The neuromuscular system The brain, nerves and skeletal muscles work together to cause movement. This is collectively known as the neuromuscular system. A typical muscle is serviced by anywhere between 50 and or more branches of specialised nerve cells called motor neurones.
These plug directly into the skeletal muscle. The tip of each branch is called a presynaptic terminal. The point of contact between the presynaptic terminal and the muscle is called the neuromuscular junction. To move a particular body part: The brain sends a message to the motor neurones.
This triggers the release of the chemical acetylcholine from the presynaptic terminals. The muscle responds to acetylcholine by contracting. Shapes of skeletal muscle Generally speaking, skeletal muscles come in four main shapes, including: Spindle — wide through the middle and tapering at both ends, such as the biceps on the front of the upper arm. Flat — like a sheet, such as the diaphragm that separates the chest from the abdominal cavity. Triangular — wider at the bottom, tapered at the top, such as the deltoid muscles of the shoulder.
Circular — a ring-shape like a doughnut, such as the muscles that surround the mouth, the pupils and the anus. These are also known as sphincters. Muscle disorders Muscle disorders may cause weakness, pain, loss of movement and even paralysis.
The range of problems that affect muscles are collectively known as myopathy. The three main types of muscle include skeletal, smooth and cardiac. 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 , Garber et al.
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. 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.
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.
The ECM of skeletal muscles is a complex meshwork consisting of collagens, glycoproteins, proteoglycans, and elastin Takala and Virtanen, ; Halper and Kjaer, Collagens form a network of intramuscular connective tissue IMCT , i. 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, The endomysium interfaces with the myofiber sarcolemma at a specialized basement membrane, which consists primarily of type IV collagen and laminin Sanes, ; Martin and Timpl, ; Kjaer, 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.
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, The dystrophin-associated glycoprotein complex is another important factor in providing a mechanical linkage between the contractile components of skeletal muscle i.
The main components linking the contractile elements of the muscle to the interstitial matrix are shown in Figure 1. Figure 1. Main components of the skeletal muscle extracellular matrix and its linkage to the contractile components of muscle. 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, Collagen type IV, a helical molecule, produces a network structure that constitutes the basis of the basal lamina Sanes, 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.
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.
Table 1. Overview of collagenous components of the skeletal muscle extracellular matrix. 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.
Gene signatures derived, e. 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. 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. The function of these anabolic factors is mostly regulated by small leucine-rich proteoglycans SLRPs.
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.
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.
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, 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.
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.
This structure increases the 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, 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. Considering the fact that a significant portion of fibers in long muscles terminate intrafascicularly without directly reaching a tendon Barrett, ; Hijikata et al.
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, Force transmission across the IMCT network occurs from contractile proteins across costameres to the endomysium Bloch and Gonzalez-Serratos, ; Peter et al.
The first information about the proportions of longitudinal and lateral force transfer in striated muscle stems from elegant experiments by Huijing et al.
More recently, Ramaswamy et al. Their results were later confirmed by Zhang and Gao 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. Indirect support for this hypothesis is provided by studies in older subjects Hughes et al. Also, lateral force transfer is thought to bridge fibers contracting either at different times or to unequal extents Yucesoy et al. Recently, Dieterich et al. 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.
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, 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, dictates that during shortening muscle fibers must undergo radial expansion, which has long been experimentally confirmed even at the sarcomeric level Brandt et al. Novel computational models and in situ measurements in frog muscles by Azizi et al. 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. 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, This fascicular organization is common in muscles of the limbs; it allows the nervous system to trigger a specific movement of a muscle by activating a subset of muscle fibers within a bundle, or fascicle of the muscle.
Inside each fascicle, each muscle fiber is encased in a thin connective tissue layer of collagen and reticular fibers called the endomysium. The endomysium contains the extracellular fluid and nutrients to support the muscle fiber. 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.
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.
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