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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


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@
© 2010 Elsevier Inc. All rights reserved.

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


nerves. allowing them to push through the existing ECM and thereby establishing new fibers within the tissue. and elastin.6 Denervation of skeletal muscle results in increased activity of MMP-2. Similarly. 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).) tween muscle types and it is believed that the make up of a specific muscle’s ECM is coupled to its functional role in that tissue. noncollagenous glycoproteins. MMP-9 is significantly up-regulated.2 In healthy human craniofacial muscle. are arranged in parallel bundles encased within the perimysium. differentiation.2 Maintenance and Mediation of ECM Turnover Of central importance to the maintenance of the ECM are the matrix metalloproteinases (MMPs). and excessive exercise.T.10 In injured muscle fibers.2 It is further upregulated in the ECM in response to inflammation. disease.10 localized to the blood vessels. is detectable during all phases of MPC differentiation.7 Of all MMPs. in a 1:1 fashion. an essential part of the regenerative response. nerves. wound healing).6. this response being far greater than that of MMP-2 in the same tissues.2. Smith et al Figure 1. the main components of the ECM can be divided into 4 classes: collagenous glycoproteins. of which 4 have been identified. most MMPs are activated through a proteolytic event that leads to the formation of a catalytically competent enzyme. Current data suggest that MMP-2 is secreted by satellite cells and intramuscular fibroblasts. leading to excessive degradation of the ECM and the subsequent atrophy of the tissue. however. almost nonexistent levels. the levels of MPC migration. in particular.2.9 MMP-2 is expressed in both MPCs and fibroblasts within all normal skeletal muscle types. The multinucleated muscle fibers.S. it is not found in fused myotubes.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. thus making them essential in the repair of damaged muscle tissue. Both enzymes are thought to play a role in the events preceding MPC fusion. The parallel orientation enables contraction in 1 direction to effect movement. The authors of studies9.9 Furthermore.6 MMP-9 in healthy.2 Regulation of ECM integrity by MMP-2. fibrosis. increase substantially in response to overexpression of MMP-2 in in vivo cell transplantation . and connective tissue maintenance.11 In this study.3 Generally. MMPs are inhibited. by the tissue inhibitors of metalloproteinases (TIMPs). 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. noncraniofacial muscle is again localized to blood vessels.10 have demonstrated that MMP-2 mRNA.136 A. and neuromuscular junctions but expressed at very low. MMP-9 expression in craniofacial muscle tissue increases just before MPC fusion. covered by the endomysium. (Color version of figure is available online. is believed to be vital for correct myofiber proliferation.8 Gelatinase activity in growing and damaged fibers facilitates the expansion and differentiation of dividing muscle precursor cells (MPCs).5 Secreted into the ECM as latent proenzymes. proteoglycans. healing. The whole muscle is contained within the epimysium and attached to bone via tendons. 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). whereas MMP-9 production is stimulated by inflammatory cells entering damaged muscle.2. and neuromuscular junctions. Schematic view of skeletal muscle architecture. as well as protein activity.8 Regular patterns of electrical stimulation have been shown to regulate MMP-2 activity and improve the recovery of denervated muscle.

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). These MPCs are then capable of fusing with damaged muscle fibers to replace those nuclei lost to trauma or. however there is no consistent misregulation of these proteins when compared en masse with control subjects. this is difficult to investigate because a single ligand molecule is . the ECM is known to play a critical part in its orchestration. -9.4 Although the focus of much study. N. Each molecule is heterodimeric. 3 are known to be involved with direct cell-to-cell adhesion and so interact minimally with the ECM.19 but most begin differentiation down the myogenic lineage. Certain muscular dystrophies that affect the craniofacial musculature (Duchenne’s.20 MPCs cultured on an ECMderived coating demonstrate a significantly increased ability to proliferate and differentiate compared with similar cells grown on collagen. or deletions of. membrane-bound adhesion molecules responsible for mediating both cell-cell and cell-ECM interactions.18. Of the 5 identified families of adhesion molecules present on skeletal MPCs. which act to highlight the extremely low levels of ECM turnover in the craniofacial musculature.2. some of the daughtercell population cycles back to replenish the tissue’s satellite cell stock. however. composed of glycoproteinous ␣ and ␤ subunits bound together in a noncovalent manner. congenital. This is well illustrated through the use of a novel in vitro skeletal muscle ECM coating for tissue culture plastic.25 Twenty-four different receptors have been identified.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. each made up from different combinations of the 18 ␣ and 8 ␤ subunits known to exist. any of these proteins will result in different forms of muscular dystrophy of varying severity. Analysis of satellite cell sur- 137 face markers can aid the identification of signaling pathways used to activate them.14 From here they can be stimulated into multiple rounds of division in response to weight-bearing stress or injury. if the damage is too great. neural cell adhesion molecule 1 and vascular cell adhesion molecule 1). and TIMP-2.21 Adhesion Maintenance of structural integrity in the muscle tissue is essential to normal function.13 ECM Function Skeletal Muscle Regeneration Satellite cells are multipotent cells that. to that end the ECM is populated with a large array of molecules responsible for connecting the various components of the tissue together. the Adams (a disintegrin and metalloproteinase domain).15-17 After activation. nevertheless.22 Defects in. are done so at very low levels. when expressed at all.26 It is believed that different integrins are responsible for mediating different cellular responses.and R-cadherin).13 There is some suggestion that MMP and TIMP expression vary among patients with facial form abnormalities (specifically long face syndrome).2. the exact cellular and molecular mechanisms that regulate and control myogenesis are not fully understood. the cadherins (M-. 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. This process is regulated using cell-cell and cell-matrix interactions as well as relying heavily on matrix secreted molecules. in healthy muscle tissue.Connective Tissue and Extracellular Matrix Signaling assays.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.13 MMP-2. blocking MMP-9 activity in these assays is sufficient to prevent migration. and the immunoglobulin superfamily (eg. of fusing with each other to create entirely new muscle fibers. lie between the sarcolemma of muscle fibers and the basal lamina in a mitotically quiescent state. Initial satellite cell activation depends on the correct up-regulation of a series of muscle specific genes and transcription factors.23.24 Integrins The integrin family is a group of cation-dependent.

2 The alternative splicing of certain ␣ and ␤ subunits (particularly ␣7 and ␤1) only acts to further complicate this matter. ␣6␤1 and ␣7␤1. (Color version of figure is available online.27.4 Of these. talin.30-32 However.33 Costameres Although faculties are present in many tissues. the major ECM components are collagen IV.27.138 A. as well as a wide array of other structural proteins. The localization of ␣7␤1 at both myotendinous and neuromuscular junctions in mature muscle suggests further roles for this integrin. rho GTPases and mitogen-activated protein kinase. and heparan sulfate proteoglycans.2 Sites of critical contact between cells and ECM molecules are mediated by integrins and known as focal adhesion complexes (FACs). along with the dystrophin-dystroglycan complex.25 It is this integrin. a striated muscle specific elaboration of this structure links it to the dystrophin-dystroglycan complex. is believed to be of primary importance in maintaining contact. thus linking the cell to the ECM. activates signaling cascades that ultimately result in alterations in gene expression.28 Phosphorylation of molecules. Facial and intraoral photographs of typical “long-face” deformity associated with muscular dystrophic disorders. linking their Z-lines to the sarcolemma and the ECM. This is vital as a means to better adapt the cell to changes in the functional demands on the tissue.34 These riblike structures are called costameres and lie at regular intervals along peripheral muscle fibers. that is believed to principally control skeletal muscle cell adhesion to the ECM.T. Smith et al Figure 2.27-29 In this way changes in ECM conditions can heavily influence gene expression within the cell.27-29 The formation of FACS also results in the intracellular tyrosine phosphorylation of a number of cytoplasmic factors.25 The laminin isoforms known to be present in developing and mature skeletal muscle are all ligands of the integrins ␣3␤1.S. Costameres are . and ␣ actinin) at that site. as well as to a cytoskeletal actin filament.29 This event triggers a clustering of similar receptors and the accumulation of actin binding proteins (eg. laminin.) often able to bind to several integrin receptors. paxilline.28 Faculties centre on the binding of an integrin receptor to its ligand in the ECM. as such. Photographs taken in occlusion. but also allows the ECM to self regulate the production of ECM factors from nearby cells. vinculin. such as focal adhesion kinase. not only in the maintenance of muscle integrity but also in neuromuscular connectivity and force transduction. of these 3 only ␣7␤1 is known to be present in mature muscle. As discussed earlier. laminin is the major cell adhesive found in skeletal muscle basement membranes and.

This mutation is the most common form of congenital muscular dystrophy. are higher following acute exercise. along with the ECM. acting as an anchor between muscle cells and the ECM and capable of binding both ␣-dystroglycan and the ␣7␤1 integrin. which together form an elastic element surrounding the muscle and running parallel to the long axis of the tissue. Force transmission continues along the myofibril in this manner until it reaches the myotendinous junction. resulting in the transmission of forces through the connective tissues.40 The role of laminins in maintaining ECM integrity.35 Longitudinal transmission of force is supplemented by lateral transmission.Connective Tissue and Extracellular Matrix Signaling believed to be essential to the maintenance of myofiber spatial organization during contraction. leading to severe muscle weakness and hypotonia.52 Together.49 Furthermore. 421. such as downhill running.42. inactivity for more than 48 hours has a dramatic. and 521. down-regulatory effect on the expression of collagens III and IV.36 The cross-linked nature of the ECM means that connecting muscle fibers to the ECM. dynamic ability of the muscle collagens to respond to changes in mechanical loading and .42 Response to Mechanical Force The functional matrix hypothesis states that the development and maintenance of all the body’s skeletal tissues and organs are compensatory responses to “temporally and operationally prior events. The ability of muscle fibers to contract means nothing if the force this generates cannot be suitably conducted to the tendons.46 highlights the importance of gravity.”44 Moreover.51 Conversely.37 Transduction of force is then further mediated by the coordinated contraction of the sarcolemma. there is evidence that collagen IV protein levels. forced contraction by electrical stimulation or prolonged periods of muscle loading.50. the inability of the dys- 139 troglycan molecule to bind laminin-211 results in its detachment from the basal lamina. 221. heterotrimeric glycoproteins that play a significant role in assembling and maintaining the basement membrane of many tissues. the breakdown and synthesis of collagen is an important factor in adapting muscle tissue to mechanical loading stimuli. the force generated is transferred to the next sarcomere in line.45 Extrinsic mechanical stimuli. these data give a strong indication as to the rapid. specifically in skeletal muscle. 411. is illustrated by specific types of muscular dystrophy.48. Enhanced collagen synthesis has been seen in response to differences in types and durations of loading.43 In such cases. cytoskeletal and intracellular structures.35-39 Laminins The laminins are a family of extracellular. Laminin-211 is an essential muscle laminin.40. Because the integrin ␣7␤1 and dystroglycan both constitute transmembrane proteins directly linking the cytoskeleton to the ECM. accounting for roughly 40% of all cases.35. the significant alteration in patterns of collagen synthesis in response to the mechanical unloading of rat hind limbs. When a sarcomere contracts. As the major component of vertebrate skeletal muscle ECM. it explains that epigenetic and extraskeletal processes are the primary cause of all adaptive responses of skeletal tissues. 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. Among other examples. ensures that all fibers are in turn linked to each other. aiding the generation of a uniformed contraction profile across the entire muscle. in both rats and humans. are therefore essential to the correct functioning and homeostasis of the skeletal muscle ECM. exercise and force transmission in the maintenance of the muscle connective tissues. were shown to respond with upregulated gene expression for collagens I.42 Patients with mutations in the laminin ␣2 chain present with a congenital muscular dystrophy 1-A phenotype. here. the contractile elements are linked to the tendon via the ECM and the generated force is passed across to the skeleton. it is likely that lateral force is transmitted across the membrane via these proteins. via costameres.41 The laminins typically seen in skeletal muscle tissue are 211.45 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.47 Rats subjected to exercise tests. III and IV.

56. is therefore dependent both on the magnitude and the pattern of strain to which the muscle is subjected.50. It is hardly surprising then that data from aged rats has shown an increase in the levels of crosslinking of the epimysial collagen fibers. A third possibility is an indirect effect. than in muscle injured during exercise.53 This leads to a characteristic stiffening of the tissue. where atrophy occurs. Several growth factors. may lead to more pronounced adaptation in the elevator and retractor muscles that are attached to the mandible. helping to explain the impairment of force generation found in the muscle tissues of the elderly subject.47 In vitro study of tissue responses to mechanical loading can have important implications for orthodontic therapies. rather than a gradual advancement. it is less well established how the cells are able to convert mechanical signals in the ECM into chemical signals and. in turn.54 Although it is understood that fibroblasts are largely responsible for producing collagen. such as focal adhesion kinase signaling. migration and differentiation of muscle cells in response to various external and internal . as well as eliciting control over other aspects of muscle biology.54 An immediate effect of changed signaling through activation of available transcription factors (such as NF-␬B) is 1 possibility. 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.55 indicating the high levels of ECM restructuring that occurs in response to load.56.47.57 MMP-2 expression.and endomysium and are attached to the ECM via integrins. via distraction histogenesis). The ability of these structures to remodel themselves and to regulate the activation. the fibroblasts are located within the peri. have been shown to be capable in vitro. Smith et al unloading. including transforming growth factor ␤1 and many insulinlike growth factor-1 splice variants.56. the MMPs. play key roles in the remodeling of the ECM structures.T. via a ramus osteotomy) rather than as a gradual process (eg. becomes more obvious and significant.S. Current theory is reviewed by SarasaRenedo and Chiquet. An alternative is a secondary effect whereby ECM molecule production is induced by increased expression of transcription factors themselves stimulated by activated pathways. an MMP-2 inhibitor.57 Similarly. repair and function improves. into altered gene expression. 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. which results in a reduction in the solubility and turnover of the molecules. Conclusions As our understanding of skeletal muscle development. and therefore ECM remodeling.47 In skeletal muscle.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.53 Endomysial collagen is primarily produced by fibroblasts although other cell lines. and MMP-2 in particular. mandibular advancement) if the procedure is carried out in a single activation (eg. the importance of the ECM in responding to external cues. contrasting strongly with the increase in TIMP-2 expression seen in overloaded muscle. where the mechanical stimulus triggers growth factor expression (or secretion) which then works in an autocrine/paracrine manner to induce ECM production.47 As discussed previously.47 This direct link allows the cells to register and respond to any mechanical stimuli transmitted through the ECM. where MMP-2 aids in the restoration of tissue function. Unloading has also been associated with reduced expression of TIMP-2.56 This finding suggests that the degradative activity of MMP-2 is higher in immobilized muscle.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 tissue’s ability to remodel itself.55. 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. a one-step activation of a myofunctional orthodontic/orthopedic appliance.140 A. can stimulate collagen synthesis and also are known to be regulated by mechanical loading in tendon and muscle. an ability that has been suggested to be essential to correct fibroblast functioning. including MPCs.

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