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.