Integrating and Orchestrating Multiple Components of Skeletal Muscle Injury and Regeneration

Abstract

As a soft tissue comprising nearly half of body mass, skeletal muscle is vulnerable to injury from many sources. Healthy muscle can regenerate from resident stem cells known as satellite cells (SCs). During homeostasis, individual SCs reside within a niche sandwiched between basal lamina (BL) and sarcolemma, dispersed along the periphery of mature myofibers. The SC niche abuts capillaries embedded in extracellular matrix (ECM) containing fibroblasts and immune cells. With integral roles for each component of muscle tissue, cellular responses to injury are integrated and orchestrated during regeneration. Following physical trauma, chemical damage, or myotoxin exposure, inflammation ensues with efferocytosis removing debris and creating space for new growth. Residual BL selectively guide regeneration of myofibers, capillaries, and nerves. SCs transition from quiescence to activation, proliferate as myoblasts, differentiate into myocytes, fuse into multinucleated myotubes (or undergo self-renewal) and return to quiescence while nascent myofibers mature. In parallel, fibroadipogenic progenitor cells transiently proliferate to support regeneration of healthy tissue. Endothelial tip cells sprout filopodia to orient capillary growth with microvascular networks remodeling as muscle blood flow is restored. Following Wallerian degeneration, axons extend filopodia to orient their regrowth within the neurolemma along tracks of endothelial cells; cues from myofibers guide reinnervation of neuromuscular junctions. Coordinated through autocrine, paracrine, and juxtacrine signaling with guidance from the immune system and ECM, interactions between myogenesis, angiogenesis, and reinnervation provide synergistic support as muscle structure and function are restored. Failure of regeneration leads to fibrosis, loss of strength, and impaired mobility.