Where is skeletal muscle

Such a scenario may be represented by muscle fibrosis Gillies et al. 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.

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.

As they produce not only fibroblasts but also adipogenic cells, IMCT fibroblasts may be considered as fibroadipogenic progenitors Uezumi et al. 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.

These complex regulatory processes occurring during embryogenic development are not covered in detail here, but have been extensively reviewed elsewhere Nassari et al.

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. 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 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, 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.

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.

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.

Also, satellite cells cultured on soft hydrogel feature greater functional capacity after transplantation into recipient muscle Cosgrove et al.

In addition, ECM components have been shown to influence stem cell division. Specifically, the proteins fibronectin Bentzinger et al. 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, , several studies point to the influence of the ECM on each of these steps.

Experiments with mouse Grefte et al. The contributions of single proteins are still poorly understood, however, the concomitant presence of poly- D -lysine and laminin Boonen et al. 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.

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. At older age, skeletal muscles typically demonstrate fibrotic morphology Lieber and Ward, As opposed to fascial densification, where the general structure of collagens may be preserved Pavan et al. Also, absolute collagen content and non-enzymatic cross-linking of collagen fibers may be increased Haus et al.

However, this increase is associated with a shift toward a higher ratio of type I to type III collagen Hindle et al. 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.

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, and may explain the lower numbers of satellite cells typically counted in old as compared to young muscle Brack et al. A review including an extensive summary of the effects of aging on skeletal muscle ECM has recently been published by Etienne et al.

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. This is further supported by findings that suggest a diminished resistance exercise-induced remodeling capacity of ECM structures in aged muscles Wessner et al. 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.

It is well known that skeletal muscle plays an important role for the insulin-stimulated uptake of glucose Richter and Hargreaves, The role of the ECM in this context might be less clear. Increased amounts of type I and III collagen were found in both type 2 diabetic and also non-diabetic obese subjects Berria et al. 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.

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.

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. The first evidence to indicate the malleability of IMCT in response to physical activity was published as early as in the s, when Suominen and Heikkinen and Suominen et al. 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.

Direct measurements of collagen content first performed in the late s confirmed that the type IV collagen content increased in the fatigue-resistant soleus muscle of rats following lifelong endurance training Kovanen et al. The exercise-induced increase in collagen notwithstanding, Gosselin et al. The effects of immobilization on the skeletal muscle ECM are not entirely unequivocal.

Early studies by Karpakka et al. Changes in collagen content in response to short-term immobilization or disuse were later found to be rather small Savolainen et al. 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.

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.

In one of the first respective studies, Williams and Goldspink severed the tendons of the plantaris and gastrocnemius muscles of male rats to overload the soleus muscles.

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 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.

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 ILknockout 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. Conversely, mRNA expression of MyoD, a transcription factor required for myo- rather than fibrogenic differentiation of satellite cells Zammit, , was significantly attenuated in animals lacking IL Jointly, these results indicate that synergist elimination induces an increase in IMCT content and, specifically, a thickening of endomysial structures in overloaded muscles.

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.

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.

Interestingly, Crameri et al. The transient upregulation of tenascin C and other ECM glycoproteins e. 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.

Interestingly, a recent study by Sorensen et al. 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, 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.

These authors performed a study in rodents and found that the activity of genes associated with collagen biosynthesis e. In humans, collagen protein fractional synthesis rates have also been proposed to be more increased following an acute bout of eccentric as compared to concentric training Holm et al. In fact, diminished MMP activity after prolonged training consisting of electrically evoked isometric contractions in rats may reflect successful ECM reinforcement Ogasawara et al. In addition to contraction mode, skeletal muscle ECM may also be sensitive to exercise intensity.

Carmeli et al. In humans, by contrast, one study by Holm et al. 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. 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. 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.

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. 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.

Extracellular matrix remodeling may also be associated with metabolic disorders, such as diabetes. In turn, such remodeling 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. 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.

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. 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. The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. Aagaard, P. A mechanism for increased contractile strength of human pennate muscle in response to strength training: changes in muscle architecture.

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Chiquet, M. Each muscle is surrounded by a connective tissue sheath called the epimysium. Fascia , connective tissue outside the epimysium, surrounds and separates the muscles. Portions of the epimysium project inward to divide the muscle into compartments.

Each compartment contains a bundle of muscle fibers. Each bundle of muscle fiber is called a fasciculus and is surrounded by a layer of connective tissue called the perimysium. Within the fasciculus, each individual muscle cell, called a muscle fiber, is surrounded by connective tissue called the endomysium.

Skeletal muscle cells fibers , like other body cells, are soft and fragile. The connective tissue covering furnish support and protection for the delicate cells and allow them to withstand the forces of contraction.

These nutrients are supplied via blood to the muscle tissue. In skeletal muscles that work with tendons to pull on bones, the collagen in the three tissue layers the mysia intertwines with the collagen of a tendon. At the other end of the tendon, it fuses with the periosteum coating the bone. The tension created by contraction of the muscle fibers is then transferred though the mysia, to the tendon, and then to the periosteum to pull on the bone for movement of the skeleton. In other places, the mysia may fuse with a broad, tendon-like sheet called an aponeurosis , or to fascia, the connective tissue between skin and bones.

Every skeletal muscle is also richly supplied by blood vessels for nourishment, oxygen delivery, and waste removal. In addition, every muscle fiber in a skeletal muscle is supplied by the axon branch of a somatic motor neuron, which signals the fiber to contract. Unlike cardiac and smooth muscle, the only way to functionally contract a skeletal muscle is through signaling from the nervous system. Because skeletal muscle cells are long and cylindrical, they are commonly referred to as muscle fibers.

During early development, embryonic myoblasts, each with its own nucleus, fuse with up to hundreds of other myoblasts to form the multinucleated skeletal muscle fibers. Multiple nuclei mean multiple copies of genes, permitting the production of the large amounts of proteins and enzymes needed for muscle contraction.

As will soon be described, the functional unit of a skeletal muscle fiber is the sarcomere, a highly organized arrangement of the contractile myofilaments actin thin filament and myosin thick filament , along with other support proteins. The striated appearance of skeletal muscle fibers is due to the arrangement of the myofilaments of actin and myosin in sequential order from one end of the muscle fiber to the other.

Each group of these microfilaments is called a sarcomere and forms the functional unit of a muscle fiber. Watch this video to learn more about macro- and microstructures of skeletal muscles. The sarcomere itself is bundled within the myofibril that runs the entire length of the muscle fiber and attaches to the sarcolemma at its end. As myofibrils contract, the entire muscle cell contracts. Because myofibrils are only approximately 1. Because the actin and its troponin-tropomyosin complex projecting from the Z-discs toward the center of the sarcomere form strands that are thinner than the myosin, it is called the thin filament of the sarcomere.

The troponin-tropomyosin complex regulates the contraction process. Likewise, because the myosin strands and their multiple heads projecting from the center of the sarcomere, toward but not all to way to, the Z-discs have more mass and are thicker, they are called the thick filament of the sarcomere. This is where the muscle fiber first responds to signaling by the motor neuron. Every skeletal muscle fiber in every skeletal muscle is innervated by a motor neuron at the NMJ.

Excitation signals from the neuron are the only way to functionally activate the fiber to contract. Every skeletal muscle fiber is supplied by a motor neuron at the NMJ. Watch this video to learn more about what happens at the NMJ.