Regeneration of Skeletal Muscle

Although it has long been known that myotube nuclei are not capable of mitosis following the fusion of mononucleate myoblasts into myofibers during late gestation and neonatal development, these myofibers grow and the number of nuclei per fiber increases in the postnatal period. Furthermore, nuclei from damaged muscle fibers can be replaced during regenerative processes, and upon overuse of muscle, not only the size of muscle fibers increases, but also the number of nuclei per fiber. The origin of these nuclei was unclear until the identification of satellite cells [26, 27], and the suggestion that the nuclei of these cells might replace the nuclei of damaged muscle fibers during regenerative processes [26]. This suggestion was confirmed, and we now know that these satellite cells are mitotically quiescent cells, initially derived from embryonic myoblasts that withdrew from the cell cycle, adhered to developing myotubes and during further differentiation became localized under the basement membrane of the myofiber. The cells are activated and start to proliferate when existing muscle fibers are injured and need to be repaired or replaced, or existing myofibers need to grow [28-30]. Muscle regeneration then recapitulates myogenesis during embryonic development, i.e. proliferating myocytes line up, withdraw from the cell cycle and fuse to form myotubes. Some of these activated satellite cells, however, do not differentiate and are embedded under the basement membrane, thus providing a new pool of mononucleate myogenic cells capable of regeneration.

The mechanisms by which quiescent satellite cells are activated in vivo are not well understood. Proliferating cells are not only recruited from sites close to the injury, but also from sites distant to the trauma or even from neighboring myofibers [31-33]. The relative number of activated satellite cells seems to decrease with increasing distance from the injured site [32], indicating that a gradient of mitogen concentration is established along the muscle length. Which mitogenic factors are responsible for satellite cell activation on the one hand, and satellite cell differentiation on the other hand, is difficult to examine in vivo. Therefore, most studies on these topics were performed with cultured satellite cells (see below). The few studies with human satellite cells show that proliferation is chiefly regulated by fibroblast growth factor (FGF) and epidermal growth factor (EGF) [34, 35], whereas differentiation and myotube protein synthesis seem to be mainly stimulated by insulin and insulin-like growth factors (IGFs) [34, 36, 37], Evidence for the in vivo and in vitro differentiation-stimulating effect of IGF-I was recently provided in several studies [38-41], and the mechanism of the stimulatory effect of IGF-I, which was mimicked by insulin in combination with dexamethasone, was shown to be mediated by a calcineurin signaling pathway [42, 43].

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