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 between 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. Satellite cells can (i) renew their own population, (ii) commit to the myoblast lineage and pro- liferate as myoblasts, and (iii) undergo terminal differentiation and fuse into existing myofibers or fuse to form new myofibers as myonuclei. Satellite cell turnover is extensive in adult muscle yet rela- tively constant numbers of satellite cells are maintained. Following an induced injury satellite cell numbers return to their pre-injury numbers, suggesting remarkably stringent control of satellite cell numbers. These observations prompt one to ask how satellite cell numbers are maintained and what is the function of satellite cell turnover? Timed EdU administration following an induced muscle injury revealed that SCs are generated only upon completion of myonuclear expansion at ~4-5d post-injury in vivo. Thus, the rapid expan- sion of myoblasts occurring upon muscle injury is exclusively devoted to cells that undergo terminal differentiation to produce myonuclei. What mechanisms prevent self-renewal early during regenera- tion and then promote self-renewal once sufficient myonuclei are generated? As SCs most likely arise by asymmetric division, a major goal of our proposed experiments in this application are aimed to gain a better understand the mechanisms governing SC self-renewal during skeletal muscle regenera- tion. We propose that asymmetric division is required for satellite cell restoration during muscle re- generation. Signaling from ectopically activated FGF Receptor 1 simultaneously represses terminal differentiation, induces asymmetry and promotes asymmetric division. We plan to test this idea by initially characterizing satellite cell self-renewal during muscle regeneration, and then identifying ge- netic interactions required for satellite cell self-renewal and then to identify genetic interactions re- quired for satellite cell self-renewal.
Skeletal muscle is essential for respiration, locomotion and elimination of waste; loss of skele- tal muscle function as a consequence of disease, injury or aging can be catastrophic, shortening lifespan and dramatically reducing overall quality of life. A better understanding of the mechanisms regulating muscle stem cell function will permit the development of therapies to directly target muscle stem cells and to better understand muscle stem cell dysfunction during aging and in skeletal muscle diseases.
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