Metabolic regulation of muscle satellite cell homeostasis

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Metabolic regulation of muscle satellite cell homeostasis and function Abstract Muscle satellite cells (MuSCs) are resident stem cells in the skeletal muscle responsible for its postnatal growth, maintenance and regeneration. MuSCs in adult homeostatic muscles are predominantly in the quiescent state. In response to injury, quiescent MuSCs are activated, enter the cell cycle and proliferate as myoblasts, then differentiate to repair the injury or self-renew to replenish the stem cell pool. The homeostasis of these various cell states (quiescence, activation, proliferation, differentiation and self-renewal) is necessary to support multiple rounds of successful and sustainable regeneration throughout the lifetime. Despite the remarkable progress accomplished in the past decades, the key regulators and signaling mechanisms underlying the homeostasis and function of MuSCs remain elusive. Lipid droplets (LDs) are cellular organelles commonly found in adipocytes, where they function as a central hub for lipid biosynthesis, storage and utilization that are crucial for cell metabolism and signaling. Recent studies have begun to elucidate a paramount role of LDs in cancer cell metabolism and pathogenesis, but the presence and role of LDs in tissue stem cells including MuSCs have only been explored very recently. Preliminary studies in the PI's laboratory have led to the discovery of highly dynamic LDs in MuSCs along their myogenic progression in vitro and in vivo. Specifically, LDs are not present in any quiescent MuSCs but emerge in activated MuSCs and increase in abundance in proliferating myoblasts. Strikingly, unequal distribution of LDs is observed in some newly divided sister cells exhibiting hallmarks of asymmetric cell fate segregation. In addition, fatty acid metabolic pathways are dynamically regulated in a pattern similar to the dynamics of LDs, and perturbations of fatty acid oxidation (FAO) disrupts MuSC homeostasis and function. Based on these observations, it is hypothesized that LDs regulate MuSC homeostasis and function through influencing cellular energy supply and/or lipid metabolite-mediated signaling. Two aims are developed to test this central hypothesis. The first aim will examine the role of LDs in MuSC homeostasis and regenerative function in vivo. The second aim will dissect how LD dynamics are regulated and how lipid metabolism in turn regulates MuSC homeostasis and function. Completion of the proposed study is expected to establish LDs as a novel cell fate marker and understand how lipid metabolism regulates MuSC fates. Previous studies have identified immortal DNA strands, centrosomes, mitochondria and various proteins as cell fate determinants, the identification of LD as an additional cell fate regulator opens a new chapter in stem cell biology. The knowledge will also facilitate the development of mitigation strategies to improve the regeneration and function of skeletal muscles during aging or under pathological conditions.