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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-
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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.)
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-
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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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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
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