The Role of Connective Tissue and

Extracellular Matrix Signaling in Controlling

Muscle Development, Function, and Response
to Mechanical Forces
Alec S. T. Smith, Rishma Shah, Nigel P. Hunt, and Mark P. Lewis
Continued improvements in orthodontic therapy are likely to rely heavily on
our further understanding of masticatory muscle biology. Specifically, the
ability of the jaw musculature to adapt to changes in load gives strong
implications as to its capability in responding to treatment. The dynamic
and adaptive nature of the extracellular matrix (ECM) is of critical importance in the correct functioning of all skeletal muscle and can have a
dramatic impact on the homeostasis of the tissue. Misregulation or mutation in ECM structures or proteins can therefore lead to a variety of clinical
conditions in both the craniofacial and noncraniofacial musculature. A complete comprehension of ECM signaling and its role in correct skeletal muscle
function will form a vital part of this improved knowledge base. This review
covers recent research into ECM signaling and functions, as well as the
possible implications such work has for the future of orthodontic therapy.
(Semin Orthod 2010;16:135-142.) 2010 Elsevier Inc. All rights reserved.

he success of orthodontic therapies, such as

myofunctional appliances and orthognathic
surgery, rely heavily on the ability of the masticatory musculature to adapt to changes in functional
length. These adaptations include changes in contractile protein expression and concurrent alterations in the connective tissue make up. Knowledge of how jaw skeletal muscle connective
tissue registers changes in load and how such
signals are communicated to other tissue components is essential to improving current protocols and thereby improving patient care and
recovery.

From the Departments of Biomaterials and Tissue Engineering

and Craniofacial Developmental Sciences, UCL Eastman Dental
Institute, London, UK.
Address correspondence to Rishma Shah, UCL Eastman Dental Institute, 256 Grays Inn Road, London WC1X 8LD, UK. Phone: 44(0)20-7915-1133; Fax: 44(0)-20-7915-1238; E-mail: R.Shah@
eastman.ucl.ac.uk
2010 Elsevier Inc. All rights reserved.
1073-8746/10/1602-0$30.00/0
doi:10.1053/j.sodo.2010.02.005

Skeletal Muscle Extracellular Matrix

(ECM) Architecture
Muscle connective tissue is formed of 3 interconnected collagenous sheaths, directly linked to
the cytoskeletons of the surrounding cell population (Fig 1).1-3 The endomysium (basal lamina) surrounds individual fibers with a random
arrangement of collagen fibers to allow for
movement during contraction.3 Fibers are in
turn collected into bundles (fascicles) surrounded by the perimysium; this structure is
multilayered and runs transversely to the fibers,
holding them in place.3 The entire muscle tissue
is then surrounded by a double layer of collagen
fibrils: the epimysium.3

ECM Components
An external lamina of type IV collagen, laminin,
and heparan sulfate proteoglycans surrounds
skeletal muscle fibers, which is supplemented by
an interstitial matrix of fibronectin, perlecan,
and collagens I, II, and III.4 The content of
skeletal muscle ECM differs significantly be-

Seminars in Orthodontics, Vol 16, No 2 (June), 2010: pp 135-142

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A.S.T. Smith et al

Figure 1. Schematic view of skeletal muscle architecture. The multinucleated muscle fibers, covered by
the endomysium, are arranged in parallel bundles
encased within the perimysium. The whole muscle is
contained within the epimysium and attached to bone
via tendons. The parallel orientation enables contraction in 1 direction to effect movement. (Color version
of figure is available online.)

tween muscle types and it is believed that the

make up of a specific muscles ECM is coupled
to its functional role in that tissue.3 Generally,
the main components of the ECM can be divided into 4 classes: collagenous glycoproteins,
noncollagenous glycoproteins, proteoglycans,
and elastin.2

Maintenance and Mediation of

ECM Turnover
Of central importance to the maintenance of
the ECM are the matrix metalloproteinases
(MMPs); MMPs are inhibited, in a 1:1 fashion,
by the tissue inhibitors of metalloproteinases
(TIMPs), of which 4 have been identified.2,5
Secreted into the ECM as latent proenzymes,
most MMPs are activated through a proteolytic
event that leads to the formation of a catalytically competent enzyme.5 Fine control of
MMP activity is essential to the maintenance of
the ECM and its importance is illustrated by
several clinical disorders that arise as the result
of disturbances in MMP-TIMP ratios (eg, fibrosis, wound healing).2,6,7
Of all MMPs, the gelatinase enzymes (MMP-2
and -9) have been most widely studied because
they are responsible for the degradation of the
major constituents of the ECM (collagen IV and
laminin).2 Regulation of ECM integrity by
MMP-2, in particular, is believed to be vital for
correct myofiber proliferation, differentiation,

healing, and connective tissue maintenance.6

Denervation of skeletal muscle results in increased activity of MMP-2, leading to excessive
degradation of the ECM and the subsequent
atrophy of the tissue.8 Regular patterns of electrical stimulation have been shown to regulate
MMP-2 activity and improve the recovery of denervated muscle.8
Gelatinase activity in growing and damaged
fibers facilitates the expansion and differentiation of dividing muscle precursor cells (MPCs),
allowing them to push through the existing
ECM and thereby establishing new fibers within
the tissue. Current data suggest that MMP-2 is
secreted by satellite cells and intramuscular fibroblasts, whereas MMP-9 production is stimulated by inflammatory cells entering damaged
muscle.9 MMP-2 is expressed in both MPCs and
fibroblasts within all normal skeletal muscle
types,10 localized to the blood vessels, nerves,
and neuromuscular junctions.2 It is further upregulated in the ECM in response to inflammation, disease, and excessive exercise.6
MMP-9 in healthy, noncraniofacial muscle is
again localized to blood vessels, nerves, and neuromuscular junctions but expressed at very low,
almost nonexistent levels.2,10 In injured muscle
fibers, MMP-9 is significantly up-regulated; this
response being far greater than that of MMP-2 in
the same tissues.2 In healthy human craniofacial
muscle, there is some data to suggest a low level
of MMP-9 expression is present in the muscle
fibers (as opposed to the nerves and blood vessels alone as with MMP-2).11 In this study, the
authors suggest that this difference could be
attributable to anatomical differences or else an
injury-associated up-regulation in response to
the removal of the muscle tissue for analysis.
Both enzymes are thought to play a role in the
events preceding MPC fusion, thus making them
essential in the repair of damaged muscle tissue.
The authors of studies9,10 have demonstrated
that MMP-2 mRNA, as well as protein activity, is
detectable during all phases of MPC differentiation. Similarly, MMP-9 expression in craniofacial
muscle tissue increases just before MPC fusion;
however, it is not found in fused myotubes.9
Furthermore, the levels of MPC migration, an
essential part of the regenerative response, increase substantially in response to overexpression of MMP-2 in in vivo cell transplantation

Connective Tissue and Extracellular Matrix Signaling

assays; blocking MMP-9 activity in these assays is

sufficient to prevent migration.12
Studies of MMP and TIMP expression in the
human masseter muscle have demonstrated that
TIMP-1 appears to be consistently expressed in
this tissue.13 MMP-2, -9, and TIMP-2, when expressed at all, are done so at very low levels,
which act to highlight the extremely low levels of
ECM turnover in the craniofacial musculature.13
There is some suggestion that MMP and TIMP
expression vary among patients with facial form
abnormalities (specifically long face syndrome),
however there is no consistent misregulation of
these proteins when compared en masse with
control subjects.13

ECM Function
Skeletal Muscle Regeneration
Satellite cells are multipotent cells that, in
healthy muscle tissue, lie between the sarcolemma of muscle fibers and the basal lamina in
a mitotically quiescent state.14 From here they
can be stimulated into multiple rounds of division in response to weight-bearing stress or injury.15-17 After activation, some of the daughtercell population cycles back to replenish the
tissues satellite cell stock,18,19 but most begin
differentiation down the myogenic lineage.
These MPCs are then capable of fusing with
damaged muscle fibers to replace those nuclei
lost to trauma or, if the damage is too great, of
fusing with each other to create entirely new
muscle fibers.4 Although the focus of much
study, the exact cellular and molecular mechanisms that regulate and control myogenesis are
not fully understood; nevertheless, the ECM is
known to play a critical part in its orchestration.
This is well illustrated through the use of a novel
in vitro skeletal muscle ECM coating for tissue
culture plastic.20 MPCs cultured on an ECMderived coating demonstrate a significantly increased ability to proliferate and differentiate
compared with similar cells grown on collagen.
Initial satellite cell activation depends on the
correct up-regulation of a series of muscle specific genes and transcription factors. This process is regulated using cell-cell and cell-matrix
interactions as well as relying heavily on matrix
secreted molecules. Analysis of satellite cell sur-

137

face markers can aid the identification of signaling pathways used to activate them.21

Adhesion
Maintenance of structural integrity in the muscle tissue is essential to normal function; to that
end the ECM is populated with a large array of
molecules responsible for connecting the various components of the tissue together. Of the 5
identified families of adhesion molecules
present on skeletal MPCs, 3 are known to be
involved with direct cell-to-cell adhesion and so
interact minimally with the ECM; the Adams (a
disintegrin and metalloproteinase domain), the
cadherins (M-, N- and R-cadherin), and the immunoglobulin superfamily (eg, neural cell adhesion molecule 1 and vascular cell adhesion molecule 1).2 The remaining 2 are responsible for
the adherence of cells to the underlying ECM
and so shall be focused on in more depth here.
The Dystrophin-Dystroglycan Complex
The dystrophin-dystroglycan complex consists of
a multisubunit protein traversing the sarcolemma and providing a direct connection between the cell cytoskeleton and the ECM.2,22
Defects in, or deletions of, any of these proteins
will result in different forms of muscular dystrophy of varying severity. Certain muscular dystrophies that affect the craniofacial musculature
(Duchennes, congenital, and myotonic) characterize themselves in the phenotype by a progressive increase in the vertical dimension of the
face leading to the long-face appearance typical of the disorder (Fig 2).2,23,24
Integrins
The integrin family is a group of cation-dependent, membrane-bound adhesion molecules
responsible for mediating both cell-cell and
cell-ECM interactions. Each molecule is heterodimeric, composed of glycoproteinous
and subunits bound together in a noncovalent manner.25 Twenty-four different receptors
have been identified, each made up from different combinations of the 18 and 8 subunits
known to exist.26 It is believed that different
integrins are responsible for mediating different
cellular responses; however, this is difficult to
investigate because a single ligand molecule is

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A.S.T. Smith et al

Figure 2. Facial and intraoral photographs of typical

long-face deformity associated with muscular dystrophic disorders. Photographs taken in occlusion.
(Color version of figure is available online.)

often able to bind to several integrin receptors.2

The alternative splicing of certain and subunits (particularly 7 and 1) only acts to further complicate this matter.2
Sites of critical contact between cells and
ECM molecules are mediated by integrins and

known as focal adhesion complexes (FACs).27,28

Faculties centre on the binding of an integrin
receptor to its ligand in the ECM, as well as to a
cytoskeletal actin filament, thus linking the cell
to the ECM.29 This event triggers a clustering of
similar receptors and the accumulation of actin
binding proteins (eg, vinculin, paxilline, talin,
and actinin) at that site.27-29 The formation of
FACS also results in the intracellular tyrosine
phosphorylation of a number of cytoplasmic factors.27,28 Phosphorylation of molecules, such as
focal adhesion kinase, rho GTPases and mitogen-activated protein kinase, activates signaling
cascades that ultimately result in alterations in
gene expression.27-29 In this way changes in ECM
conditions can heavily influence gene expression within the cell. This is vital as a means to
better adapt the cell to changes in the functional
demands on the tissue, but also allows the ECM
to self regulate the production of ECM factors
from nearby cells.
As discussed earlier, the major ECM components are collagen IV, laminin, and heparan
sulfate proteoglycans.4 Of these, laminin is the
major cell adhesive found in skeletal muscle
basement membranes and, as such, is believed to
be of primary importance in maintaining contact.25 The laminin isoforms known to be
present in developing and mature skeletal muscle are all ligands of the integrins 31, 61
and 71.30-32 However, of these 3 only 71 is
known to be present in mature muscle.25 It is
this integrin, along with the dystrophin-dystroglycan complex, that is believed to principally
control skeletal muscle cell adhesion to the
ECM. The localization of 71 at both myotendinous and neuromuscular junctions in mature
muscle suggests further roles for this integrin,
not only in the maintenance of muscle integrity
but also in neuromuscular connectivity and
force transduction.33
Costameres
Although faculties are present in many tissues, a
striated muscle specific elaboration of this structure links it to the dystrophin-dystroglycan complex, as well as a wide array of other structural
proteins.34 These riblike structures are called
costameres and lie at regular intervals along peripheral muscle fibers, linking their Z-lines to
the sarcolemma and the ECM. Costameres are

Connective Tissue and Extracellular Matrix Signaling

believed to be essential to the maintenance of

myofiber spatial organization during contraction.35,36 The cross-linked nature of the ECM
means that connecting muscle fibers to the
ECM, via costameres, ensures that all fibers are
in turn linked to each other, aiding the generation of a uniformed contraction profile across
the entire muscle.
The ability of muscle fibers to contract means
nothing if the force this generates cannot be
suitably conducted to the tendons. When a sarcomere contracts, the force generated is transferred to the next sarcomere in line. Force transmission continues along the myofibril in this
manner until it reaches the myotendinous junction; here, the contractile elements are linked to
the tendon via the ECM and the generated force
is passed across to the skeleton.35 Longitudinal
transmission of force is supplemented by lateral
transmission, whereby contractile force is passed
from the z-disk of 1 myofibril to the z-disk of the
adjacent myofibril and so on until it reaches the
costameres. Because the integrin 71 and dystroglycan both constitute transmembrane proteins directly linking the cytoskeleton to the
ECM, it is likely that lateral force is transmitted
across the membrane via these proteins.37 Transduction of force is then further mediated by the
coordinated contraction of the sarcolemma,
along with the ECM, cytoskeletal and intracellular structures, which together form an elastic
element surrounding the muscle and running
parallel to the long axis of the tissue.35-39
Laminins
The laminins are a family of extracellular, heterotrimeric glycoproteins that play a significant
role in assembling and maintaining the basement membrane of many tissues.40,41 The laminins typically seen in skeletal muscle tissue are
211, 221, 411, 421, and 521.40
The role of laminins in maintaining ECM
integrity, specifically in skeletal muscle, is illustrated by specific types of muscular dystrophy.
Laminin-211 is an essential muscle laminin, acting as an anchor between muscle cells and the
ECM and capable of binding both -dystroglycan and the 71 integrin.42 Patients with mutations in the laminin 2 chain present with a
congenital muscular dystrophy 1-A phenotype.42,43 In such cases, the inability of the dys-

139

troglycan molecule to bind laminin-211 results

in its detachment from the basal lamina, leading
to severe muscle weakness and hypotonia. This
mutation is the most common form of congenital muscular dystrophy, accounting for roughly
40% of all cases.42

Response to Mechanical Force

The functional matrix hypothesis states that the
development and maintenance of all the bodys
skeletal tissues and organs are compensatory responses to temporally and operationally prior
events.44 Moreover, it explains that epigenetic
and extraskeletal processes are the primary
cause of all adaptive responses of skeletal tissues.45 The active genes in skeletal muscle cells
are not therefore directly responsible for any
responsive activity of the skeletal unit but rather
subservient to extrinsic and epigenetic information generated by or transmitted through the
surrounding matrix.45
Extrinsic mechanical stimuli, resulting in the
transmission of forces through the connective
tissues, are therefore essential to the correct
functioning and homeostasis of the skeletal muscle ECM. Among other examples, the significant
alteration in patterns of collagen synthesis in
response to the mechanical unloading of rat
hind limbs,46 highlights the importance of gravity, exercise and force transmission in the maintenance of the muscle connective tissues.
As the major component of vertebrate skeletal muscle ECM, the breakdown and synthesis of
collagen is an important factor in adapting muscle tissue to mechanical loading stimuli. Enhanced collagen synthesis has been seen in response to differences in types and durations of
loading.47 Rats subjected to exercise tests, such
as downhill running, forced contraction by electrical stimulation or prolonged periods of muscle loading, were shown to respond with upregulated gene expression for collagens I, III
and IV.48,49 Furthermore, there is evidence that
collagen IV protein levels, in both rats and humans, are higher following acute exercise.50,51
Conversely, inactivity for more than 48 hours has
a dramatic, down-regulatory effect on the expression of collagens III and IV.52 Together,
these data give a strong indication as to the
rapid, dynamic ability of the muscle collagens to
respond to changes in mechanical loading and

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A.S.T. Smith et al

unloading. It is hardly surprising then that data

from aged rats has shown an increase in the
levels of crosslinking of the epimysial collagen
fibers, which results in a reduction in the solubility and turnover of the molecules.53 This leads
to a characteristic stiffening of the tissue, helping to explain the impairment of force generation found in the muscle tissues of the elderly
subject.53
Endomysial collagen is primarily produced by
fibroblasts although other cell lines, including
MPCs, have been shown to be capable in vitro.47
In skeletal muscle, the fibroblasts are located
within the peri- and endomysium and are attached to the ECM via integrins.47 This direct
link allows the cells to register and respond to
any mechanical stimuli transmitted through the
ECM; an ability that has been suggested to be
essential to correct fibroblast functioning.47,54
Although it is understood that fibroblasts are
largely responsible for producing collagen, it is
less well established how the cells are able to
convert mechanical signals in the ECM into
chemical signals and, in turn, into altered gene
expression. Current theory is reviewed by SarasaRenedo and Chiquet.54 An immediate effect of
changed signaling through activation of available transcription factors (such as NF-B) is 1
possibility. An alternative is a secondary effect
whereby ECM molecule production is induced
by increased expression of transcription factors
themselves stimulated by activated pathways,
such as focal adhesion kinase signaling. A third
possibility is an indirect effect, where the mechanical stimulus triggers growth factor expression (or secretion) which then works in an autocrine/paracrine manner to induce ECM
production. Several growth factors, including
transforming growth factor 1 and many insulinlike growth factor-1 splice variants, can stimulate
collagen synthesis and also are known to be
regulated by mechanical loading in tendon and
muscle.47
As discussed previously, the MMPs, and
MMP-2 in particular, play key roles in the remodeling of the ECM structures. Muscle overloading
and unloading in the rat model has been shown
to result in an increase in both pro-MMP-2 and
active MMP-2 expression,50,55 indicating the
high levels of ECM restructuring that occurs in
response to load. Unloading has also been associated with reduced expression of TIMP-2, an

MMP-2 inhibitor; contrasting strongly with the

increase in TIMP-2 expression seen in overloaded muscle.55,56 This finding suggests that
the degradative activity of MMP-2 is higher in
immobilized muscle, where atrophy occurs, than
in muscle injured during exercise, where MMP-2
aids in the restoration of tissue function.47
In vitro study of tissue responses to mechanical loading can have important implications for
orthodontic therapies. Analysis of MMP expression data in stretched 3D collagen gel models of
skeletal muscle has demonstrated that a continuous 15% strain greater than 6 hours can induce
a significant increase in MMP-2 expression compared with unstrained controls.57 Models
stretched with the use of a continuous-strain
regime also were shown to up-regulate MMP-2
expression to a greater degree than those models held in a cyclic pattern.56,57 MMP-2 expression, and therefore ECM remodeling, is therefore dependent both on the magnitude and the
pattern of strain to which the muscle is subjected. Skeletal muscle and its surrounding soft
tissues have thus been shown to be more capable
of responding positively to changes in environment caused by surgical intervention (eg, mandibular advancement) if the procedure is carried out in a single activation (eg, via a ramus
osteotomy) rather than as a gradual process (eg,
via distraction histogenesis).56,57 Similarly, a
one-step activation of a myofunctional orthodontic/orthopedic appliance, rather than a
gradual advancement, may lead to more pronounced adaptation in the elevator and retractor muscles that are attached to the mandible.56,57 Further study of the molecular
responses of skeletal muscle to alterations in
strain will likely provide new insight into the
effect of invasive surgery with regards to the
muscle tissues ability to remodel itself.

Conclusions
As our understanding of skeletal muscle development, repair and function improves, the importance of the ECM in responding to external
cues, as well as eliciting control over other aspects of muscle biology, becomes more obvious
and significant. The ability of these structures to
remodel themselves and to regulate the activation, migration and differentiation of muscle
cells in response to various external and internal

Connective Tissue and Extracellular Matrix Signaling

stimuli cannot be biologically or medically overlooked. With respect to orthodontics, as the

knowledge base regarding the response to therapies increases, modifications to how certain
therapies are undertaken (eg, functional appliances and orthognathic surgery) will follow.
This, in turn, should ensure that the most successful and stable outcomes are achieved for all
patients.

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