated and their
nuclei are post-mitotic. The activity and mass of the muscles in the body make them susceptible to constant injury. When
this occurs, myonuclei can be increased or replaced by the adult stem cells of muscle, satellite cells (SCs). These SCs are
vital for normal growth, repair and regeneration. This review collates recent studies to determine the size of the nuclear
domains and its change with activity. The relationship between the percent change in myonuclear number, cross-sectional
area, and myonuclear domain indicates that the nucleus generally maintains a highly regulated domain size in spite of
large variations in fiber size. The SC divides to add nuclei for growth and repair, and the SC identification and number are
discussed. It is concluded that SC number does not reflect a change in regenerative ability by the muscle. However, the
SC number increases with changes in muscular activity, and any reduced number of satellite cells in the elderly does not
appear to reflect a decline in reparative or regenerative ability. The effects of aging on SC function are reviewed, and the
significance of the SCs connective tissue environment is emphasized as being a major factor in the decrement of the SCs
ability to repair and regenerate the aging muscle. Therefore growth factors and cytokines in the connective tissue around
the SC are major influences in the decline of SC function with age.
Keywords: Myonuclear domains, hypertrophy, atrophy, satellite cell niche, matrix metalloproteases.
INTRODUCTION
Mature vertebrate nerve and striated muscle cells are
post-mitotic. For muscle, this poses a significant problem
because of major or minor injury caused by some types of
movement and other trauma; as the tissue making up most of
the mass of the body, it is also exposed to mechanical dam-
age. This review will deal with the ramifications of the post-
mitotic condition on the adult skeletal muscle. Skeletal mus-
cle cells (fibers) are not only post-mitotic, but are large syn-
cytia. Each muscle fiber consists of many hundreds or thou-
sands of cells that have fused and lost the compartmentaliz-
ing cell membranes. During development, as the precursor
cells (myoblasts) become committed, they undergo their last
(quantal) mitosis, and the nucleus gets withdrawn from the
cell cycle, becoming post-mitotic [1]. Once the cell contain-
ing this nucleus is in this stage, it can fuse with other cells to
become a multinucleated myotube, and then a mature fiber.
As development continues, more cells fuse, and each cell
contributes a nucleus (myonucleus) to this enlarging syn-
cytium. Some cells do not fuse, but remain closely associ-
ated with the myotube without being incorporated into it.
These become the muscle satellite cells. Maturation of the
syncytial myotube occurs when the nuclei move to a periph-
eral subsarcolemmal position to become a mature muscle
fiber. These two cell types, the muscle fibers and the satellite
cells, form the basis for the muscle fiber maintenance and
growth and repair. The post-mitotic nature of the myonuclei
mandates that any damage or condition that requires myonu-
clei to be added or replaced must come from the satellite or
other stem cell population from bone marrow precursors [2-

*Address correspondence to this author at the Ohio Musculoskeletal and
Neurological Institute (OMNI), Department of Biomedical Sciences Ohio
University College of Osteopathic Medicine, Athens, OH 45701, USA;
Tel: 740) 593-2323; Fax: (740) 593-2400; E-mail: hikida@ohio.edu
4]. This review will discuss the effect of the post-mitotic
multinucleated condition on muscle fiber maintenance and
the changes with age. Throughout this review, studies of
both human and non-human muscle will be discussed. Gen-
erally, human studies will be emphasized, but the use of
animal models/studies will be noted.
NUCLEAR POPULATIONS IN MUSCLE
Myonuclei account for 50-67% of the nuclear population
of muscle [5-7], but the percentage is variable in different
muscles. The nuclear composition of mammalian (rat) mus-
cles was analyzed in several studies [5-7] using the soleus
and other muscles. Some studies included satellite cells with
myonuclei [7] while others [5,6,8] separated them out; some
of the interstitial nuclei were identified in one study [6]. In
order to compare these data, Table 1 lists the muscle nuclei
as the percentage of total nuclei in the muscle. Where satel-
lite cells were identified, the estimates are listed in parenthe-
ses; the remainder consists primarily of connective tissue
(interstitial) and vascular tissue nuclei. The muscles are
listed by age of the rats.
Myonuclear numbers in cross-sectional profiles of human
muscles at different ages have been reported [9] based on 24
muscle biopsies divided into four age groups. The number of
myonuclei per fiber was 0.9 in infants (1-2.5 years), then
remained constant in the young (12-30 years), and middle
aged (32-55) at 2.2 per fiber, and then increased to 2.5 per
fiber in the elderly (60-71). The fiber diameters for all
groups but the infant were similar. The mean fiber diameters
for all but the infants were similar. This increase in myonu-
clear population in the elderly muscles is also reflected in
summary studies of human muscles, as will be discussed
later.
280 Current Aging Science, 2011, Vol. 4, No. 3 Robert S. Hikida
Table 1. Myonuclear Percentage in Rat Muscles (Satellite Cell
Percentages in Parentheses)
Age Soleus Extensor Digitorum
longus
Reference
1 mo. 44.7 (9.6) 49.5 (7) [8]
6 w 59.6 58 [7]
2 mo. 56 (7.9) [6,7]
3 mo. 56 57 [5,7]
12 mo. 36.8 (6.6) 49.9 (2.9) [8]
24 mo. 41.5 (4.7) 50.3 (1.9) [8]

The addition of nuclei to growing multinucleated muscle
fibers occurs in two stages. In the first stage, the nuclei occur
in excess in the rapidly growing muscle fibers. At this time,
there are so many myonuclei that extensive cellular growth
can continue even in the absence of satellite cell proliferation
and incorporation of new nuclei [10]. In later stages of
growth, the muscle fibers are stable and nuclei must be
added from the satellite cell pool for the muscle fiber cyto-
plasm to increase.
Numbers of myonuclei and satellite cells in rodent mus-
cles are difficult to summarize because the counts are made
using different types of preparations: the isolated whole fiber
segment and the cross-sectional profiles of groups of muscle
fibers (studies using these two methods are listed in Table 2).
In the former, most investigators use number of myonuclei
per mm of fiber. Significant aspects of this method are that
the isolation method may remove part or all of the basal lam-
ina (affecting the satellite cells); it is difficult to fiber type;
the fiber may contract, affecting number of nuclei per unit
length; sample sizes are relatively small. The other presenta-
tion of results is from cross-sectional slices (usually 5-12m
thick). Because many serial sections of the same fibers can
be used to assay different properties, much information
about the same fiber can be obtained. Sample area for any
single fiber is very small, but many fibers can be used. Fiber
types, myonuclear profiles and satellite cells can be counted.
The state of contraction is unknown. Nuclei are counted as
number per cross-sectional area. Animal models use either
method, but human studies generally analyze muscle sec-
tions. The myonuclear domain from fiber segments can often
be estimated in terms of cross sectional-area by dividing by
100 (assuming a 10m thick section).
SATELLITE CELLS
The satellite cell (SC) was first described 50 years ago by
Mauro [11] as a cell lying in a depression closely associated
with the skeletal muscle fibers surface, and oriented be-
tween the muscle cell membrane and the fibers basal lam-
ina. That original paper, about a page long, described the cell
and its probable origin and function, and this same descrip-
tion continues to be valid today. One function Mauro [11]
did not mention was that the SC contributes nuclei to normal
growth of the muscle fiber [see 3, 12 for recent reviews].
Identification of satellite cells in muscle fibers is a difficult
process. The gold standard for identification is by electron
microscopy (Fig. 1), since satellite cells were defined as cells
with very little cytoplasm that were situated between the
muscle fibers sarcolemma and its basal lamina [11]. The
problems with using the electron microscope for studies of
satellite cell distribution are: 1) the mass of the tissue being
studied is limited by the preparative techniques so only very
small (usually less than 1X2 mm) samples can be studied; 2)
the small sample for study is further limited by the specimen
support (specimen grid) which usually shows only a small
fraction of the slice of tissue; 3) it is a laborious technique.
Because of these problems, immunohistochemical markers
for SCs have been developed to distinguish between the two
populations of muscle nuclei.
The use of light microscopy allows relatively large sam-
ples to be studied, but the location of the satellite cell at the
muscle fiber surface makes it difficult to distinguish between
it and the myonucleus, which also occupies a peripheral lo-
cation in the skeletal muscle fiber. A problem with the study
of satellite cells by light microscopy is that identification
other than by electron microscopy is not yet well established.
To deal with this, several antibodies have been used to verify
the identification of the satellite cell. The two most common
antibodies are against cell adhesion molecules, Neural Cell
Adhesion Molecule (NCAM) and M-cadherin (m-cad),
which reside on the cell surface of myogenic cells. The
method used to label the satellite cells with antibodies to the
adhesion molecules is usually accompanied by an antibody
against the basal lamina (laminin). The combination is used
to establish that the cell showing the label for the adhesion
molecule occupies the position between the basal lamina and
the muscle fiber surface.
The cell surface protein, m-cad, has been studied by
Wernig et al. [13] after their group first described it a decade
earlier [14]. The Wernig study [13] systematically and tedi-
ously analyzed the mouse tibialis anterior fibers using m-cad
to peroxidase label the cells in whole isolated muscle fibers.
The fibers were embedded, serially sectioned for electron
microscopy, and sections were examined for nuclei each
10m. If present, thin sections were made and analyzed by
electron microscopy to identify myonuclei or SCs. If it was a
satellite cell, unstained sections were examined for presence
of peroxidase label; no unlabeled satellite cells were ob-
served out of 50 satellite cells examined. This study con-
cluded that mouse (and human and rat) muscle fibers contain
quiescent and proliferative satellite cells that are labeled with
m-cad.
This unambiguous identification was complicated by an
analysis performed by Dedkov et al. [15] who compared
NCAM and m-cad staining of control and denervated young
and old rat muscles (Table 3). Both antibodies stained satel-
lite cells, but m-cad stained four times more cells than
NCAM in control muscles, and 1.5 to 2 times more satellite
cells in denervated muscles. Their study also showed that
satellite cell activation was not reduced with aging. NCAM
is a popular antibody marker to identify satellite cells, but it
does not appear to label all of the SCs.
The distribution of satellite cells labeled with m-cad,
NCAM and several other antibodies related to division and
proliferation was analyzed in young (8 week-old) overloaded
Aging Changes in Satellite Cells and Their Functions Current Aging Science, 2011, Vol. 4, No. 3 281
Table 2. Percent Changes in Muscles (Rat Soleus Unless Indicated) after Alterations in Activity
Age Protocol Fiber
Type
XSA % Change Myo-Nuclei % Change Domain (in m
3)
%
Change
Refer-
ences
ATROPHY
3 month HLS -- 2076 -17% 162/mm -56% 13049 -46 [119]
I# 2100 -41.5 165/mm -17 12600 +16 -- SF
II 1950 +10 135/mm -18 14500 +7
[67]
6 month 2977 -62 2.2/fiber profile -36 1400* -41
20 month 2990 -53 2.0/fiber profile -7.5 1500* -46
32 month
HLS --
2184 -58 2.25/fiber profile -2 1050* -57
[120]
I# 2300 -23 1723* -10 210g SF
II 2360 -10 2016* -3
[69]
I# 4671 -55 154/mm +20 33000 -33 4 month
HLS
II 4270 -55 145/mm +16 29000 -45
[121]
I 2967 +2 98/mm +11 30000 -10 Plant-4
month
HLS
II# 4423 -30 76/mm +29 65000 -20
[121]
HYPERTROPHY (FUNCTIONAL OVERLOAD)
I 900 +94 80/mm +68 150000 0
IIA 1000 +48 54/mm +67 185000 -27
180g Plant
FO
IIX# 1300 +40 60/mm +66 225000 -18

[122]
250g FO -- 2000 +10 150/mm +23 13800 -7 [123]
Mouse
Plant 3
week
335 -29 440/mm -20 4200* -5
4 month

Dener

--
900 -15 1000/mm 0 15000* -57
[35]
#predominant fiber type; * Myonuclear domain expressed as cross-sectional area(m
2
); Plant: plantaris; SF: spaceflight; HLS: hindlimb suspension; FO: functional overload; Den-
erv: denervation

Fig. (1). Satellilte cell obtained from a human soleus muscle. The
arrow indicates the basal lamina that is continuous with that of the
muscle fiber. Notice the gap between the satellite cell and muscle
fiber.
Table 3. Percentage of fibers expressing either NCAM or m-
cad in Rat Tibialis Anterior Satellite Cells [15]
Label Control Denervated (2 Months)
m-cad 5.6 16.2
Young
NCAM 1.4 7.5
m-cad 2.3 15.9
Old
NCAM 0.5 10.1

rat plantaris muscles by Ishido et al. [16]. Co-expression of
NCAM and m-cad was examined in the SCs of contralateral
control muscles. Most of the SCs labeled (84-90%) co-
expressed the two markers, but the remaining 10-16% ex-
pressed only one, with more expressing the NCAM alone.
Important observations in this study were that no indication
of proliferation was noted in any satellite cells of control
muscles compared to overloaded muscles. These control
muscles also had SCs that were labeled with both NCAM
and m-cad. The SCs had different combinations of cell sur-
face antigens expressed at different durations of overload.
This study and that of Dedkov [15] show that different stages
of activity of SCs result in transitory changes in expression
of cell surface antigens, and in these cases m-cad may not
label all SCs. These studies demonstrate that neither of these
markers identifies all the SCs when used alone, and SC acti-
vation increases the percentage of cells expressing just one
of these. Thus, different cell surface proteins are expressed
during different stages of activation and different species
may have different isoforms of the cell surface proteins that
are reflected in variation in antibody binding.
Grounds [4] discussed advantages and disadvantages of
satellite cell markers. The m-cad antibody is a reliable
marker for the satellite cells [3,12,14], but NCAM is used by
many laboratories. However, the distribution of label using
m-cad and NCAM do not agree between different studies, as
discussed above. Irintchev et al. [14] used denervated, nor-
mal or regenerating mature mouse soleus muscles, and con-
cluded that m-cad labeled quiescent, activated, or replicating
satellite cells. In contrast, they showed that NCAM labeled
only SCs from denervated muscle fibers, and did not label
most satellite cells of normal muscle fibers. Grounds [4] had
similar results with mice and rats. The discrepancy between
the results by Irintchev [14] and Ishido [16] is difficult to
explain. Both of these careful and systematic studies com-
pared expression at different stages of overload, denervation,
or regeneration. Different animals (rat and mice), muscles
(plantaris and soleus), ages (8 week rats and mature mice)
and sources of antibodies were used. The use of NCAM has
been extensive in this decade, and it is possible that the
mouse model may show some peculiarities in SC and/or
myonuclear properties [see 17].
Not only is the identification of SCs a source of variabil-
ity, but their further quantification also requires improve-
ment. In order to address this, Sajko et al. [18] used stere-
ological methods to quantify SCs and myonuclear percent-
ages and numbers per mm by using thick cryosections and
confocal microscopy from large samples of human autopsy
samples. This technique for quantifying SC content in skele-
tal muscle fibers is unbiased and reliable. The data for
myonuclear numbers and percent SCs were comparable to
other rodent and human studies, respectively, but this
method must be used more routinely to be useful for compar-
ing SCs from subjects of different ages and activities. A later
study [19] discussed the possible problems and variables that
would influence this method. It is not clear whether this
method distinguishes interstitial cell nuclei from SC or
myonuclei.
A recent paper [20] analyzed human muscle biopsies
using antibodies for myosin (for fiber type identification),
NCAM, Ki67 (identifying proliferating cells), and Pax 7 for
satellite cell identification. Serial sections were analyzed to
determine the distance that immunofluorescent activity ex-
tended from the cell. Active satellite cells were defined as
those cells expressing both NCAM and Ki67. Several inter-
esting points established in that study were that satellite cells
were seen in two adjacent sections (covering 14 m), but
NCAM activity was expressed for about 40m. Type 1 fibers
had 2.09 myonuclei per fiber, and 0.08 SC/fibers per cross
section. Type II fibers, had 2.58 myonuclei and 0.06 SC per
cross-sectional profile [20]. By contrast, myonuclei are gen-
erally considered to be more numerous in type I fibers than
type II fibers (Tables 4 & 5 and [21]).
The percentage of satellite cells (in relation to myonu-
clei) change during development, and especially during early
development. Satellite cell (myogenic precursor cell) per-
centages in the rat lumbrical muscles analyzed by electron
microscopy were reported as 62% at Embryonic Day-17, to
17% at birth, to 10% at 7 days, and 3% at 3 months [5].
Schmalbruch and Lewis [7] estimated 19% satellite cells in
the 6 week old rat, and 2-4.5% (EDL, soleus) in the 20 week
old rat, this latter value agreeing with that of Wigmore et al.
[5].
The SC content in the mouse soleus was compared at
different ages and between control and mdx (muscular dys-
trophic) mice [22]. The frequency and number of SCs were
highly variable between individuals, even within the same
age groups. The number of SCs was very similar in muscles
from either side of the animal in both mdx and wild-type
animals. It would be interesting to determine whether such
variability occurs in other rodent and human muscles.
Satellite cells are stimulated by activity or injury from a
quiescent to a proliferative state. In so doing, the SC under-
goes mitoses to increase its population. Some of these SCs
become incorporated as myonuclei while others revert to the
quiescent state. These occurrences are common at the muscle
fiber surface. Most exercise studies, irrespective of the type
of exercise, cause the SC number to increase due to prolif-
erative activity. This increase in SC numbers occurs at least
within two days, and remains elevated through 8 days [23].
Unfortunately, the presentation of SC numbers as percent of
muscle nuclei (myonuclei plus SC nuclei) assumes that
myonuclei are relatively stable, which is clearly not the case
(Tables 4 & 6). Because myonuclear numbers may also be
changing, characterization of satellite cell percentages are
not as useful as numbers of SCs per muscle fiber.
Human Muscles
This section will begin with the myonuclei and satellite
cells in muscles from young versus old human subjects and
then explore the changes that occur with various protocols to
alter the fiber size. The summary of the characteristics of
untrained human muscle fibers is given in Table 7. The
means of the groups indicate that aging causes an atrophy of
muscle fibers (reduced cross-sectional area), more myonu-
clei, and reduced population of satellite cells. The values for
myonuclear domains (MNDs) conflict between the different
sets of data. Estimation of myonuclei per cross-sectional area
(XSA) indicates that the young have larger domains than the
elderly, but the estimated MNDs show either similar values
or slightly larger domains for the elderly (Table 4). The dif-
ferences may relate to different fiber type composition (more
type I fibers in the elderly) and the tendency to enhance type
II fiber size by activity in the young (see below). Type I fi-
bers may increase in percentage in elderly muscles [24], and
type I fibers have smaller domain sizes than type II fibers
[21]. The larger domain size of the elderly muscles (that pre-
sumably have more type I fibers), contradicts this paradigm.
This suggests that the domain size is not as well regulated in
Table 4. Control Human Muscles
Muscle/sex XSA Myon/Fiber SC/F % SC Cytopl/Myon Reference
YOUNG HUMAN MUSCLES
Vastus lateralis female 4000 2.5 0.091 4.0 1750
Vastus lateralis male 4600 2.45 0.11 4.3 1800
[40]
Vastus lateralis male, type I 5589 3.0 0.07 2.4 1849
Vastus lateralis male, type II 6126 2.3 0.08 2.9 2549
[124]

Vastus lateralis male 6300 2.56 0.07 2.86 -- [23]
Vastus lateralis male 4891 1.17 0.22 1.92 3731 [125]
Tibialis anterior male 2.57 0.19 6.9 --
Tibialis anterior female 2.25 0.17 7.1
[114]

Vastus lateralis male 4300 2.8 0.14 -- 1500 [126]
Vastus lateralis male 5971 2.01 0.10 5.0 -- [127]
Vastus lateralis male, type I 4010
Vastus lateralis male, type II 3649
4.07 0.024 2.02 [19]
Trapezius male, type I 4165 2.8 4
Trapezius male, type II 4633 3.8
[128]
Vastus lateralis, male type I 6431
Vastus lateralis, male type II 6257
2.56 .07 2.86

[130]
Trapezius Female 2958 2.1 3.7 1408 [129]
MEANS 4925 (15) 2.60 (15) 0.111 (12) 3.84 (12) 2084 (7)
ELDERLY HUMAN MUSCLES
Vastus lateralis female 3200 2.3 0.11 4.6 1450
Vastus lateralis male 4800 2.6 0.12 4.4 1800
[40]

Vastus lateralis male, type I 6012
Vastus lateralis male, type IIA 4966
3.3 0.09 2.4 [131]
Vastus lateralis male Type I 5804
Vastus lateralis, male Type II 4714
2.34 0.07 2.81 2321 [130]
Tibialis anterior male 3.16 0.12 3.9
Tibialis anterior female 2.79 0.13 4.4
[114]

Vastus lateralis male 3602 0.97 3920 [132]
Vastus lateralis male 5559 2.51 0.11 4.43
Vastus lateralis female 3486 1.86 0.11 5.75
[133]

Vastus lateralis male, Type I 6635 3.6 0.089 2.6 1918
Vastus lateralis male, Type II 5438 2.8 0.048 1.8 2029
[134]

Vastus lateralis male, Type I 5471 3.5 0.082 2.4 1562
Vastus lateralis male, Type II 4451 2.6 0.044 1.5 1760
[124]
Vastus lateralis male, Type I 6222
Vastus lateralis male, Type IIA 5069
2.8 0.07 2.3 2029 [135]
MEANS 5029 (15) 2.65 (14) 0.092 (13) 3.33 (13) 2088 (9)
Abbreviations: XSA: cross-sectional area (in m
2
); Myon/fiber: myonuclei per fiber profile: SC/F: satellite cells per fiber profile; % SC: percent satellite cells; Cytopl/Myon: cyto-
plasmper myonucleus or myonuclear domain (in m
2
).

Table 5. Myonuclear and Satellite Cell Content in Rodent Muscles
Age Or Weight Muscle Fiber Type XSA Myonuclei Myonuclear Domain* SC% Reference
RAT
I 3135 116# 30,000 180g Soleus
II 1731 54# 40,000
[136]
I 3143 2.39 1300 m
2
/f* 1.86 5 month
IIA 2249 1.49 1700 m
2
/f* 4.57
I 3229 3.18 1000 m
2
/f* 1.62 24 month
Soleus
IIA 2435 2.46 1000 m
2
/f* 2.44
[137]
250g Soleus -- 2000 150 13,800 [123]
4 mo, 250g Soleus -- 4671 154 33,000 [121]
6mo, 389g 3000 2.2 1400m
2
/f*
20mo, 487g 2990 2.0 1500 m
2
/f*
32 mo, 459g
Soleus --
2184 2.25 1000 m
2
/f*
[120]
4 mo Plantaris -- 4423 76 65,000 [121]
I 1636 1.14 1450 m
2
/f* 7.59
IIA 1724 1.22 1500 m
2
/f* 2.53
5 mo
IIB/D 3642 1.79 1900 m
2
/f* 1.86
I 1491 1.31 1200 m
2
/f* 5.57
IIA 1768 1.22 1450 m
2
/f* 4.25
24 mo
Plantaris
IIB/D 3491 1.87 1800 m
2
/f* 1.79
[137]
I 900 76 155,000
IIA 1050 54 185,000
180g Plantaris
IIX/B 1250 58 220,000
[122]
180g Plantaris F 4066 44 112,000 [136]
I 850 1300 12,500
IIA 950 1600 12,000
IIX 1600 1750 19,500
Adult Diaphragm
IIB 2500 1500 35,500
[138]
MOUSE
3 weeks -- 325 440 4200*
4 mo
Plantaris
-- 900 1000 15,000*
[35]
2 mo 700 55 12,000
14 mo 1000 70 15,000
23 mo
Soleus
900 55 17,000
4 mo 800 42 20,000
14 mo 2000 50 35,000
23 mo
EDL
11,000 40 30,000
[44]
XSA: cross-sectional area; Myonuclei #: number per mmof fiber; Myonuclear domain: indicated as volume (m3) unless indicated by * (per cross-sectional area).
Table 6. Percent Changes of Selected Variables in Human Muscles
Sex Muscle Regimen Duration XSA Myonuc/fib SC/fib % SC Cytopl/nucl Reference
YOUNG SUBJECTS
F Trap RT 10 w +36% +71 - +46 -20 [129]
F VL RT 16 w 23 4 27 15 17 [40]
M VL RT 12 w 16 -2 29 20 [126]
M VL Ecc Exerc 24 h - 6 157 111 6 [130]
M VL RT 8 w 25 19 - 28 -1 [125]
M VL RT 16 w 32 16 49 21 13.5 [40]
ELDERLY SUBJ ECTS
F VL RT 12 w 9 17 18 -2 - [133]
F VL RT 16 w 25 4.5 26 20 13 [40]
M Deltoid RT 14 w 6.5 3 44 1 [135]
M VL Endur T 14 w 10 4 31 7 [135]
M VL RT 12 w 0 4 36 30 - [123]
M VL Ecc Exerc 24 h - -1 43 47 - [130]
M VL RT 16 w 29 14 8 [132]
M VL Endur T 14w 11 6 22 29 5* [131]
M VL RT 16 w 15 4 20 18 8 [40]
MEAN PERCENT CHANGES
ALL YOUNG 26.4 19.3 65.5 44.2 5.9
ALL ELDERLY 13.2 6.2 27.5 27.4 7.1
Abbreviations: Trap: trapezius; VL: vastus lateralis; RT: resistance training; Ecc Ex: eccentric exercise; Endur T; Endurance training; XSA: cross-sectional area; Myonuc/fib; Myonu-
clei per fiber; SC/fib: satellite cell per fiber; %SC; percent satellite cells; Cytopl/nucl: cytoplasmper nucleus or Nuclear Domain.

Table 7. Human Muscle Characteristics (Data from References for Table 5)
XSA Myonuclei/Fiber Satellite Cells/fiber % Satellite Cell Myonuclear Domain
VL, Young Males 5795995 (11) 2.500.75 (10) 0.083.032 (9) 2.900.94 (11) 2140877 (6)
VL, Young Females 4000 2.5 0.091 2.571.25 (3) 1750
VL, Elderly Males 5172847 (15) 2.930.79 (12) 0.075.026 (11) 2.480.99 (13) 2328903 (8)
VL, Elderly Females 3343202 (2) 2.320.47 (3) 0.1170.01 (3) 4.541.48 (4) 1450 (1)
Deltoids, Elderly male I: 5202
II: 6566
3.0 0.73 2.4 1890
Tib. Ant. Elderly Male 3.16 0.12 3.9
Tib. Ant. Elderly Female 2.79 0.13 4.4
Tib. Ant. Young male 2.57 0.19 6.9
Tib. Ant. Young female 2.25 0.17 7.1
Trapez young female 2958 2.1 3.7 1408
Trap young male 4400 3.3 4.0

the elderly as in the young, or that fibers transformed to type
I in the transplants do not become as oxidative as in younger
muscles. The changes in nuclear and satellite cell content
with changes in activity will be reviewed below.
Do these values mean anything? Satellite cells retain
their proliferative ability in old muscles [12, 25], although
the proliferative ability of the SCs decrease by about two
proliferative doublings each ten years of life [25]. Even if
satellite cell numbers are reduced in old muscles, this does
not have an effect on SC function in regeneration and repair.
One expects that a satellite cell population would be main-
tained by sufficient proliferative divisions of the satellite cell
nuclei, and myonuclear incorporation would occur as
needed. Therefore since proliferation occurs readily, only a
minimal number of satellite cells should be able to maintain
the myonuclear population in elderly muscles.
Changes In Myonuclei and Satellite Cells With Activity
Various studies investigating the effects of training on
human muscles [reviewed in 26], make it possible to deter-
mine the influence that activity (usually exercise) has on
effecting changes in satellite cells and myonuclear composi-
tion (Table 6). Although women have been used in exercise
studies for many years, few of these studies, as shown in this
table, have incorporated women as subjects because the rela-
tionship between SC and myonuclear composition is a rela-
tively recent topic of interest. Some of the human exercise
studies that have pre- and post-training biopsies are included
in the table. Since SC content is presented in two ways, the
mean number of SCs per fiber and relative percentage of SCs
(calculated as number of satellite cells divided by number of
satellite cells plus myonuclei multiplied by 100) are given.
Satellite cell content increased with increased activity in all
groups (Table 6), with the young showing a more robust
change than the elderly. Again, because women constituted
so few of the subjects in the study populations, generaliza-
tions about differences between gender are not given. The
MN changes were not as dramatic as those by the SCs. The
MN increased more in the young than the elderly, which
expressed only very little increase. More will be discussed
about this below.
Myonuclear Domains
The concept of nuclear domains has been discussed for
many years [27], but became a focus for study around 1990
[28-32]. This concept, peculiar to multinucleated skeletal
muscles, proposes that a myonucleus synthesizes mRNA
(and thus many proteins) that remain localized within a re-
gion surrounding the nucleus (its domain). After the estab-
lishment of the MND, studies were conducted to determine
how the domain was affected by exercise (hypertrophy) or
inactivity (atrophy) [reviewed in 21, 33]. The domain size is
related to the metabolism of the fiber, and this metabolism
varies with fiber type, muscle type, and species. Metabolic
activity between the three most commonly investigated spe-
cies (mice, rats, humans) varies widely, with the mouse mus-
cles being the most oxidative [34]. Because of this, compari-
sons or generalizations between species are difficult, and this
review will reflect this difference between species. This is
especially apparent when considering that a human nuclear
domain cross-sectional area is often larger than the entire
cross section of many mouse muscle fibers. Because the ac-
tivity of a muscle fiber determines the size of the MND, oxi-
dative fibers have smaller domains than glycolytic fibers and
slow fibers with their more chronic activity have smaller
domains than fast fibers.
The concept of myonuclear domains, whether carrying
that name or not, has been discussed for many decades. The
modern discussion began in the late 1980s when the term
nuclear domain was used by Hall and Ralston and Pavlath
et al. [31, 32]. They used chimeric cells to follow the mRNA
from the introduced nucleus. The mRNA remained within a
100 m area (domain) of the nucleus [30]. The role of the
satellite cells in supplying myonuclei was well established
by that time [reviewed in 2] and muscle biologists began to
experimentally alter the size of the muscle fibers to deter-
mine whether muscle satellite cells would contribute myonu-
clei with increased muscle fiber size.
Is the myonuclear domain (MND) a viable concept? A
recent review [33] has questioned how constant a domain
size (amount of cytoplasm) can be maintained, stimulated by
work on mouse muscles. Several laboratories [33, 35-36]
using adult mouse muscle models showed that the adult
muscles do not maintain a constant MND after developing a
highly regulated system early in postnatal life [17, 35]. Their
studies showed that the domain was regulated early in
growth and unregulated in middle and old ages. Mouse and
rat muscle fibers are relatively small, but their nuclear do-
main sizes, although smaller than human domains, are not
correspondingly small. The atrophy or hypertrophy of rodent
muscles is insufficient to exceed the size of their nuclear
domains. In spite of that, in the majority of studies using rats,
an increase in fiber size is accompanied by an increase in the
myonuclear population, or vice versa (Table 2). This is dis-
cussed further in the review of human muscles. More studies
using mouse muscles are needed to determine whether the
relationship is not valid for this group. Because rodent mus-
cle fibers and MNDs have such small sizes, studies of these
muscles often use whole fiber segments rather than using
cross-sectional analysis. When fiber segments are used, the
basal lamina may be removed, which frees the satellite cells;
therefore all nuclei associated with the fiber are myonuclei.
A disadvantage to using isolated fiber segments is that the
sample sizes tend to be very small. In contrast, analysis of
MNDs using cross-sectional analysis makes it easy to do
multiple analyses on the same fiber, makes fiber size meas-
urements easy, and allows many hundreds of fibers to be
analyzed. Disadvantages are that it may be difficult to differ-
entiate satellite cells from myonuclei, and only a very small
volume of each fiber is analyzed at any time.
Human muscle MNDs can be analyzed by using the
cross-sectional area as the basis for the measurements. Be-
cause human muscle fibers are so large, the MND is usually
smaller than 50% of the XSA (Table 4). Table 4 summarizes
some human muscle studies published within the past dec-
ade. The vastus lateralis muscle is most often used because it
can be targeted in strength exercise studies and a biopsy can
be safely taken because biopsy sites are usually free of major
blood vessels and nerves. The table separates young (less
than 40 years old) from elderly (over 55 years old) muscles,
and gender is not segregated. Fibers from men are larger than
those from women (Tables 4, 7). Control muscle fiber sizes
are larger in elderly muscles than young muscles. This is
surprising because of the sarcopenia usually attributed to
elderly muscles. This discrepancy may be due to differences
in muscle mass versus muscle fiber size. Further, much vari-
ability in mean fiber sizes is present in the different studies.
Myonuclear composition is similar in young and old mus-
cles, but satellite cell composition is reduced in elderly mus-
cles. Surprisingly, the myonuclear domain size (cytoplasm
per myonucleus) is identical between young and elderly (Ta-
ble 4).
Changes in Myonuclear Domains with Altered Activity
The large size of human skeletal muscle fibers makes the
analysis of the muscles similar in many studies and also
makes clear the patterns of change. The muscle fibers are
generally enlarged by resistance exercises, and hypertrophy
of the fibers by 15% or more generally causes a correspond-
ing increase in myonuclear population (Table 6). Because of
the nuclear increase, the MND size changes by less than
10%. Some studies show relatively little hypertrophy, which
is due to either insufficient effectiveness of strength training
(little change in maximal voluntary contraction) or incorpo-
rating endurance training, which does not result in sufficient
hypertrophy. Muscles from elderly subjects are capable of
maintaining their MND regulation (Table 4).
To study MNDs, the usual method is to alter the size of
the muscle fibers to determine whether myonuclei are added
or removed to maintain the domain size in the muscle fibers.
Different protocols are used to alter fiber size in humans
compared to non-human animals. The most commonly used
method to manipulate muscle fiber size to study the myonu-
clear domain and nuclear composition of human fibers is
exercise, and specifically resistance (strength)-training stud-
ies. To do this, muscle biopsies are taken prior to the training
period, then muscle-specific strength training exercises are
conducted for a number of weeks or months. A post-exercise
biopsy is taken after the training period, and intermediate
biopsies may be taken during the training. Relatively few
studies have been conducted on human muscles to study the
effects of muscle atrophy and the changes in MNDs, al-
though several disuse models were developed in the past
[37-39]. An atrophy model that uses rats is microgravity in
space. Spaceflight is an ideal model for producing muscular
inactivity, but the number of human astronauts for any mis-
sion is quite small; therefore some gravity-based protocols
have been used (head-down bedrest models) to simulate mi-
crogravity [39], but MNDs were not analyzed in those stud-
ies.
Although the general concept of myonuclear domains has
long been appreciated, the role of SCs in maintaining this is
relatively new. Exercise studies incorporating the study of
myonuclei, satellite cells and nuclear domains have been
carried out for less than 20 years. A number of these studies
were analyzed for this review, and they are presented in
summary tables because the raw data are presented in many
ways. Table 6 presents the data from different human studies
on the effects of different types of activity and the percent
changes in muscle fiber size compared to percent changes in
myonuclear domain. When this is done, a wide range of fiber
size changes is noted, but no matter what the range of these
changes is, the mean change in the MND associated with the
altered fiber size is usually less than 10%. This indicates that
no matter how much the fiber size enlarges, the amount of
muscle fiber cytoplasm associated with each nucleus remains
similar. Therefore new nuclei are added to the muscle fiber
to accommodate the increased fiber size, keeping the change
in MND size minor.
If the mean myonuclear domain size in human men is
2100-2300m
2
, and the mean XSA of the fibers is approxi-
mately 5000m
2
(Table 4), then a hypertrophy of around
40% would be expected to result in nuclei being added. This
assumption, based on approximately 15 studies, agrees with
the estimate by Petrella et al. [40], who indicated that a
maximum MND of 2000 m
2
would be needed for nuclear
addition. Because most exercise studies show less than a
40% hypertrophy with resistance training (Table 6), but have
an increased myonuclear content, it suggests that the satellite
cells are activated to proliferate before the need for muscle
hypertrophy occurs. Myonuclear number increases before the
XSA increases to more than 2000 or 2200m
2
, suggesting
that these values reflect the approximate maximum domain
size (although a few studies in Table 4 indicate a larger
MND). Does this 2200 m
2
human domain size relate to
other mammals? Several factors affect the response of the
MND to change in muscle fiber size, especially in rodent
muscles. First, the fiber type (both predominant type and the
one primarily targeted by the activity) strongly influences the
domain size. Second, the amount of oxidative activity re-
quires smaller domains than glycolytic activity [reviewed in
21].
In order to compare different studies, the summary data
are presented as percent change in response to exercise.
When this is done, the percent hypertrophy can be compared
to the percent increase in myonuclei and percent changes in
MND. The results show that hypertrophy in response to ex-
ercise was greater in young muscles than elderly, and the
nuclear population increased in both groups, although more
in the young. The changes in fiber size and myonuclear con-
tent resulted in no change in MND size in the young, and a
slight increase in elderly muscle (6%). These demonstrate
that the dynamic muscle fibers are maintained at a constant
MND size in spite of large increases in fiber XSA. This rela-
tionship is maintained in the elderly muscle, showing that SC
activity does not diminish in the aging skeletal muscle.
Most of the changes in XSA are less than the MND size
(2000-2200m
2
), and the muscle domain size changes negli-
gibly. This suggests that the myonuclei had proliferated suf-
ficiently to maintain the MND size even before increasing
enough to attain the MND value. The domain size is there-
fore maintained by first increasing the nuclear content and
then increasing the proteins until the domain size is attained.
There is no difference in the response of elderly versus
young or men versus women in this process. Therefore, ag-
ing does not diminish the ability of the satellite cells to be
activated to contribute to myonuclei [25]. As Table 6 also
shows, the satellite cell composition of the muscles is vari-
able, as would be expected from cells that daily respond to
minor traumas. Satellite cell numbers decrease with age, as
shown by many studies (Table 4).
Much variability in human subjects responses to exer-
cise has always been observed, and this variability was re-
flected in a difficulty to achieve statistical significance be-
cause of relatively small numbers of subjects and this varia-
tion in response to exercise. Several publications from
Bammans group [40-42] have provided valuable insight into
why this variability exists. They had three important factors
in their experimental design and analysis: 1) they had suffi-
cient numbers of subjects (66); 2) they related morphological
analyses to mRNA expression; 3) they used post-hoc cluster
analysis to group the subjects based on the muscle fiber hy-
pertrophic response to 16 weeks of resistance training. By
determining the degree of response, their subjects were ana-
lyzed by group as extreme, modest, and non-responders to
training. The basis for the responses were dissected out as
being due to muscle (or mechanical) growth factor, myo-
genin, and IGF-IEa, which were expressed at different times
during the training [41]. Further analysis of their biopsies
using the group separation by cluster analysis led to cleaner
and more significant results/conclusions [42]. The variation
in SC number and frequency noted by Schafer et al. [22]
between mice of the same strain may be due to other similar
myogenic influences, and should be investigated further.
Animal Models of Myonuclear Domains
Different models are used to study the significance of
satellite cells and myonuclei in adapting to muscle fiber size.
The models used normally differ between humans and other
animals. For example, it is difficult to induce animals to per-
form heavy resistance exercises, and compensatory hyper-
trophy studies are not usually performed in human subjects.
However, the effect of microgravity on skeletal muscles has
been studied in both human and other animals. Studies using
denervation to induce atrophy may be a problem because the
absence of a neural influence may disrupt some of the cellu-
lar signaling pathways that affect nuclear proliferation or
degeneration.
Rat Muscles
The study of nucleocytoplasmic relationships in rats and
other animals is different than humans. The fiber sizes in
human muscles are much larger than those in rat or mouse
muscles, and many different muscles are used from rodents;
models for altering fiber size differ between humans and
rodents. A factor that introduces variability in rodent studies
is that the age of the animal is not sufficiently considered. In
human muscles, the difference between a growing and ma-
ture individual is clear, but it is rather inconsistently evalu-
ated in rats and mice. If an animal in a rapidly growing phase
of its life is subjected to protocols to alter its muscle activity,
then growth is superimposed upon the activity pattern. In
spite of that, investigators often use young growing animals
because they are more easily handled than adult or old ani-
mals and tend to train better than older animals to experi-
mental protocols such as exercise.
The review of the animal work will concentrate on rat
studies, and the basic descriptive studies will be followed by
experiments that alter muscular activity. Most studies of rat
muscles use the soleus, although a valuable study showing
ontogenetic landmarks in muscular development was done
using the plantaris muscle of rats [43]. Wistar rats were stud-
ied between three and 20 weeks age to determine when the
growth curve leveled off, and adult values were attained.
Some of the results are indicated here:
Growth Changes in Wistar Rat Plantaris Muscles [43]
9 weeks: satellite cell proliferation ceases
10 weeks: break in body weight curve (at 300g)
11-12 weeks: muscle mass slows its increase
12 weeks: fiber XSA slows its increase; fiber numbers
stop increasing
Based on this study, active plantaris growth and satellite
cell proliferation slowed at three months of age (less than
300 g body mass). Comparison of the growth changes seen
in the table above with the ages and body weights of animals
in Table 2 or Table 5 show that several studies have used
growing animals. It is possible that studies using young ani-
mals are superimposing normal growth changes onto ex-
perimental results.
Rat Soleus MND
The adult rat soleus muscle has a mean cross-sectional
area of 2720824 (13 studies), and the mean myonuclear
domain size (volume) is 17,0009500 m
3
(12 studies, Table
5). In comparing the various studies, many studies of rat
muscles have been done on animals that are actively growing
(based on weight). Again, the results of such studies show
the experimental protocol being superimposed upon (and
perhaps influenced by) the normal growth changes. Because
of the importance of investigating a stable system, it is im-
portant for studies to define the age, weight, and breed of the
animal. Some breeds of rats continue to increase in mass
with age, while the growth curve of other breeds may plateau
at maturity. The MND for rodent muscles is estimated as a
volume (by those studying whole fiber segments), or as a
cross-sectional area because of the use of muscle sections
(slices). Most estimates of MND in lower mammals use a
volume per mm estimate. To relate it to human measure-
ments, the volumes are divided by 100 by assuming that a
typical section or slice used for cross-sectional analysis
would be 10 m thick.
The experimental techniques using animal models to in-
duce hypertrophy or atrophy give inconsistent results (Table
2). The changes in values depend upon duration, method,
muscle, and fiber type. Two major methods to investigate
atrophy are microgravity (spaceflight) or hindlimb suspen-
sion. These inactivity models generally affect weight-bearing
or postural muscles much more than non weight-bearing
muscles. Because of this, the soleus muscle responds much
more than the plantaris. In most of the atrophy-inducing ex-
periments, the main fiber type in the muscle (type I in so-
leus) lose myonuclei to accompany the myofiber atrophy,
but the myonuclear domain change is usually quite large.
Myonuclear loss is generally associated with muscular atro-
phy; although results are variable, it is clear that regulation
of the MND is not as well regulated in the rat as in human
muscles (Table 2). For muscular overload, the studies
showed a very significant hypertrophy of the muscle fibers,
and this was associated with extensive myonuclear addition,
leading to a better MND maintenance than with atrophy.
Mouse Muscles
Mouse muscles have at least two stages of growth. Dur-
ing early postnatal growth, the growth in fiber size is accom-
panied by an increase in number of myonuclei [35,44] (Table
5). This is especially evident in the soleus. From middle age,
the nuclear number and fiber size are uncoupled. Mouse
muscles have been studied extensively by Gundersens [17,
33,44,45] and Wadas [35,36] groups. Both of these labora-
tories demonstrated that the nucleo-cytoplasmic relationship
is not tightly regulated but has some unusual characteristics.
The nuclei of young (one and two months old) mouse mus-
cles increase with increasing fiber size [35,44], but in middle
age (four to 14 months), denervation atrophy occurs while
myonuclei remain constant [35] (Table 2); this appears to be
unique for mice because rat muscle fibers lose their myonu-
clei with denervation atrophy [7]. In very old mice, the nu-
cleo-cytoplasmic regulation appears to be regained [35]. Al-
though other extensive studies of the MND changes with
activity in mice are not available, it appears that the MND
size may be comparable between mouse and rat muscles, and
mouse fiber sizes are about 35-50% of the size of the rat fi-
bers.
Care must be taken when studying nucleo-cytoplasmic
relationships and satellite cell incorporation using animal
models. The problem is that the nuclear activity in the life of
a muscle consists of at least three general stages: prenatal
stage, postnatal and growth stage, and adult. In the prenatal
muscle the precursor cells proliferate to form myoblasts
which then become incorporated into developing myotubes
and muscle fibers. In the postnatal stage, the muscle precur-
sor cells continue to proliferate and incorporate into the
growing muscle fibers so the nuclei can maintain their nu-
clear domain sizes. Satellite cell populations are high (20%
in 6 week old rats [7]) compared to the adult (normal) levels
during this stage. In the adult stage, SC populations have
stabilized, muscle fiber growth has plateaued, and the satel-
lite cell incorporation into the muscle fibers is greatly re-
duced, occurring primarily for additional growth or regenera-
tion/repair. The satellite cell content of the muscle fibers has
stabilized to the adult levels (2-8% of muscle nuclei). This
stage continues through old age, and although sarcopenia
occurs with aging, this sarcopenia begins soon after attain-
ment of the adult stage, and so is regarded here as part of the
normal adult stage. In humans, the stage between growth and
adult occurs in the second decade [46]. In animal models,
this transition between growth and adult is often not consid-
ered. There have not been many studies matching ages and
satellite cell contents in rat muscles, but other measures can
be used to estimate stages (Tables 1&5). The two main
breeds of rats used are the Sprague-Dawley and the Fisher
NIH breeds. The Sprague-Dawley rats continue to gain
weight with age, while the Fisher breed plateaus at maturity
and only slowly gains weight thereafter.
Human Versus Animal Models
It is expected that animal models simulate human muscle
characteristics, and this is generally true. It appears, how-
ever, that several breeds of mice may not regulate their do-
main sizes [33,36]. Not only may breeds differ in their regu-
lation of the MND, but the domain may differ during various
stages of development. An example of the complexity of
these changes is shown by Rosser et al. [47], who showed
variation along the length of the avian muscle fibers that was
related to a gradation in development. More studies analyz-
ing variation within and between species are needed to de-
termine the developmental changes and muscle fiber type
differences in various groups of organisms. This is especially
true for human muscles because almost nothing is known
about the changes in SC and MND with growth. For this
reason, the animal studies are valuable to define and experi-
mentally alter the developmental patterns.
AGING
This section will discuss several factors associated with
aging of the muscle and its SC population. These factors will
include the reduction in number of proliferative divisions
and telomere length with age, apoptosis with aging and in-
jury, and the role of the SC niche in aging changes. All of
these factors interact to affect the SC function in regenera-
tion and repair as the organism ages.
Motor Neurons and Fiber Sizes.
Aging induces changes in the neuromuscular relation-
ships. It is clear that motor neuron numbers decline with age
in both humans [24,48] beginning from 25 years of age [49]
and rats [50]. This loss of motor neurons induces some rein-
nervation of the denervated muscle fibers by surviving motor
neurons, leading to larger motor unit action potentials [51].
This reinnervation is insufficient to compensate for the death
of motor neurons because muscle fiber loss with age is ex-
tensive [24,49,52]. Fiber type proportions may not change
[52], or there may be loss of type IIB units [53]. Despite this
uncertainty, the percentage area occupied by type II fibers
progressively decreases [49,54,55]. The reinnervation of
denervated type II fibers by type I motor neurons induces
mixed myosin isoforms to a greater extent in elderly than
young muscles [56]. The decrease in muscle mass with aging
is now considered to be due to type II fiber size reduction
and loss [57].
The MND, myonuclear content, and SC activity in the
aged individuals are unstable and undergoing constant altera-
tions due to this interaction between the dying motor neurons
and surviving and reinnervating motor units. Since type I
fibers have smaller domains than type II [21], the possible
adoption of type II fibers by type I motor neurons may in-
crease the MN content (and SC activity) in the elderly mus-
cles. This appears to explain the numbers observed in
Table 4.
Telomeres and Nuclear Aging
Each time a cell divides, a segment of the chromosomes
telomere is broken off and the enzyme, telomerase, inserts
the telomere segment back on the DNA. Embryonic and im-
mune cells express high levels of telomerase, but most adult
cells have low levels of the enzyme, which causes the divid-
ing somatic cells to shorten their telomere lengths after each
division until they reach the Hayflick minimum [58]. This is
aging [59], and the study of aging cells has been stimulated
by the analysis of telomeres. Hayflicks limit is the maxi-
mum number of replications a cell can undergo. The original
studies of Hayflicks limit were done with fibroblast cells in
culture, and this limit is generally accepted as the cause of
senescence [59]. The telomere system is regarded as the
mechanism for aging, but the telomeric analysis to interpret
aging of nuclei in skeletal muscle must be interpreted care-
fully. The post-mitotic nature of myonuclei means that the
majority of these myonuclei have not divided since being
incorporated into the muscle fiber. Minimum telomere
lengths may be useful to determine the injury or satellite cell
activation history of the muscle precursor cells. However,
entire muscles or fragments of muscles are used for analysis,
and their nuclear composition consists of approximately 55
to 80% myonuclei, and only about 8% of the nuclear popula-
tion consists of muscle precursor cells (see above and Table
1). The remainder consists of nuclei of connective tissue,
blood vessels, immune cells, and other interstitial cells [5,6].
Considering these factors, determination of either mean or
minimum telomere length for nuclei of skeletal muscle may
not be meaningful. Many of the studies relating telomere
length to aging refer to minimum telomere length, suggest-
ing this to reflect the satellite cell population. However, be-
cause satellite cells make up such a small percentage of the
non-muscle nuclear population, this assumption may not be
valid. The nuclear population that is non-muscular is ap-
proximately 35% [5-7] of the nuclei in muscles.
A number of studies over the past two decades have in-
vestigated the telomere length in skeletal muscle. Because a
major characteristic of skeletal muscle is that its nuclei are
post-mitotic, the study of telomere length in muscle would
seem of little purpose. However, because the telomere length
reflects the replicative history of the nucleus, the study might
show how active the cells were prior to entering the post-
mitotic state (G-1). Several other factors contribute to the
telomere variation: 1. Satellite cells are not arrested mitoti-
cally, and proliferate to contribute nuclei to the fiber during
growth or to repair fibers. Because they divide during their
life, any incorporated nuclei may have different telomere
lengths than myonuclei. 2. Do myonuclei undergo some
normal turnover so the original nuclei do not survive the life
of a muscle fiber? If telomere length reflects the number of
replications, then analysis of a muscle containing myonuclei
and satellite cells should give a southern blot pattern contain-
ing a main mass of relatively uniform telomere lengths, and
containing an extended lower range, which contains the sat-
ellite and other cell populations that have divided exten-
sively, especially in biopsies from elderly muscles. A study
of importance to this discussion was done by Schmalbruch
and Lewis [7] who used continuous bromodeoxy-uridine
infusion to label nuclei that had divided in soleus and exten-
sor digitorum longus (EDL) of growing rats, comparing den-
ervated and contralateral innervated muscles. Myonuclei
turned over at a maximum of 1-2% a week after the main
growth period.
Human satellite cells decrease their telomere lengths and
replicative capacity with age in the first two decades of life,
and then remain relatively constant through old age [46].
This reflects the growth pattern for muscle nuclei as de-
scribed above. The range of telomere lengths increases with
age because the minimum length is enhanced due to satellite
cell proliferation or perhaps to aging of interstitial cells. This
suggests that although the main mass of elderly muscles did
not decrease telomere length, the minor nuclear population
(of satellite or other cells) did, but not extensively because
SC proliferation decreases after the initial growth period, as
indicated by Decary et al. [46].
Telomere shortening does not occur in myonuclei
[46,60]. The telomere length of human satellite cells de-
creases during the first 20 years of life then remains stable.
However, Decary et al. [46] showed a negligible loss of 13
base pairs per year (presumably from satellite cells). In spite
of that, each division of human DNA results in 113 bps lost
at the telomere [60]. Therefore these numbers indicate that
satellite cells do not lose significant telomeres during the
adult life of human muscles, again substantiated by Schafer
et al. [25]. Although the absence of significant telomere loss
[61] indicates little proliferation of satellite cells during adult
life, the replicative potential of satellite cells decreases with
age [60], indicating that satellite cells undergo senescence
independently of cell divisions. No gender or age effects
were noted for mean telomere length or minimal telomere
length.
Another factor that influences the studies of telomere
length and aging in skeletal muscle is the presence of non-
muscle nuclei. As indicated earlier, the nuclear composition
of muscles includes a significant population of non-
myogenic nuclei (30-60% in various adult rat muscles) [6-
7,9]. These non-myogenic cells undergo normal cell replica-
tion, and these most certainly contribute to the telomere
analysis in the various muscle studies. Therefore, although
telomere analysis of muscles uses minimal telomere lengths
to estimate the replicative history of the satellite cells, it is
likely that these studies are assaying non-myogenic cells
because of the much greater population of these cells over
SCs.
Dystrophic muscles undergo a series of muscle injuries
and repairs, and their nuclei may show evidence of an en-
hanced aging process. The most widely used model of mus-
cular dystrophy is the mdx mouse, which has muscles that
undergo constant degeneration and regeneration. The satel-
lite cell population is activated constantly with muscle inju-
ries, and telomeres shorten significantly more than in control
mice. This is reflected in the mean and minimum telomere
lengths of old mdx mice compared to controls [62]. A similar
result was reported in human leg muscles from patients with
Fatigued Athlete Myopathic syndrome [63]. These athletes
had mean telomere lengths about 33% the length of normal
athletes, and minimum telomere length was less than 20% of
controls. These results were interpreted to be caused by ex-
tensive damage/regeneration occurring in these muscles.
Diseased muscles with inflammatory conditions have exten-
sive connective tissue and inflammatory cells that contribute
to the telomere analysis. The regulation of telomere length
appears to be determined genetically, and independent of
tissue type or age [64]. These studies relating telomere
analysis to aging suggest that unless a cleaner nuclear
preparation is used to assay for telomere length, this method
may not be useful for the study of muscle or satellite cell
aging. Until better methods are developed, telomere results
must be estimated and interpolated from culture studies. Fur-
ther, some studies have suggested that aging may not be re-
lated to the telomeric stage of the DNA [65]. In spite of the
question concerning telomeric analysis in muscle, it is clear
that the number of proliferative divisions decline with aging
[60,61].
Apoptosis
Apoptosis is cell death that is distinct from necrosis. It
consists of a series of programmed events that maintain the
integrity of the cell membrane while reducing cell size and
breaking down the nucleus into apoptotic bodies, which are
then phagocytosed. In most cells apoptosis results in loss of
the cell, but in skeletal muscles, the process leads to the loss
of nuclei and the cell (muscle fiber) atrophies. Apoptosis was
not well recognized in skeletal muscles until several studies
of inactivity in rat muscles showed a loss of myonuclei ac-
companying the atrophy [66-69], from which Allen et al.
[43] proposed apoptosis as a mechanism for this nuclear loss.
Other studies using skeletal muscle showed that apoptotic
factors associated with mitochondria signaled the apoptosis
[70]. Aging sarcopenia was attributed to nuclear apoptosis
occurring without damage to the muscle fiber [71,72]. Once
the mechanism of apoptosis was proposed for skeletal mus-
cle, a series of studies was initiated, and skeletal muscle ap-
pears to be unique in some of its apoptotic characteristics
compared to normal eukaryotic cells.
The classical mechanism of apoptosis in most cells of the
body is by a cytochrome-c release from mitochondria to ac-
tivate a caspase-dependent pathway leading to apoptosis.
The mechanism of nuclear destruction in other cell types
may not be the mechanism in skeletal muscle because of its
multinucleated, syncytial condition. An intriguing discovery
by Leeuwenburgh and his colleagues [73] has shown that
aging rat muscle undergoes extensive apoptosis that may be
associated with the proapoptotic endonuclease G (EndoG),
which is moved from mitochondria to the nucleus in old and
atrophied muscles. This endonuclease functions in the sub-
sarcolemmal mitochondria to copy mitochondrial DNA. In
the apoptotic process, endoG is translocated to the nucleus
where it destroys the nuclear DNA [74]; it therefore causes
nuclear apoptosis without cell death. This pathway bypasses
the traditional cytochrome c-dependent apoptosis occurring
in most cells. The EndoG pathway is prevalent in normal
muscles from old animals [75] and is activated to a greater
degree in old than young muscles by hindlimb suspension
(HLS). Leeuwenburghs study suggested that young muscles
might use the caspase pathway for apoptosis [73], but further
study [75] indicated that the interstitial cells were using the
caspase-activated apoptosis, while the EndoG pathway was
used by both young and old muscles. These studies suggest
that atrophy-activating protocols in rats involve the follow-
ing sequence [75]:
a) within 12 hours, early translocation of EndoG from the
mitochondria to nucleus; nuclear fragmentation
b) within 2 days: fiber atrophy; interstitial cells undergo
apoptosis via the caspase pathway
c) within 4 days, decreased muscle mass.
Endonuclease G activation and translocation by HLS in
young rats was compared in myonuclei and interstitial cell
nuclei within the soleus muscle [75]. By comparing EndoG
and activated caspase 3 in muscle tissues, the authors con-
cluded that the muscle nuclei and interstitial nuclei were
undergoing apoptosis by different mechanisms, activated by
EndoG and caspase-3 respectively [75]. The EndoG-
mediated apoptosis is one of the earliest responses of the
muscle to HLS; it precedes atrophy, is localized in subsar-
colemmal mitochondria, and is enhanced in old muscles after
HLS.
Satellite Cells and Aging
One of the early themes in studies of satellite cells and
aging was that the number of satellite cells declined with age
[8]. Part of this decline is due to the early changes in SC con-
tent (Table 1). Although a slight reduction in SC content is
observed in the summary tables (Table 8 for humans and
Table 5 for rodents), the difference in numbers of SCs with
aging are not remarkable and reflect the general uncertainty
of whether SC numbers decline with age. The reduction in
numbers of SCs with age, if it occurs, may not be relevant
because SCs are inactive and await activation to proliferate
and incorporate and/or regenerate in a fiber. As long as SC
function is capable of being maintained, the SC number may
not be relevant to the reduction of repair or regeneration with
age.
By collating the various studies investigating the effects
of training on skeletal muscles [reviewed in 26], it may be
possible to determine whether general changes in SCs and
MN incorporation are occurring (Table 7 for humans, and
Table 2 for rats). These show that the SC numbers are not
different and that myonuclear increases are similar in young
and elderly. They also suggest that SC numbers are similar
and they continue to proliferate in the elderly. The summary
tables showing the SC content of young versus elderly mus-
cles showed a slight reduction with age, but examining indi-
vidual studies that compared young to old muscles do not
show this difference with age. This is especially noteworthy
in a large population of subjects studied by Petrella et al.
[40] that showed the elderly muscles had more SCs in both
men and women. Although some inconsistencies in counting
SCs (this may be related to problems with identification as
indicated above), exist, it is clear that SCs become less capa-
ble of maintaining their regeneration potential with age [76-
78], as discussed below.
For SCs to be activated, the Notch signaling pathway
with its ligand, Delta, must be upregulated [79,80]. The
pathway then activates the SC to proliferate. Delta increases
following injury, but in aged muscles, it is not as readily
upregulated, and the SC activation is reduced [80]. Serum
factors appear to restore the system to its full capacity
[79,80]. These studies show that the cell numbers are not as
important as the signaling system. Another factor is that the
myogenic (satellite) cell population is heterogeneous, and a
small percentage of these cells (marked by Pax7) remains
capable of being activated for regeneration or repair in the
aged muscles [81]. That study also showed that the larger
segment of the population had none of the myogenic mark-
ers, and those cells were susceptible to apoptotic destruction.
Although the discussion above de-emphasizes the sig-
nificance of the number of satellite cells in favor of their
activation potential, the studies from Yablonka-Reuvenis
group [82] support the opposite view, using Pax7 immu-
nostaining to identify satellite cells in isolated mouse muscle
fibers. Dividing the samples into four age groups (young,
adult, old, and senile), they showed that the soleus had sig-
nificantly fewer SCs in senile fibers than in old or adult. The
young had more SCs than all other groups. The number of
cell progeny from the SCs of the various groups also de-
creased in the senile, while the adult and older groups were
again similar. It is possible that the reduced number of SCs
(stained with Pax7) was similar to the minority population of
SCs with the capability of regeneration or repair, as de-
scribed by Collins et al. [81].
The heterogeneity of SCs is further demonstrated in a
recent study [83] examining the importance of Pax7 and
Pax3 on the function of the SCs. When the genes for Pax7
and Pax3 were inactivated in adult mice, SC activation and
function were unaffected. Pax7 was shown to be required for
the transition of the myogenic precursor cell into the quies-
cent SC in the developing muscle. These studies indicate a
heterogeneity, a gradual change in function, and a systemic
change in support and activation of the satellite cells with
aging.
The Aging Satellite Cell Niche: Role of the Connective
Tissue
The importance of the immediate environment in regulat-
ing the stem cell activity has been appreciated for some time
[reviewed in 84], but the niche concept for satellite cells has
only recently been articulated [85,86]. The main elements of
the niche are the muscle fiber, basal lamina (BL), and the
connective tissue (CT) associated with the fiber. This niche
is especially important in relating its changes to satellite cell
function in aging. The CT is vital not only as a component of
the SC niche, but also important in transmitting the forces
produced by the contractile mechanism to the tendon [87].
This requires a coupling of the fibers cytoskeletal system
and costameres to the extracellular matrix (ECM). The de-
sign of the cytoskeletal system-membrane-ECM complex
facilitates the coupling of the contractile movement with
alterations in the cell surface (SC niche). Normal CT is regu-
lated or turned over by a matrix metalloprotease (MMP) sys-
tem of proteolytic enzymes that degrades the CT fibers [88].
By breaking down the BL and releasing the SC for migration
and differentiation, the MMP may be involved in initiating
the activation of the SCs. A single bout of exercise can acti-
vate the MMP [89] and may have a preferential action on the
fast type II fibers [90]. The MMP has been used as a thera-
peutic aid to enhance healing in experimentally-induced
muscle injury in mice [91]. The MMP injection into a wound
site increased the number of regenerating fibers and de-
creased fibrous tissue that inhibited healing. The enhance-
ment of fibrosis may be a characteristic of aged muscle, and
may be due to non-myogenic stem cells associated with
muscle [92]. These non-myogenic stem cells appear to be
derived from SCs of aged muscle [92] that convert from the
myogenic to fibrogenic lineage under the influence of the
Wnt signaling pathway [76]. This change from the myoblast
to fibroblast line is brought about by a change in cell surface
signaling proteins (Sca-1: stem cell antigen). A myogenic
cell is negative for Sca-1, and the non-myogenic stem cell
contains these receptors [93]. These cells can interconvert, as
shown by Brack [76] and Alexakis [94]. The aging changes
associated with diminished skeletal muscle growth and re-
pair are not only due to a reduced proliferative capacity of
the SCs, but also brought about by changes in the SC niche
that may lead to the conversion of SCs to non-myogenic cell
lines. Because of this, aged muscles may contain a high
population of stem cells adjacent to the muscle fiber, but
occurring OUTSIDE of the basal lamina. These non-
myogenic stem cells must be differentiated very carefully by
those investigators using antibodies to SCs in combination
with laminin for the basal lamina.
Not only do the CT fibers degenerate with MMP and
aging, but the fibroblasts that synthesize these collagen fi-
bers undergo aging processes that result in fragmented colla-
gen fibers that no longer hold the tissues together [95]. Ag-
ing related to the CT affects many different tissues, and is
most studied in the skin, where aging-associated changes in
various collagen and elastic fibers are well studied [96]. The
ECM plays a significant role in regulating secretion of
growth factors and is vital for tissue remodeling, such as in
wound healing. The ECM is regulated in large part by the
MMPs and their inhibitors (TIMPs: tissue inhibitors of met-
alloproteinases). In most cases, MMPs are activated by other
MMPs [97]. Recent studies have shown that type I collagen,
the major ECM protein, although long lived, becomes frag-
mented with age [95]. Fibroblasts, the major producer of
ECM, also secrete MMPs, making the fibroblast both the
creator and destroyer of ECM. Intact collagen attaches to
fibroblasts and mechanical forces on the attachment plaques
maintain fibroblast shape. As long as the fibroblast is not
collapsed, it secretes ECM proteins; a collapse of the cell
turns off collagen synthesis and turns on MMP secretion.
Aging collagen gets fragmented, which then turns off colla-
gen synthesis [98], causing MMP to break down more colla-
gen. The decline in ECM with aging may be explained by
this sequence of events. The MMPs not only break down
collagen I, but also destroys other ECM components, includ-
ing type IV collagen (basal lamina) [89]. Because the basal
lamina forms the immediate protective coat for the SC, dis-
ruption of the BL alters the SC niche (see above).
The significance of the ECM regulation in skeletal mus-
cle has been appreciated for several decades, especially as it
relates to skeletal muscle regeneration [7,77]. The impor-
tance of the ECM has recently been described as a major
factor affecting muscle regeneration [91,99] by controlling
fibrosis. Even after a single (65 min) bout of progressive
cycling exercise, both MMP-2 and MMP-9 were increased at
two hours after exercise. These MMPs act on the various
collagen molecules, and MMP-9 specifically is thought to
break down the BL, freeing the SC [100]. Carmeli et al. [90]
demonstrated MMP-2 expression in rat leg muscles after two
weeks of high intensity treadmill running.
The aging of the CT is also observed in vitro by using
satellite cell cultures from young versus aging mice. Those
from the aged mice had a higher percentage becoming fibro-
genic after several replications, and this is thought to be as-
sociated with increased Wnt signaling from the serum of
aged animals acting upon the myogenic progenitors [76].
Recent studies [94] have reinforced the significance of me-
chanical forces exerted by the ECM on skeletal muscle activ-
ity. The ECM production is altered in muscular dystrophy
causing fibrotic buildup, which then acts on the muscle fi-
bers to alter their function. In normal muscle, basal lamina
thickens and becomes more rigid with age, and fibrosis in-
creases. This increased fibrosis is not due to more collagen
synthesis, which is decreased with age, but to disrupted deg-
radation of collagen [101].
Satellite Cells, Muscle Regeneration and Aging
Studitsky [102] originally published in 1977; translation
in 1988] recognized the importance of the satellite cells and
their role in the plastic state of muscles. The extensive re-
generation research in the former Soviet Union in the 1940s
and 1950s led to the characterization of the plastic charac-
teristics of muscles, and many of these characteristics were
later recognized as being due to the development and activa-
tion of satellite cells [102]. The regeneration of skeletal mus-
cle can entail a relatively minor trauma such as repairing
damage to the sarcolemma of muscle fibers, to the extensive
process of degeneration and repair of an entire muscle that
has been minced, freely autografted, or induced to degener-
ate and regenerate using a myotoxin such as bupivacaine or
lidocaine. The more extensive regenerative processes will be
summarized here. Information on regeneration of minced
muscle fragments was summarized by Carlson [103], while
many other aspects of muscle regeneration were reviewed in
a symposium in 1978 [104].
Several factors influence the quality of regeneration.
Among these are: age of the organism [105]; how the regen-
eration was induced (free grafting maintains the BL tubes
with SCs within them; mincing may preserve some SCs, but
will not maintain the BL tubes); most myotoxic drugs will
maintain the BL and SCs and cause muscle fiber degenera-
tion [106]. Older organisms will regenerate more slowly than
young in response to bupivacaine degeneration [107]. To
determine whether this slower regeneration is due to the
muscle or systemic factors, Zacks and Sheff [108] investi-
gated the comparative regenerative capacity of young to old
mice by studying the regeneration of the tibialis anterior
muscle from 18 day to 120 day old mice. Minced muscle
fragments from old mice into muscle beds of young mice
produced good regeneration, comparable to young muscle
autografts. A similar response was obtained in rat EDL mus-
cles hetero-transplanted between young and old rats [109].
Minced muscles from old animals into old muscle beds pro-
duced a less successful regeneration than old minced mus-
cles into young muscle beds [109]. Thus the systemic envi-
ronment is more important than the host muscle in determin-
ing the quality of regeneration. Another factor involved in
successful regeneration is the efficiency of phagocytosis by
macrophages [110]. Transplanted muscles are quickly
phagocytosed, and mononuclear cells proliferate and differ-
entiate to form regenerating muscle fibers. These studies
show that muscle atrophy associated with aging is not due to
impairment of muscle regeneration. Individual fibers or mo-
tor units may undergo atrophy with selective death of fast 2B
(or 2X) fibers [111].
Many studies have indicated that muscle regeneration
and muscle repair are impaired with age. This decrement in
regenerative/reparative ability has been suggested by muscle
transplantation/regeneration experiments [109] and by com-
paring the regeneration of muscles in rats of different ages.
Sadeh [107] used the myotoxic agent, bupivacaine, to com-
pare regeneration in the tibialis anterior muscle of rats of 3
months, one year, and two years age. Although muscles re-
gained their normal structure after two weeks in 3 month and
one year old rats, they had not regained their normal struc-
ture after two months in the old rats.
The process of repair/regeneration of muscle varies de-
pending upon the extent and type of damage, but generally
SCs get activated, proliferate, and form muscle fibers. If the
cell membrane is damaged, the stumps of the fibers are
sealed off and the basal lamina tube directs the shape of the
resulting fiber. Minor damage involves disruption of the cy-
toskeletal system and local changes in the myofibrillar appa-
ratus [112]. When the more dramatic regenerative changes
are considered, it is clear that SC activation and proliferation
are not affected. Although the proliferative capacity is di-
minished, sufficient capacity remains to easily replace the
entire musculature [25,113]. This is true whether the SCs
decline with age [114] or not. These studies suggest that the
number of satellite cells does not reflect the capacity or suc-
cess of the muscle to effect regeneration or repair, if a criti-
cal minimum population is present.
Since even a reduced proliferation of SCs in the aged
muscle fibers does not influence the quality of regeneration,
other factors must be considered that would show regenera-
tion in the older organism. Cross-transplantation experiments
were carried out in rats [115] and mice [116]. Whole intact
EDL muscles were cross-transplanted between rats of differ-
ent age groups (young muscle into old site; old muscle into
young site) for two months [115]. Contractile properties and
structural studies revealed that both old and young muscles
transplanted into young sites regenerated to the same extent.
Conversely, young and old muscles into old sites resulted in
less successful regeneration based on force production, mus-
cle mass, and maturity of fibers regenerated. For both this
study and that using two strains of mice, the regenerative
properties of the grafted muscle were determined by the host
site and not by the properties of the donor muscle.
Gulatis studies [91] indicated that many components of
the BL are broken down during muscle regeneration, but
enough of the SC niche remained to maintain the SC position
at the muscle fiber surface. The BL is thought to constrain
the growth and migration of activated SCs, thereby orienting
the regeneration of new muscle fibers [117]. There is uncer-
tainty as to whether the presence of the basal lamina is re-
quired to maintain correct orientation of regenerating muscle
fibers [117,118].
CONCLUSIONS
Satellite cells are essential for the repair and regeneration
of skeletal muscle. When muscle fibers hypertrophy, SCs are
incorporated into the fiber to increase the myonuclear con-
tent. In contrast, the effects of atrophy on MND have been
less well studied, but evidence indicates that nuclear apopto-
sis occurs when atrophy occurs. The negative influence of
excessive myonuclei should be further explored. These ob-
servations indicate that the regulation of MND drives the
activity of SCs, and maintenance of the MND size has been
demonstrated in muscles of rats, humans, and many breeds
of mice. In order for the SC content of muscles and meas-
urement of myonuclear domains to give consistent results, a
more reliable and uniform method for demonstrating and
quantifying satellite cells and myonuclei must be applied.
Cell surface receptors used to identify SCs change with dif-
ferent phases of activity, so currently there are no reliable
commercially-available antibodies that consistently demon-
strate SCs. When these become available, a quantitative
method such as described by Sajko et al. [18] promises to be
valuable.
The review of the SC and its incorporation into myofi-
bers has revealed that muscles of different breeds of animals
may respond differently from muscles of humans and other
mammals. These may be due to the breeds having different
growth characteristics. An analysis comparing animal groups
and the completion of more developmental studies would
provide valuable information on the regulation by satellite
cells of the myonuclear domain. Mice are critical to these
studies because of their obvious genetic role in molecular
genetics. This necessitates the determination of whether mur-
ine muscles behave differently from muscles of other mam-
malian groups. Along with these comparisons, there is a
great need for studies of developmental/ontogenetic analyses
of SC, MN populations, and MNDs in human muscles. More
comparisons must be made between human and ro-
dent/murine muscles when the human postnatal growth is
characterized more fully.
The major factors associated with SCs and aging are the
proliferative history, rate of activation and proliferation, and
changes in satellite cell numbers. In normal non-diseased
individuals, the number of cell divisions a SC has undergone
has a sufficient safety factor to accommodate the lifetime
requirements of the cell/muscle, but the proliferative capac-
ity declines with age, and various muscle diseases/injuries
require greater numbers of proliferations. Therefore the use
of SCs as a clinical tool for regeneration must consider the
reproductive history of the cells used as donors. Although
the number of proliferative divisions limits the life of the SC,
the quality of its function is related to its environment. The
detailed interaction between the SC and connective tissue
must be more fully elucidated. Connective tissue fibers ap-
pear to provide shape and mechanical forces to maintain SC
function, but experimental studies must determine the nature
of the interactions and how this may influence SC function.
The decline in SC function with age appears to be related to
this immediate connective tissue environment consisting of
the basal lamina and connective tissue/growth factors that
change with age. These changes in interaction between the
SC and its niche during the aging process should be a major
topic of future investigation.
In the half century since its discovery, much of the biol-
ogy of the SC has been described, but as with any system,
even more questions have been raised. The next half century
will likely be noted for the extensive use of SCs in clinical
therapies as the biology of these cells becomes more fully
characterized.
ABBREVIATIONS
BL = Basal lamina
CT = Connective tissue
ECM = Extracellular matrix
EDL = Extensor digitorum longus
EndoG = Endonuclease G
HLS = Hindlimb suspension
m-cad = m-cadherin
MMP = Matrix metalloprotease
MND = Myonuclear domain
NCAM = Neural cell adhesion molecule
SC = Satellite cell
XSA = Cross-sectional area
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Received: April 14, 2010 Revised: J une 17, 2010 Accepted: August 5, 2010

Aging Changes in Satellite Cells and Their Functions

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