**5. MMPs and skeletal muscle**

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 that MMP-2 is essential for myoblast migration [125], while in vitro study indicates MMP-2 is secreted at all stages from cell to myotubes [126]. Acute muscle ischemia results in remodeling of the basal lamina which is accompanied by increased MMP gelatinases [127]. And increased MMPs (MMP-2 and MMP-9) are also responsible to the degradation of ECM in skeletal muscle atrophy [128]. Furthermore, satellite cells are reported to synthesize and secrete MMP-2 and induce MMP-9 activity in human skeletal muscles [129]. During regeneration, MMP-2 activation appears go along with the formation of new myofibers, whereas MMP-9 expression is related to the inflammatory response [43]. Expression changes of MMPs have been involved in different myopathies. Distinctly increased MMP-9 appears in inflammatory myopathies [130], MMP-7 upregulation is prominent in case of polymyositis, whereas MMP-2 is only slightly elevated in inflamed muscle [131].
