**6. Conclusion**

treatments using decorin and TGF-β inhibitors in injured muscle enhance regeneration and

Fibrin, a structural component of the ECM, accumulates in areas of degeneration and inflammation in dystrophic muscle, whereas knockout fibrinogen was shown to reduce fibrosis development in mdx mice. Fibrin can induce the expression of TGF-β to promote fibrosis [104]. Fibrin can activate fibroblasts to synthesize and secrete collagens by binding to αVβ3 integrin receptor [105]. Considering the synthesis and degradation of collagens is controlled by MMPs, the importance of proteases in muscle fibrosis is absolutely obvious [106]. On the other hand, defects in or deficiencies of ECM molecules will cause myopathies and inherited connective tissue disorders. As we mentioned before, ECM and cytoskeleton are connected by transmembrane proteins named dystroglycan, sarcoglycan, integrin. Dystrogly‐ can has two subunits α and β, β-dystroglycan intracellularly binds to dystrophin and extrac‐ ellularly to α-dystroglycan, which is associated with the ECM proteins laminin α2, biglycan, and perlecan [16, 107]. Defects in α-dystroglycan can lead to congenital muscular dystrophy (MDC) and limb–girdle muscular dystrophy (LGMD) that can also be caused by deficiency of laminin α2 [108]. Sarcoglycans can extracellularly binds to biglycan and is closely associated with the dystroglycan complex [109–111]. Mutations in sarcoglycans result in autosomalrecessive limb–girdle muscular dystrophies. In integrin knockouted mice, mild form of muscular dystrophy appears [112]. Furthermore, clinical studies show that collagen VI deficiency lead to Bethlem myopathy and Ullrich congenital muscular dystrophy [61, 113, 114]. Extracellular fat is another pathological response of skeletal muscle to disease or injury that is accompanied by pathological diseases include Duchenne muscular dystrophy, obesity, type-2 diabetes, and aged muscle [115–117]. Recent studies have identified a PDGFRα+ progenitor cell population that is responsible for intracellular fat deposition as the cell can differentiate into adipose tissue under nonregenerating conditions [118]. Moreover, these cells were found

MMPs are famous for its irreplaceable role in degrading ECM compositions. In skeletal muscle, MMP-2 and MMP-9 [43] can degrade type-IV collagen, fibronectin, PGs, and laminin, while MMP-1 [48] and MMP-13 [120] degrade types I and III collagen. The activities of MMPs are controlled by tissue inhibitors of matrix metalloproteinases (TIMPs). TIMP-1 binds to active forms of MMPs forming noncovaent complexes, whereas TIMP-2 stabilizes the inactive form of the enzyme, and thus inhibits the formation of active proteolyticenzyme [47, 48]. In normal muscle tissues, the expression of MMPs are very low but increased in injured muscles mainly because they are secreted by inflammatory cells [121]. Although studies rarely show the functions of MMPs in skeletal muscle, they have been implicated in many pathological processes including myogenesis, muscle growth, development, aging, and regeneration [122, 123]. MMP-2 knockout mice developed significantly less hypertrophy and ECM remodeling in response to overload compared to a significant increase in MMP-2 activity and upregulation of ECM components and remodeling enzymes in wild-type mice [124]. In vivo study shows

prevent fibrosis [101–103].

30 Composition and Function of the Extracellular Matrix in the Human Body

to distribute more in perimysium than endomysium [119].

**5. MMPs and skeletal muscle**

Skeletal muscle fibers are surrounded by ECM, and the ECM is an important part of the cellular microenvironment consists of a complex mixture of structural and functional proteins including glycoproteins, collagen, and PGs. These molecules interact with each other and form a super molecular network in order to maintain skeletal muscle integrity and participate in the development of skeletal muscle. Additionally, skeletal muscle fibrosis, characterized by abnormal accumulation of ECM, is an obvious clinical characteristic of myopathies such as age-related sarcopenia, muscular dystrophy, and Duchenne muscular dystrophy. Genetic diseases, dysregulation of TGF-β signaling and physical activity can cause defects in or deficiencies of molecules within the skeletal muscle ECM.
