In vertebrates, adult muscle satellite cells (i.e., muscle stem cells, or MuSC) are absolutely indispensable for injury-induced muscle regeneration. In uninjured adult muscles, most MuSC reside in a quiescent state (a unique cellular “hibernating” state with minimum cellular activities and energy requirement). Upon muscle injury, these quiescent MuSC (QSC) are activated, re-enter the cell cycle to proliferate, and then differentiate and fuse to repair the damaged muscles. Interestingly, it takes much longer time (~36-48 h vs 8-10 h for cycling cells to go through subsequent cell cycles) for QSC to enter the first cell cycle, which is absolutely crucial and tightly regulated. Dysregulation during this period prevent QSC from reentering the cell cycle and result in severe muscle regeneration defects. It remains unclear how the transitions from QSC to cycling myoblasts are regulated.

Here, using different mouse models we generated that display defects in early activation of adult MuSC, we propose to perform comprehensive and systematic molecular, cellular, and mouse-based studies in order to understand how adult QSCs are regulated to become cycling myoblasts upon muscle injury. Through such systematic and in-depth mechanistic studies, we hope that we will gain better understanding of the molecular, epigenetic, and signaling mechanisms that regulate quiescence and early activation of adult MuSC. The results from our studies will be beneficial to future development of MuSC-based regenerative medicine for the treatment of various muscle diseases including muscle atrophy (e.g., sarcopenia) in aged people.