Skeletal Muscle Extracellular Matrix – What Do We Know About Its Composition, Regulation, and Physiological Roles? A Narrative Review

Abstract

Skeletal muscle represents the largest body-composition component in humans. In addition to its primary function in the maintenance of upright posture and the production of movement, it also plays important roles in many other physiological processes, including thermogenesis, metabolism and the secretion of peptides for communication with other tissues. Research attempting to unveil these processes has traditionally focused on muscle fibers, i.e., the contractile muscle cells. However, it is a frequently overlooked fact that muscle fibers reside in a three-dimensional scaffolding that consists of various collagens, glycoproteins, proteoglycans, and elastin, and is commonly referred to as extracellular matrix (ECM). While initially believed to be relatively inert, current research reveals the involvement of ECM cells in numerous important physiological processes. In interaction with other cells, such as fibroblasts or cells of the immune system, the ECM regulates muscle development, growth and repair and is essential for effective muscle contraction and force transmission. Since muscle ECM is highly malleable, its texture and, consequently, physiological roles may be affected by physical training and disuse, aging or various diseases, such as diabetes. With the aim to stimulate increased efforts to study this still poorly understood tissue, this narrative review summarizes the current body of knowledge on (i) the composition and structure of the ECM, (ii) molecular pathways involved in ECM remodeling, (iii) the physiological roles of muscle ECM, (iv) dysregulations of ECM with aging and disease as well as (v) the adaptations of muscle ECM to training and disuse.

Full text

fphys-11-00253 March 17, 2020 Time: 16:37 # 1
REVIEW
published: 19 March 2020
doi: 10.3389/fphys.2020.00253
Edited by:
Olivier Seynnes,
Norwegian School of Sport Sciences,
Norway
Reviewed by:
Stefano Schiaffino,
Veneto Institute of Molecular Medicine
(VIMM), Italy
Dieter Blottner,
Charité – Universitätsmedizin Berlin,
Germany
*Correspondence:
Robert Csapo
robert.csapo@umit.at
Specialty section:
This article was submitted to
Striated Muscle Physiology,
a section of the journal
Frontiers in Physiology
Received: 06 December 2019
Accepted: 05 March 2020
Published: 19 March 2020
Citation:
Csapo R, Gumpenberger M and
Wessner B (2020) Skeletal Muscle
Extracellular Matrix – What Do We
Know About Its Composition,
Regulation, and Physiological Roles?
A Narrative Review.
Front. Physiol. 11:253.
doi: 10.3389/fphys.2020.00253
Skeletal Muscle Extracellular
Matrix – What Do We Know About Its
Composition, Regulation, and
Physiological Roles? A Narrative
Review
Robert Csapo1*, Matthias Gumpenberger1and Barbara Wessner2
1Research Unit for Orthopaedic Sports Medicine and Injury Prevention, Institute for Sports Medicine, Alpine Medicine &
Health Tourism, UMIT - Private University for Health Sciences, Medical Informatics and Technology, Hall, Austria,
2Department of Sports Medicine, Exercise Physiology and Prevention, Centre for Sport Science and University Sports,
University of Vienna, Vienna, Austria
Skeletal muscle represents the largest body-composition component in humans.
In addition to its primary function in the maintenance of upright posture and the
production of movement, it also plays important roles in many other physiological
processes, including thermogenesis, metabolism and the secretion of peptides for
communication with other tissues. Research attempting to unveil these processes has
traditionally focused on muscle fibers, i.e., the contractile muscle cells. However, it is a
frequently overlooked fact that muscle fibers reside in a three-dimensional scaffolding
that consists of various collagens, glycoproteins, proteoglycans, and elastin, and is
commonly referred to as extracellular matrix (ECM). While initially believed to be relatively
inert, current research reveals the involvement of ECM cells in numerous important
physiological processes. In interaction with other cells, such as fibroblasts or cells of
the immune system, the ECM regulates muscle development, growth and repair and is
essential for effective muscle contraction and force transmission. Since muscle ECM is
highly malleable, its texture and, consequently, physiological roles may be affected by
physical training and disuse, aging or various diseases, such as diabetes. With the aim
to stimulate increased efforts to study this still poorly understood tissue, this narrative
review summarizes the current body of knowledge on (i) the composition and structure
of the ECM, (ii) molecular pathways involved in ECM remodeling, (iii) the physiological
roles of muscle ECM, (iv) dysregulations of ECM with aging and disease as well as (v)
the adaptations of muscle ECM to training and disuse.
Keywords: muscle remodeling, matrix metallopeptidase, exercise training, aging, diabetes, fibrosis, connective
tissue, gene expression
INTRODUCTION
Skeletal muscle is an important body-composition component in humans, typically accounting for
more than 40% and 30% of total body mass in men and women, respectively (Kim et al., 2002).
The most apparent function of skeletal muscles is to generate the forces required to maintain an
upright posture and produce movement. However, skeletal muscles do also play important roles in
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many other physiological processes, including thermogenesis
(Rowland et al., 2015), metabolism (Baskin et al., 2015) and the
secretion of numerous peptides for communication with other
tissues (Pedersen and Febbraio, 2012). Thus, the promotion and
maintenance of skeletal muscle health is of vital importance.
Although, in recent years, pharmacological exercise mimetics
have attracted increasing scientific interest (Fan and Evans, 2017),
it is still physical exercise that is considered the by far most potent
and universally applicable tool for these purposes.
Over the past decades, thousands of training studies have
been performed in an attempt to identify the exercise modalities
most suited to increase muscle size and improve its functional
characteristics in different cohorts (for instance, at the time
this manuscript was written, Pubmed yielded more than 24,000
results for the search operators “exercise” and “muscle strength”).
The outcomes of these studies have inspired various exercise
prescription guidelines, probably the best known of which are
the position stands published and updated in irregular intervals
by the American College of Sports Medicine (2009),Garber
et al. (2011). Most studies base their evaluation of the efficacy
of training interventions on the examination of contractile
muscle cells. Frequently studied parameters involve muscle size
as measured at the organ (Fisher et al., 2011) or cellular level
(Schoenfeld, 2010), fiber type distribution (Adams et al., 1993),
architecture (Aagaard et al., 2001) as well as neural drive to
muscles (Folland and Williams, 2007).
The wealth of information on the malleability of skeletal
muscles notwithstanding, it is a frequently overlooked fact
that muscle fibers are embedded into an extracellular matrix
(ECM) consisting of a mesh of collagenous components
as well as a mixture of further macromolecules, such as
various glycoproteins and proteoglycans. Recent research has
demonstrated that the ECM plays an important role in the
development (Thorsteinsdóttir et al., 2011), growth (Fry et al.,
2017) and repair of muscles (Calve et al., 2010) as well as the
transmission of contractile force (Street, 1983). While evidence to
demonstrate the malleability of the ECM exists, only a paucity of
studies has reported its reactions to different forms of training,
suggesting that the physiological role of the ECM is not yet
fully appreciated by exercise specialists. Aiming to stimulate
further research into the training responses of the non-contractile
components of skeletal muscles, we provide an overview over
the current state of knowledge concerning the composition,
structure and regulation of the ECM, its physiological roles,
dysregulations associated with aging and metabolic disorders as
well as adaptations to physical exercise.
COMPOSITION AND STRUCTURE OF
SKELETAL MUSCLE ECM
The ECM of skeletal muscles is a complex meshwork consisting
of collagens, glycoproteins, proteoglycans, and elastin (Takala
and Virtanen, 2000;Halper and Kjaer, 2014). Collagens form
a network of intramuscular connective tissue (IMCT), i.e.,
the central, fibrous components of the ECM. The IMCT is
typically depicted to be organized in three layers: (i) the
endomysium, representing the innermost layer that encloses
individual muscle fibers, (ii) the perimysium bundling groups
of muscle fibers, and (iii) the epimysium enveloping the entire
muscle. The great structural complexity of the IMCT network
evidenced by scanning electron micrographs suggests that this
traditional classification may be simplistic and that a higher order
organization of muscle ECM yet needs to be defined (Gillies and
Lieber, 2011). Research into fascial tissues further considers the
layers of IMCT as part of a complex system of interconnected
and interwoven connective tissues that “surrounds, interweaves
between, and interpenetrates all organs, muscles, bones and
nerve fibers, endowing the body with a functional structure, and
providing an environment that enables all body systems to operate
in an integrated manner” (Adstrum et al., 2017;Stecco et al.,
2018). This system, which is commonly referred to as fascial
system, is increasingly recognized as important target in sports
medicine (Zügel et al., 2018).
The IMCT contains various forms of collagens with types I
and III being most abundant (Duance et al., 1977;Light and
Champion, 1984;Gillies and Lieber, 2011;McKee et al., 2019).
The endomysium interfaces with the myofiber sarcolemma at a
specialized basement membrane, which consists primarily of type
IV collagen and laminin (Sanes, 1982;Martin and Timpl, 1987;
Kjaer, 2004). The concentration of these two components has
been found to differ in dependency of muscle fiber type, with
slow twitch fibers featuring substantially greater concentrations
of collagen IV but lower concentrations of laminin (Kovanen
et al., 1988). Laminin, in turn, serves as ligand for two
sarcolemmal receptors – the dystrophin-associated glycoprotein
complex and the α7β1 integrin (Grounds et al., 2005) –
located at costameres, which are membrane-bound protein
structures aligned in register with the Z-disks of myofibrils.
Integrins are thought to act in a bidirectional manner, allowing
intracellular signaling molecules to regulate external adhesion
(“Inside-Out” signaling), and transferring external stimuli to
affect cellular processes (“Outside-In” signaling) (Boppart and
Mahmassani, 2019). Thereby, cytoskeletal sheer stress induces
the intracellular binding of proteins such as talin, vinculin
or kindlin, leading to a conformation change of the integrin
receptor and allowing the extracellular domains of the receptor
to extend toward proteins within the ECM. In addition, integrin
ligands from the extracellular space such as laminin, collagen or
fibronectin facilitate the formation of a high-affinity upright state,
leading to increased binding to ECM proteins and to integrin
clustering especially along focal adhesion complexes (Boppart
and Mahmassani, 2019). The dystrophin-associated glycoprotein
complex is another important factor in providing a mechanical
linkage between the contractile components of skeletal muscle
(i.e., actin) and the interconnected layers of the IMCT (Ervasti,
1993;Peter et al., 2011). The main components linking the
contractile elements of the muscle to the interstitial matrix are
shown in Figure 1.
The collagen superfamily contains a total of 28 different
members, of which types I, III, IV, V, VI, XII, XIII, XIV,
XV, XVIII, and XXII have been shown to be present in
mature skeletal muscle at the gene and/or protein level
(Table 1). The fibril-forming types I and III are by far
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FIGURE 1 | Main components of the skeletal muscle extracellular matrix and its linkage to the contractile components of muscle.
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TABLE 1 | Overview of collagenous components of the skeletal muscle extracellular matrix.
Gene(s) Skeletal muscle
RNA expression
(protein
expression
myocytes)*
Protein Form Appearance Role Source
COL1A1-2 1: 11.0 NX (not
detected) 2: 12.1
NX (low)
Collagen type I
alpha 1 and 2
chains
Fibrils Endo-, peri-, and
epimysium
Forms strong parallel fibers, confers
tensile strength and rigidity
Kovanen (2002)
COL3A1 14.5 NX (not
detected)
Collagen type III
alpha 1 chain
Fibrils Endo- and perimysium,
myotendinous junction
Forms a loose meshwork of fibers,
confers compliance
Kovanen (2002)
COL4A1-6 1: 24.6 NX (not
detected) 2: 26.3
NX (high) 3: 17.8
NX (not detected)
4: 7.5 NX (no data)
5: 4.8 NX (no data)
6: 1.0 NX (no data)
Collagen type IV
alpha 1-6 chains
Helices Basal lamina Produces a network structure,
constitutes the basis of the basal
lamina
Sanes (2003)
COL5A1-3 1: 5.0 NX (not
detected) 2: 3.7 NX
(no data) 3: 15.4
NX (medium)
Collagen type V
alpha 1-3 chains
Fibrils Endomysium Control of collagen fibrillogenesis Kovanen (2002)
COL6A1-6 1: 20.0 NX (not
detected) 2: 30.6
NX (not detected)
3: 31.8 NX (not
detected) 4: no
data 5: 0.2 NX (low)
6: 0.0 NX (medium)
Collagen type VI
alpha 1-6 chains
Beaded
filaments
Endo-, peri-, and
epimysium (α6-chain)
Basal lamina (α3-chain)
Myotendinous junction
(α5-chain)
Interacts with a large number of
molecules and cell surface
receptors, maintains muscle
functional integrity. Mutations
associated with fibrosis and Ullrich,
Bethlem or Myosclerosis
myopathies
Bönnemann
(2011),Sabatelli
et al. (2012),
Cescon et al.
(2015)
COL12A1 21.6 NX (medium) Collagen type XII
alpha 1 chain
FACIT Endo- and perimysium,
myotendinous junction
Linkage protein between fibrillar
collagens and other ECM
components
Jakobsen et al.
(2017)
COL13A1 2.7 NX (not
detected)
Collagen type XIII
alpha 1 chain
MACIT Neuromuscular junction Regulation and formation of
neuromuscular synapse. Lack
associated with myasthenia
Härönen et al.
(2017),Heikkinen
et al. (2019)
COL14A1 7.6 NX (not
detected)
Collagen type XIV
alpha 1 chain
FACIT Endo- and perimysium,
myotendinous junction
Linkage protein between fibrillar
collagens and other ECM
components. Increases following
training at myotendinous junction
(protection against strain injury?)
Jakobsen et al.
(2017)
COL15A1 12.8 NX (low to
medium)
Collagen type XV
alpha 1 chain
Multiplexin Basement membrane Stabilizes muscle cells and
microvessels. Guides motor axons
toward muscle targets. Deficiency
increases vulnerability to
exercise-induced muscle injury and
leads to mild forms of myopathies
Eklund et al.
(2001),Guillon
et al. (2016)
COL18A1 8.1 NX (not
detected)
Collagen type XVIII
alpha 1 chain
Multiplexin Basement membrane May bind growth factors. May link
the basement membrane to other
basement membrane glycoproteins
and endomysium
Gillies and Lieber
(2011),
Heljasvaara et al.
(2017)
COL19A1 3.7 NX (low) Collagen type XIX
alpha 1 chain
FACIT Basement membrane Presence at early embryonic stages
is relevant for the muscle tissue
differentiation. Acts as a
cross-bridge between fibrils and
other extracellular matrix molecules
Khaleduzzaman
et al. (1997),
Sumiyoshi et al.
(2001)
COL22A1 0.5 NX (not
detected)
Collagen type XXII
alpha 1 chain
FACIT Myotendinous junction Integrates ECM and contributes to
mechanical stability of the
myotendinous junction.
Knockdown of COL22A1 results in
dystrophy-like muscle phenotype in
zebrafish
Koch et al.
(2004),Charvet
et al. (2013)
*RNA expression summary shows the consensus RNA-data based on normalized expression (NX) data and protein expression comprises profiles using single as well as
independent antibodies directed against different, non-overlapping epitopes on the same protein from the Human Protein Atlas (http://www.proteinatlas.org, Uhlen et al.,
2010). FACIT, Fibril Associated Collagen with Interrupted Triple Helices; MACIT: Membrane Associated Collagen with Interrupted Triple Helices. Multiplexin: Collagen with
Multiple Triple Helix Interruptions.
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most abundant, with proteomic studies suggesting that they
jointly account for approximately 75% of total muscle collagen
(McKee et al., 2019). The strong parallel fibers of type I
collagen, which are present in the endo-, peri-, and epimysium,
are assumed to confer tensile strength and rigidity to the
muscle, whereas type III collagen forms a loose meshwork
of fibers that bestows elasticity to the endo- and perimysium
(Kovanen, 2002). Collagen type IV, a helical molecule, produces
a network structure that constitutes the basis of the basal
lamina (Sanes, 2003). Collagen type VI has been detected in
the epimysial, perimysial, and endomysial interstitium, but in
particular in the neighborhood of the basement membrane,
where it interacts with the carboxyl-terminal globular domain
of type IV collagen (Kuo et al., 1997). Interestingly, collagen
VI possesses untypical non-collagenous regions forming a
distinct microfibrillar network in most connective tissues (Maaß
et al., 2016). Collagen VI mutations result in disorders with
combined muscle and connective tissue involvement, including
Ullrich congenital muscular dystrophy, Bethlem myopathy, the
autosomal dominant limb-girdle muscular dystrophy and the
autosomal recessive myosclerosis (Bushby et al., 2014).
Collagen types XII, XIV, XIX, and XXII belong to the Fibril
Associated Collagens with Interrupted Triple helices (FACIT;
Chiquet et al., 2014;Calvo et al., 2020), whereby collagen type
XXII seems to be expressed exclusively at tissue junctions such
as the myotendinous junction in skeletal and heart muscle
(Koch et al., 2004).
Bioinformatic tools to screen the human proteome of
normal and diseased tissues allowed to characterize the
global composition of the ECM proteome, or “matrisome.”
In total, 1,027 genes have been linked to the ECM, whereby
core matrisome proteins (ECM glycoproteins, collagens,
and proteoglycans) could be distinguished from matrisome-
associated proteins (ECM-affiliated proteins, ECM regulators,
and secreted factors that may interact with core ECM proteins)
(Naba et al., 2016). Given the complexity of human skeletal
muscle tissue involving multinucleated muscle fibers, immune
cells, endothelial cells, muscle stem cells, non-myogenic
mesenchymal progenitors, and other mononuclear cell
(Bentzinger et al., 2013a), future research would be needed
to elucidate the contribution of each of these cells to the structure
and remodeling of the IMCT. Gene signatures derived, e.g., from
RNA-seq of isolated muscle fibers and other cell types comprise
a promising tool in the deconvolution of bulk skeletal muscle
tissue (Rubenstein et al., 2020).
PHYSIOLOGICAL REGULATION OF ECM
GENES
The homeostasis of the ECM is maintained through finely
tuned anabolic and catabolic processes that are governed by
various growth factors, proteoglycans and enzymes responsible
for collagen degradation. After binding to membrane-bound
receptors, growth factors belonging to the transforming growth
factor beta (TGF-β) superfamily have been found to induce the
phosphorylation of Smad proteins that transduce extracellular
signals to the nucleus where they activate downstream gene
transcription resulting in collagen production (MacDonald
and Cohn, 2012). Another, albeit less described, factor of
similar function is the connective tissue growth factor (CTGF),
overexpression of which has been reported to provoke dystrophy-
like muscle fibrosis and functional deficits (Morales et al., 2011).
The function of these anabolic factors is mostly regulated by
small leucine-rich proteoglycans (SLRPs). Decorin, the prototype
member of this family, deactivates the profibrotic TGF-βand
CTGF (Zhu et al., 2007;Brandan and Gutierrez, 2013) and also
limits fibrillogenesis by directly binding to type I collagen (Reese
et al., 2013). Another SLRP is represented by biglycan, which
competes with decorin for the same binding site on collagen
(Schönherr et al., 1995) and is likely to play a role in both muscle
formation and regeneration (Brandan et al., 2008).
Transcriptional regulation of protein formation seems to
be an important factor in ECM plasticity. In this respect, it
has been shown that protein expression in skeletal muscle is
weakly regulated at the mRNA level leading to big differences
in mRNA and protein abundance in various tissues (Wang
et al., 2019). Interestingly, the pattern of protein regulation
depends on protein function, whereby the association between
mRNA and protein is higher for ECM and collagen fibril
organization (Makhnovskii et al., 2020). Another interesting
aspect in the regulation of the amount of ECM proteins is the
fact that induction of transcription seems to be rather slow for
collagen as it takes almost 3 days to fully induce transcription.
In contrast secretion rates are adapted quickly as they are
elevated in less than 1 h. In high collagen producing cells, the
pathway is controlled by post-transcriptional regulation which
requires feedback control between secretion and translation rates
(reviewed in Schwarz, 2015).
With respect to tissue remodeling, two families of enzymes,
matrix metalloproteinases (MMPs) and tissue inhibitors of
metalloproteinases (TIMPs), are involved in the regulation of
ECM homeostasis. MMPs are proteolytic enzymes that degrade
various types of collagens and are inhibited by TIMPs (Visse
and Nagase, 2003;Alameddine, 2012). Specifically, MMP-1
and MMP-8 initiate the degradation of collagens I and III
(prevalent in endo-, peri-, and epimysium), whereas MMP-2 and
MMP-9 break down type IV collagen (the major collagenous
component of the basement membrane) (Corcoran et al., 1996).
TIMP-1, -2, and -4 are capable of inhibiting all known MMPs
(Christensen and Purslow, 2016).
ECM AND SKELETAL MUSCLE FORCE
The interaction of actin and myosin as well as many other
sarcomeric proteins results in shortening of muscle fibers.
Traditional biomechanical models often depict muscle-tendon
units as systems, in which the forces generated through fiber
shortening are transmitted longitudinally along the muscle fiber
and further, at the myotendinous junction, onto the tendon.
Close to the myotendinous junction, myofibers feature finger-
like processes, which are made from invaginations of the plasma
membrane (Knudsen et al., 2015). This structure increases the
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surface area available for force transmission. Force transmission
is expected to occur between the finger-like processes of the
muscle fiber and collagen fibers located within the invaginations
through shearing of the basal lamina (Huijing, 1999). The
collagens contained here are types XXII, which forms an inner
layer, as well as III, VI, XII, and XIV, which lie further away from
the muscle fiber membrane (Jakobsen et al., 2017). Although
its precise role is still unclear, it is interesting to note that in
muscles collagen XXII is exclusively located at the myotendinous
junction. In zebra fish, deficiency of collagen XXII has been found
to result in muscle dystrophy (Charvet et al., 2013), suggesting
that this collagen may serve to maintain the structural integrity
and stabilize the myotendinous junction.
Considering the fact that a significant portion of fibers in long
muscles terminate intrafascicularly without directly reaching
a tendon (Barrett, 1962;Hijikata et al., 1993), however, it is
clear that the myotendinous pathway cannot represent the only
mechanism of force transfer. Intrafascicularly terminating fibers
must rely on a medium arranged in parallel with them to transmit
their forces onto the passive components of the locomotor system
(Sheard, 2000). As first recognized by Street (1983), it is the
network of IMCT within the ECM that facilitates such lateral
transfer of contractile force. Force transmission across the IMCT
network occurs from contractile proteins across costameres to
the endomysium (Bloch and Gonzalez-Serratos, 2003;Peter et al.,
2011) – as modeling studies suggest through shearing (Sharafi
and Blemker, 2011;Zhang and Gao, 2012) – and further to
the perimysium which finally merges with aponeuroses and
tendons (Passerieux et al., 2007). The first information about the
proportions of longitudinal and lateral force transfer in striated
muscle stems from elegant experiments by Huijing et al. (1998).
After severing the direct connections of multiple heads of the
rat extensor digitorum longus muscle, corresponding to 55%
of the total muscle mass, from the joint tendon, Huijing et al.
(1998) observed that force was maintained at 84% of that of
intact muscle. More recently, Ramaswamy et al. (2011) used a
yoke apparatus to directly measure the forces transmitted via
the longitudinal and lateral pathway. Their results not only
confirmed that more than 50% of force was transmitted laterally
but also showed that lateral force transfer was significantly
reduced in both dystrophic and old rodents. Their results were
later confirmed by Zhang and Gao (2014).
Several arguments suggest that the lateral transmission
of force is a biomechanical necessity to maintain muscle
integrity and improve contraction efficiency. First, it helps to
distribute contractile forces over the entire surface of myofibers,
which reduces mechanical stress and protects fibers from
overextension. This may be particularly important in fiber end
regions, which are usually tapered and therefore ill-suited to
tolerate excessive forces (Monti et al., 1999). Indirect support
for this hypothesis is provided by studies in older subjects
(Hughes et al., 2016) or patients suffering from Duchenne
dystrophy (Virgilio et al., 2015), in whom dystrophin (i.e., a
costameric protein that establishes the mechanical connection
between cytoskeleton, sarcolemma and ECM and, thus, facilitates
lateral force transmission) is either lost or impaired and the
susceptibility for muscle strain injuries is increased.
Also, lateral force transfer is thought to bridge fibers
contracting either at different times or to unequal extents
(Yucesoy et al., 2006), which would help maintain fiber
alignment and, thus, the muscle’s structural integrity (Purslow,
2002). Recently, Dieterich et al. (2017) compared the onset of
contraction as determined by electromyography and M-mode
ultrasound imaging. Counterintuitively, the authors found the
motion onset to precede the electromyography signal in ∼20%
of trials, which might be explained by lateral force transfer.
Indeed, while longitudinal transmission of forces may be delayed
by the need to tauten the elastic elements placed in series with
the muscle (Nordez et al., 2009), the translaminar shear linkage
between muscle fibers and the IMCT network may allow for
immediate force transmission. Finally, lateral force transmission
provides a mechanism whereby force may still be generated
and transmitted from muscle fibers that are interrupted due to
microtrauma or during muscle growth (Purslow, 2010).
In addition to its role in the lateral transfer of contractile
force, the ECM may also affect muscle fiber shortening. The
contractility of myofibers is often assumed to be constrained by
the geometry of its constituting sarcomeres: Sarcomere and, thus,
fiber shortening stops when z-bands come in contact with myosin
filaments. However, these ideas consider only the behavior
of the sarcomere as an independent actuator. Under in vivo
conditions, muscle fibers are embedded into the IMCT network
which may interfere with fiber shortening. Indeed, the constant
volume principle (Baskin and Paolini, 1967) dictates that during
shortening muscle fibers must undergo radial expansion, which
has long been experimentally confirmed even at the sarcomeric
level (Brandt et al., 1967). Novel computational models and
in situ measurements in frog muscles by Azizi et al. (2017)
have demonstrated that muscle shortening is hindered when
radial expansion is limited through physical constraints. Hence,
changes in the amount and mechanical properties of the IMCT
network into which muscle fibers are embedded may directly
affect skeletal muscle contractility. Such a scenario may be
represented by muscle fibrosis (Gillies et al., 2017).
ECM IN SKELETAL MUSCLE
DEVELOPMENT, GROWTH, AND REPAIR
Apart from force transfer, the skeletal muscle ECM fulfills several
important functional roles. Apparently, the IMCT network
provides mechanical support to muscle fibers as well as the
nerves and blood vessels supporting them. Blood capillaries
run in the interstices occupied by endomysium, with their
number and density being contingent upon muscle fiber size
(Janácek et al., 2009). In addition to this most obvious role, the
interaction between myoblasts, differentiated muscle fibers and
ECM components is of central importance for the embryogenic
development, further growth, and repair of muscle tissue.
The cellular source of the collagenous components of muscle
ECM are dedicated IMCT fibroblasts, which originate from
different embryogenic sources, including the somites (Nowicki
et al., 2003), the lateral plate mesoderm (Pearse et al., 2007)
and the neural crest cells (Olsson et al., 2001). As they produce
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not only fibroblasts but also adipogenic cells, IMCT fibroblasts
may be considered as fibroadipogenic progenitors (Uezumi et al.,
2010). Recent research has provided evidence that, in addition to
these obvious roles, IMCT fibroblasts and the connective tissues
produced by them influence both myogenesis (i.e., the formation
of muscle progenitors and their differentiation into multinucleate
myofibers) and muscle morphogenesis (i.e., the process in
which myofibers are assembled into muscles), thus acting as
important regulators of muscle development. These complex
regulatory processes occurring during embryogenic development
are not covered in detail here, but have been extensively
reviewed elsewhere (Nassari et al., 2017;Sefton and Kardon,
2019). In brief, the IMCT guides muscle progenitors to their
designated target regions, through a combination of attractive
(Hepatocyte Growth Factor, Stromal Cell-Derived Factor) and
repulsive signals (Ephrin) (Dietrich et al., 1999;Swartz et al.,
2001). Through a myriad of transcription factors expressed in
IMCT fibroblasts, the IMCT then promotes the proliferation,
survival and differentiation of neighboring myoblasts into mature
myofibers (Kardon et al., 2003;Hasson et al., 2010;Iwata et al.,
2013;Vallecillo-García et al., 2017). Thus, it may be speculated
that the IMCT serves as a mesodermal prepattern that controls
the sites of myofiber differentiation and, consequently, the
ultimate position, size, and shape of muscles.
As post-mitotic tissues, skeletal muscles depend on satellite
cells to adapt and regenerate throughout life. These stem cells
reside in specialized niches between the sarcolemma of muscle
fibers and their encapsulating basement membranes. Satellite
cell maintenance, activation and differentiation are governed by
complex cascades of transcription factors. For an extensive review
of these cellular circuitries, readers are referred to the recent
review by Almada and Wagers (2016). Of particular relevance
to this manuscript, a growing body of evidence suggests that
satellite cell fate is also strongly influenced by the interactions
with the ECM niche in which they reside. Indeed, as a dynamic
environment, the stem cell niche transmits mechanical and
chemical signals that act to protect quiescent stem cells or induce
activation, proliferation, and differentiation.
In the quiescent state, satellite cells express the canonical
cell regulator paired box protein 7 (PAX7) (Olguin and Olwin,
2004). In vitro studies have demonstrated that a greater portion
of satellite cells express PAX7 when cultured on matrigel, a
mixture of ECM proteins and growth factors (Wilschut et al.,
2010;Grefte et al., 2012). Further support for the notion that
the ECM is actively involved in the maintenance of satellite cell
quiescence comes from reports that satellite cells removed from
their niche quickly enter the cell cycle and lose their capacity
for myogenic differentiation (Gilbert et al., 2010). Intriguingly,
satellite cells appear to also be able to sense and respond to
different ECM mechanical properties. In fact, PAX7 expression
and satellite cell survival are greater when cultured on hydrogels
that mimic the physiological stiffness of muscle (Gilbert et al.,
2010). Also, satellite cells cultured on soft hydrogel feature greater
functional capacity after transplantation into recipient muscle
(Cosgrove et al., 2014).
In addition, ECM components have been shown to influence
stem cell division. Specifically, the proteins fibronectin
(Bentzinger et al., 2013b) and collagen VI (Urciuolo et al.,
2013) as well as the proteoglycans syndecan 3, syndecan 4,
perlecan, and decorin (Cornelison et al., 2001;Brack et al., 2008)
have been identified as the niche constituents influencing the
balance between differentiation and self-renewal and, thus, the
maintenance of skeletal muscles’ regenerative capacity.
Upon muscle trauma or in response to increased loading,
the usually mostly quiescent satellite cells become activated and
differentiate into myoblasts to finally fuse into mature myofibers.
While this process requires the timely expression of various
transcription factors, such as myogenic factor 5, myogenic
determination protein or myogenin (Almada and Wagers, 2016),
several studies point to the influence of the ECM on each
of these steps. Experiments with mouse (Grefte et al., 2012)
or porcine myoblasts (Wilschut et al., 2010) have shown that
myoblast fusion is positively influenced by matrigel but not by
single substrates present in the ECM niche. The contributions
of single proteins are still poorly understood, however, the
concomitant presence of poly-D-lysine and laminin (Boonen
et al., 2009), glycosaminoglycans (Rønning et al., 2013), and
heparin sulfate proteoglycans (Gutiérrez and Brandan, 2010)
appear to play a prominent role in satellite cell proliferation
and differentiation. Upon activation of skeletal muscle stem cells,
local remodeling of the ECM is accompanied by the deposition
of laminin-α1 and laminin-α5 into the basal lamina of the
satellite cell niche (Rayagiri et al., 2018). In mice, it has been
shown that muscle satellite cells produce ECM collagens to
maintain quiescence in a cell-autonomous manner with collagen
V being a critical component of the quiescent niche, as depletion
leads to anomalous cell cycle entry and gradual diminution
of the stem cell pool (Baghdadi et al., 2018). Just as for the
maintenance of quiescence, adequate mechanical properties of
the ECM niche may also be important for satellite cell maturation.
Indeed, myotubes have been found to differentiate optimally
on substrates with muscle-like stiffness (Engler et al., 2004).
Jointly, these data suggest that ECM stiffening accompanying
both different musculo-skeletal disorders and the aging process
may negatively influence a muscle’s regenerative capacity.
REMODELING OF MUSCLE ECM WITH
AGING
At older age, skeletal muscles typically demonstrate fibrotic
morphology (Lieber and Ward, 2013). As opposed to fascial
densification, where the general structure of collagens may be
preserved (Pavan et al., 2014), age-associated muscle fibrosis
is characterized by the loss of the clear two-directional
lattice orientation of healthy perimysial collagen fibers and its
replacement by an erratic fiber network featuring decreased
crimp formation (Järvinen et al., 2002). Also, absolute collagen
content and (non-enzymatic) cross-linking of collagen fibers may
be increased (Haus et al., 2007b). Thereby, the elastic modulus of
the ECM can be increased approximately 35-fold (from ∼12 kPa
in young to ∼418 kPa in old muscle; Yin et al., 2013), with
this effect being driven by an accumulation of densely packed
and extensively cross-linked collagen (Wood et al., 2014). In
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large-bodied, long-lived animals, such as the Weddell seals, a
35–40% increase in extracellular space has been observed as
total and relative collagen contents increase with age. However,
this increase is associated with a shift toward a higher ratio of
type I to type III collagen (Hindle et al., 2009). Furthermore,
collagen type IV concentration is enhanced in the basal lamina
of slow twitch muscles, whereas laminin concentration seems
to decrease with age (Kovanen et al., 1988). The increased
deposition of basal lamina proteins has also been shown to expel
satellite cells from their niches, which affects the regulation of
satellite cell divisions (Snow, 1977) and may explain the lower
numbers of satellite cells typically counted in old as compared
to young muscle (Brack et al., 2007). The loss and functional
inactivation of stem cells that negatively affects tissue homeostasis
can be considered a general hallmark of aging (López-Otín et al.,
2013) that must be considered a universal force driving the
aging of muscle (Brack and Muñoz-Cánoves, 2016) and other
tissues (Oh et al., 2014). In addition to its effects on satellite
cells, a dysregulated basal lamina is also expected to disturb
the muscle’s regenerative capacity through inadequate support of
muscle fibers and disorganized scaffold orientation (Sanes, 2003).
A review including an extensive summary of the effects of aging
on skeletal muscle ECM has recently been published by Etienne
et al. (2020).
Interestingly, data from transcriptional profiling of muscles
derived from young and old rats suggest that out of 682
probe sets that differed significantly between young and old
animals, 347 genes actually decreased (rather than increased)
in aged/sarcopenic muscle relative to young muscles. Of these
genes, 24% have been shown to exert a biological role in the
ECM and cell adhesion (Pattison et al., 2003). These data support
the hypothesis that age-associated changes in the ECM might
be driven by a decreased degradation capacity rather than by
increased synthesis of collagenous structures. Especially, MMPs
seem to play an important role in these processes (de Sousa Neto
et al., 2018). This is further supported by findings that suggest
a diminished resistance exercise-induced remodeling capacity of
ECM structures in aged muscles (Wessner et al., 2019). While the
mechanisms are not yet fully understood, these changes are also
believed to directly impair muscle function by hindering fiber
contractility (Azizi et al., 2017) and lateral force transmission
(Sharafi and Blemker, 2011).
DYSREGULATION OF SKELETAL
MUSCLE ECM CONSEQUENT TO
METABOLIC DISORDERS
It is well known that skeletal muscle plays an important role for
the insulin-stimulated uptake of glucose (Richter and Hargreaves,
2013). The role of the ECM in this context might be less clear.
Muscle-specific integrin β1-deficient mice exhibit a reduction of
the insulin-stimulated glucose infusion rate and glucose clearance
despite no alterations in food intake, weight, fasting glucose,
insulin levels, and GLUT4 protein expression (Zong et al., 2009)
suggesting a relationship between aberrant integrin signaling
and the development of type 2 diabetes. Furthermore, it has
been shown in an animal model of diabetes that impaired
insulin sensitivity is associated with reduced protein levels of the
Dp427 isoform of dystrophin and the alpha/beta-dystroglycan
subcomplex (Mulvey et al., 2005).
Increased amounts of type I and III collagen were found
in both type 2 diabetic and also non-diabetic obese subjects
(Berria et al., 2006) and overfeeding in humans was associated
with increases in the expression of genes associated with the
IMCT (collagens I, III, IV, V, SPARC, integrin; Tam et al.,
2014) and alterations in gene pathways related to ECM receptor
interaction, focal adhesion, and adherens junction (Tam et al.,
2017). However, feeding a high-fat diet to mice led to a reduction
of COL1, COL3, and COL6 gene expression levels, but not
protein levels (Tam et al., 2015).
The degradation of collagens through MMPs has been shown
to be an essential constituent of ECM remodeling (Cui et al.,
2017). Whether this might also be true in the context of diabetes
has been investigated in an animal study. Interestingly, the
genetic depletion of MMP9 did not induce insulin resistance
in lean mice despite resulting in an increase of collagen IV.
However, when mice were fed a high-fat diet the deletion caused
a profound state of insulin resistance. These results further
strengthen the role of IMCT components in the progress of
muscle insulin resistance, especially in a state of overfeeding
(Kang et al., 2014).
Finally, hyaluronan, a major constituent of the ECM is
increased in high-fat diet-induced obesity in mice. Treatments
with PEGPH20, which dose-dependently reduces hyaluronan in
muscle ECM is suggested for the treatment of insulin-resistance
with a concomitant decrease in fat mass, adipocyte size, as well as
hepatic and muscle insulin resistance (Kang et al., 2013).
To summarize, various components of the ECM have been
shown to be affected in various stages of diabetes. Studies on
whether diabetes is linked to muscle weakness are controversial
(Leong et al., 2015;Li et al., 2016) and it remains to be
elucidated whether the changes in ECM-related pathways are
directly involved in this context.
ADAPTATIONS TO PHYSICAL TRAINING
AND DISUSE
The first evidence to indicate the malleability of IMCT in
response to physical activity was published as early as in the
1970s, when Suominen and Heikkinen (1975) and Suominen
et al. (1977) found greater levels of prolyl hydroxylase (an
enzyme promoting the biosynthesis of collagen) in endurance-
trained athletes as well as, in a longitudinal study, after eight
weeks of aerobic training. The effect of endurance exercise on
the pro-collagenous enzymatic activity was later found to be
more prominent in red as compared to white muscle (Takala
et al., 1983). Direct measurements of collagen content first
performed in the late 1980s confirmed that the (type IV) collagen
content increased in the fatigue-resistant soleus muscle of rats
following lifelong endurance training (Kovanen et al., 1988).
The exercise-induced increase in collagen notwithstanding,
Gosselin et al. (1998) found that the muscle stiffening observed
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with advancing age could be countered by an endurance
exercise intervention, which the authors related to reduced
hydroxylysylpyridinoline cross-linking of collagen fibers.
The effects of immobilization on the skeletal muscle ECM
are not entirely unequivocal. Early studies by Karpakka et al.
(1990, 1991) found both hydroxylase activity and hydroxyproline
(an amino acid constituting collagens) content to be reduced
in rats. Changes in collagen content in response to short-term
immobilization or disuse were later found to be rather small
(Savolainen et al., 1988;Haus et al., 2007a), which may be
explained by a relatively slow turnover rate. A more recent
study, by contrast, found the content of collagen I and the
biomechanical properties (elastic modulus, max stress and yield
stress) of crural fascia ensheathing the rat triceps surae muscle
to be significantly increased after as little as 21 days of hindlimb
unloading (Huang et al., 2018). Interestingly, these changes
could be prevented through the application of vibration to
the rats’ hind paws twice a day. In non-exercising humans,
immunohistochemical staining suggested no changes in the
density of the collagen I network after 60 days of bed rest.
In subjects performing a countermeasure exercise protocol
consisting of reactive jumps on a sledge system, by contrast,
collagen I immunoreactivity was reduced as compared to baseline
levels (Schoenrock et al., 2018).
Yet another model that allows for the adaptability of muscles’
ECM to be studied is functional overload induced by surgical
synergist elimination. In one of the first respective studies,
Williams and Goldspink (1981) severed the tendons of the
plantaris and gastrocnemius muscles of male rats to overload the
soleus muscles. The muscle hypertrophy observed three weeks
after tenotomy was accompanied by increases in the IMCT
concentration (>45%) and the IMCT-to-muscle tissue ratio.
Histological analyses further suggested that the increase in IMCT
was mostly due to a thickening of the endomysium. Focusing
on the myotendinous junction, Zamora and Marini (1988)
performed similar experiments and isolated the rat plantaris
muscle through tenotomy of the soleus and ablation of the
gastrocnemius muscles. In comparison with control animals, the
fibroblasts located at the myotendinous junction developed a
higher degree of activation of cytoplasm, nucleus and nucleolus
after as little as one to two weeks of functional overload.
A more recent study tested the effect of IL-6 on overload-
induced ECM remodeling by comparing wild-type and IL-6-
knockout mice (White et al., 2009). While the gains in myofiber
cross-sectional area were similar after 21 days of functional
overload, the increases in muscle wet weight were significantly
larger in IL-6-knockout mice. Histological analyses confirmed
that this surplus gain in muscle weight could be explained by
significantly larger increases in non-contractile tissue content and
hydroxyproline concentration, which is indicative of collagen
content and fibrosis. In agreement with this observation,
procollagen-1, IGF-1, and TGF-βmRNA levels were significantly
higher in IL-6-deficient mice. Conversely, mRNA expression
of MyoD, a transcription factor required for myo- rather than
fibrogenic differentiation of satellite cells (Zammit, 2017), was
significantly attenuated in animals lacking IL-6. Jointly, these
results indicate that synergist elimination induces an increase
in IMCT content and, specifically, a thickening of endomysial
structures in overloaded muscles. These adaptations may serve
to modulate the muscles’ non-contractile structures to increased
functional demands. IGF-1 appears to play an important role in
the regulation of this process, as lack of IGF-1 has been shown
to lead to excessive accumulation of IMCT and, potentially,
impaired muscle regenerative potential.
One of the first studies to test and compare different forms
of resistance-like exercise in men was performed by Brown et al.
(1999) who reported that, following a single bout of concentric
contractions, markers of collagen breakdown (hydroxyproline
and serum type I collagen) were not increased. By contrast,
eccentric muscle action increased serum collagen levels by
>40% for up to 9 days post-exercise, indicating that eccentric
contractions may be superior in promoting collagen breakdown.
These results were confirmed in two later studies similarly
using high-intensity eccentric exercise that found both increased
procollagen processing and type IV collagen content as well
as higher MMP and TIMP activities (Crameri et al., 2004;
Mackey et al., 2004). Interestingly, Crameri et al. (2004, 2007)
also reported an increase in tenascin C, a glycoprotein present
in the ECM that is assumed to direct cell migration following
injury, irrespective of whether muscle damage was induced by
voluntary or electrically induced muscle damage. The transient
upregulation of tenascin C and other ECM glycoproteins (e.g.,
fibronectin and hyaluronic acid) is usually referred to as the
“transient matrix,” the appearance of which is considered an
essential first step for successful muscle repair, as it provides
important cues driving muscle stem cell regenerative potential
(Calve et al., 2010;Tierney et al., 2016). The release of ECM
glycoproteins is reportedly accompanied by increased MMP-9
activity in young, but decreased MMP-9 and MMP-15 activity
in old subjects (Wessner et al., 2019). These findings suggest
that an acute bout of resistance exercise triggers a catabolic
response in young muscle but that this effect may be impaired
at older age. The subsequent anabolic reaction, characterized by
the upregulation of structural collagens (I, III, IV) and laminin,
has been found to occur with a significant delay, thus suggesting
that muscle repair consequent to an acute bout of damaging
(lengthening) contractions follows a biphasic nature (Mackey
et al., 2011;Hyldahl et al., 2015). Interestingly, a recent study by
Sorensen et al. (2018) found that the appearance of the transient
matrix was blunted in physically active old as compared to young
subjects. This observation supports the notion that dysregulated
ECM cues may be responsible for the increased ECM deposition
and reduced stem cell activity typically seen in older muscle
(Grounds, 1998).
One of the first studies to directly compare different forms of
muscular contraction in terms of their acute ECM remodeling
potential was published by Heinemeier et al. (2007). These
authors performed a study in rodents and found that the
activity of genes associated with collagen biosynthesis (e.g.,
collagens I and III) as well as growth factors (e.g., TGF-β1)
were upregulated after all forms of physical exercise but most
prominently so after eccentric training. In humans, collagen
protein fractional synthesis rates have also been proposed to be
more increased following an acute bout of eccentric as compared
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to concentric training (Holm et al., 2017), although this notion
is not unchallenged (Moore et al., 2005). Jointly, these results
suggest that particularly eccentric exercise is a potent stimulus
that induces microtrauma and IMCT cell turnover, with the
latter assumed to represent the organism’s attempt to prevent
the muscle from re-injury (Mackey et al., 2011;Hyldahl et al.,
2015;Takagi et al., 2016). In fact, diminished MMP activity after
prolonged training consisting of electrically evoked isometric
contractions in rats may reflect successful ECM reinforcement
(Ogasawara et al., 2014), whereas prolonged increases in MMP-
and TIMP-activity in the plantaris muscle of mice following
surgical removal of the gastrocnemius and soleus muscle could
be indicative of ongoing ECM remodeling (Mendias et al., 2017).
In addition to contraction mode, skeletal muscle ECM may
also be sensitive to exercise intensity. Carmeli et al. (2005) tested
the effects of treadmill running at either high or low intensity
in rats and found that MMP-2 (one of the enzymes responsible
for the breakdown of collagen IV mainly present in the
muscle’s basement membrane) was increased after high-intensity
exercise only. In humans, by contrast, one study by Holm
et al. (2010) compared the effects of unilateral knee extension
exercise as performed at either low or high (16% or 70% of the
individual one-repetition maximum, respectively) intensity, with
the number of repetitions adjusted to match the interventions for
the total load lifted. In this study, collagen fractional synthesis
rates were evenly increased following both interventions.
In terms of ECM adaptations to prolonged resistance training,
only data from animal studies exist. de Sousa Neto et al. (2018)
reported that 12 weeks of resistance training consisting of ladder
climbs with progressive, additional loads equivalent to 65–100%
of each individual’s maximum carrying capacity upregulated
MMP-2 activity in the plantarflexor muscles of old rats, while
down-regulating MMP-2 and MMP-9 in blood circulation. The
authors’ conclusion that resistance training might, therefore, be
a useful tool to maintain ECM remodeling at older age has
recently received empirical support by another training study
in rats that used the same training protocol and showed a
reduced deposition of connective tissue in trained older muscles
(Guzzoni et al., 2018).
To summarize, several studies investigating the acute effects
of physical activity in both rodents and men have indicated
that exercise may stimulate both the degradation and synthesis
of collagen in skeletal muscle. The repair of exercise-induced
microtrauma follows a biphasic pattern, in which glycoproteins
first create a transitional matrix to guide catabolic processes,
and anabolic processes to reinforce the IMCT structure occur
with a significant delay. The potential of exercise to induce
ECM remodeling seems to be dependent on contraction mode
with eccentric contractions triggering a greater response than
either concentric or isometric muscle action. Few studies testing
the results of different exercise intensities are available, with
so-far results suggesting that protein breakdown (but not
synthesis) may be provoked more strongly by higher intensities.
Disuse acutely downregulates the activity of enzymes related
to the biosynthesis of collagens, although at the protein-level
changes occur at a slow rate. Cross-sectional comparisons
involving (mostly endurance-) trained rodents suggest that
chronic physical activity may result in a reinforced IMCT
phenotype. The only long-term longitudinal training studies
available to date have been performed in rodents and suggest
that prolonged resistance training may be useful in countering
excessive IMCT accumulation at older age. The physiological and
functional consequences of training-induced IMCT remodeling
require further investigation.
CONCLUSION
The present review aimed to provide an overview over the current
state of knowledge concerning the skeletal muscle ECM, which
plays an essential, albeit frequently underestimated role in the
maintenance of muscle homeostasis, influences muscle function
and adaptation and may be a key for the treatment of muscular
and metabolic disorders consequent to aging or disease.
As a complex meshwork of various collagens, glycoproteins,
proteoglycans and elastin, the ECM embeds contractile
muscle fibers and serves via integrins and the dystrophin-
associated glycoprotein complex, respectively, as biochemical
and mechanical interface between muscle cells and their
surroundings. The assembly of its collagenous scaffold is mostly
promoted by the growth factors TGF-βand CTGF, which
are regulated by different proteoglycans, such as decorin and
biglycan. Moreover, proteolytic enzymes (MMPs) as well as their
inhibitors (TIMPs) are involved in ECM regulation.
Functionally, the ECM serves as medium for the transmission
of contractile force, which may not only serve to increase
the efficiency of muscular contraction but also to protect
muscle fibers from excessive stress and facilitate healing
of microtrauma. In addition to its functional role, the
ECM is actively involved in the regulation of the muscle’s
pool of satellite cells. ECM niches, established between
sarcolemma and basement membrane, protect satellite cell
from entering the cell cycle and, thus, help maintain the
muscle’s regenerative potential. Specific ECM components, such
as fibronectin, collagen VI and different proteoglycans, may
additionally promote stem cell division. Conversely, laminin,
glycosaminoglycans and other proteoglycans have been shown
to promote satellite cell differentiation and their fusion into
mature myofibers.
Scientific evidence further demonstrates that the ECM
of skeletal muscles is a malleable tissue that may undergo
remodeling processes consequent to aging, disease, physical
training or disuse. Specifically, aging typically leads to overall
increased deposition of collagenous tissue, changes in collagen
composition (shift toward higher type I to type III collagen)
and increased non-enzymatic collagen cross-linking (through
advanced glycation end products). These changes, which are
possibly mediated through decreased MMP activity, lead to
stiffening of the muscle’s ECM and may impair the muscle’s
function and regenerative potential.
Extracellular matrix remodeling may also be associated with
metabolic disorders, such as diabetes. Excessive food intake has
been found to lead to increased expression of ECM-related genes
(collagens I, III, IV, V, SPARC, integrin). In turn, such remodeling
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Csapo et al. Skeletal Muscle ECM
may impair integrin signaling, thus reducing insulin sensitivity.
Further ECM components potentially representing targets for
insulin resistance are hyaluronan, the dystrophin-dystroglycan
complex as well as MMP9.
Finally, ECM remodeling may be triggered by physical
exercise. While actual training studies are scant, there is
evidence to show that exercise may acutely promote both
increased collagen synthesis (collagens I, III, TGF-β1) and
degradation (MMP2, MMP9). Cross-sectional studies in humans
and longitudinal studies in rodents further suggest that such
increased collagen turnover may lead to reinforced collagenous
structures in chronically trained subjects and prevent excessive
collagen deposition (i.e., fibrosis) in elderly muscle. Studies
investigating the consequences of prolonged disuse have shown
controversial results. While early studies reported decreased
hydroxylase activity and hydroxyproline content after short-term
immobilization, more recent works found increased collagen
I content after 21 days of hindlimb unloading in rats but no
change after 60 days of bed rest in humans. Further research and
particularly human training studies are required to investigate
the influence of different training modalities on ECM structure
and composition.
AUTHOR CONTRIBUTIONS
RC contributed to the literature research and drafted the
manuscript. MG and BW contributed to the literature research
and revised the manuscript. All authors have approved the final
version of the manuscript and agreed to be accountable for all
aspects of the work. All persons designated as authors qualify for
authorship, and all those who qualify for authorship are listed.
ACKNOWLEDGMENTS
We gratefully acknowledge the financial support for this study
received from the Austrian Science Fund (FWF): KLI 738-B27.
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Conflict of Interest: The authors declare that the research was conducted in the
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