Regeneration of mammalian skeletal muscle. Basic mechanisms and clinical implications

Mammalian skeletal muscles can regenerate following injury and this response is mediated by a specific type of stem cell, the satellite cell. We review here the three main phases of muscle regeneration, including i) the initial inflammatory response and the dual role of macrophages as both scavengers involved in the phagocytosis of necrotic debris and promoters of myogenic differentiation, ii) the activation and differentiation of satellite cells and iii) the growth and remodeling of the regenerated muscle tissue. Nerve activity is required to support the growth of regenerated myofibers and the specification of muscle fiber types, in particular the activation of the slow gene program. We discuss the regeneration process in two different settings. Chronic degenerative diseases, such as muscular dystrophies, are characterized by repeated cycles of segmental necrosis and regeneration involving scattered myofibers. In these conditions the regenerative capacity of satellite cells becomes exhausted with time and fibrosis prevails. Acute traumatic injuries, such as strain injuries common in sport medicine, cause the rupture of large myofiber bundles leading to muscle regeneration and formation of scar tissue and new myotendinous junctions at the level of the rupture. Mechanical loading is essential for muscle regeneration, therefore, following initial immobilization to avoid the risk of reruptures, early remobilization is required to induce correct growth and orientation of regenerated myofibers. Finally, we discuss the causes of age-dependent decline in muscle regeneration potential and the possibility of boosting regeneration in aging muscle and in muscular dystrophies.