Replicative Potential of Muscle Stem Cells

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Project Summary Skeletal muscle tissue is maintained and can be dynamically modeled to fit ongoing needs by changes in muscular activity. Myofibers, the primary cells that comprise the contractile elements of skeletal muscle, are post-mitotic and maintained by a pool of stem cells, termed satellite cells, which are localized to a niche be- tween the myofiber and overlying basal lamina. Loss of mobility arising from loss of skeletal muscle function occurs following an injury, is an inevitable consequence of aging and a consequence of many neuromuscular diseases, the latter two resulting in reduced quality of life and increased morbidity, requiring hospitalization or home care, significantly raising health care costs. These complex physiological changes are well documented but the mechanisms responsible for these changes are not understood. SCs (satellite cells) maintain muscle throughout life, providing a constant source of new myonuclei that appears to occur primarily by asymmetric division. Loss of SC asymmetric division contributes to age-related losses of SC function during aging and to the dystrophic muscle phenotype. Enhancing the ability of SCs to di- vide asymmetrically improves strength in aged muscle and improves dystrophic muscle function. The depend- ence of skeletal muscle health on SC maintenance, which in turn requires SCs divide asymmetrically empha- sizes an essential role for SC asymmetric division that has not been adequately addressed. EGFR (epidermal growth factor receptor) and FGFR1 signaling promote SCs to divide asymmetrically, identifying these as two critical signaling pathways involved in maintaining SCs. Activation of EGFR signaling improves dystrophic muscle phenotypes and activation of FGFR1 signaling in SCs from aged muscle rescues asymmetric division restoring SC numbers to youthful levels and increases strength in aged mice, suggesting that SC asymmetric division is essential to maintain skeletal muscle health. The primary premise for the proposed experiments in this application is that driving SCs to divide asymmetrically improves muscle health. However, SCs comprise a minor population of cells within skeletal muscle (1-3%) and thus, how can improvement of SC health affect an entire muscle? To fulfill this knowledge gap, we plan to identify the pathways driving SCs to divide asymmetri- cally and elucidate the mechanisms by which stimulation of SC asymmetric division enhances skeletal muscle function.