Adult mouse muscle satellite cells (MuSCs) are quiescent in uninjured muscles. Upon injury, MuSCs exit quiescence to become activated, re-enter the cell cycle to proliferate, then differentiate to repair the damaged muscles. It remains unclear which extrinsic signal and intrinsic signaling pathway regulate quiescence exit during MuSC activation. Here, we demonstrated that inducible MuSC-specific deletion of p110α, a catalytic subunit of phosphatidylinositol 3-kinase (PI3K), rendered MuSCs unable to exit quiescence, resulting in severely impaired MuSC proliferation and muscle regeneration. Genetic reactivation of mTORC1, or knockdown of FoxOs, in p110α-null MuSCs partially rescued the above defects, making them key effectors downstream of PI3K in regulating quiescence exit. c-Jun was...[ Read more ]

Adult mouse muscle satellite cells (MuSCs) are quiescent in uninjured muscles. Upon injury, MuSCs exit quiescence to become activated, re-enter the cell cycle to proliferate, then differentiate to repair the damaged muscles. It remains unclear which extrinsic signal and intrinsic signaling pathway regulate quiescence exit during MuSC activation. Here, we demonstrated that inducible MuSC-specific deletion of p110α, a catalytic subunit of phosphatidylinositol 3-kinase (PI3K), rendered MuSCs unable to exit quiescence, resulting in severely impaired MuSC proliferation and muscle regeneration. Genetic reactivation of mTORC1, or knockdown of FoxOs, in p110α-null MuSCs partially rescued the above defects, making them key effectors downstream of PI3K in regulating quiescence exit. c-Jun was found to be a key transcriptional target of the PI3K/mTORC1 signaling axis essential for MuSC to exit quiescence. Moreover, induction of a constitutively active PI3K in quiescent MuSCs resulted in spontaneous MuSC activation in uninjured muscles and subsequent depletion of the MuSC pool. Thus, PI3K is both necessary and sufficient for MuSCs to exit quiescence in response to activating signals.