The AMPK/p27(Kip1) Axis Regulates Autophagy/Apoptosis Decisions in Aged Skeletal Muscle Stem Cells

Skeletal muscle stem cell (MuSC) function declines with age and contributes to impaired muscle regeneration in older individuals. Acting through AMPK/p27(Kip1), we have identified a pathway regulating the balance between autophagy, apoptosis, and senescence in aged MuSCs. While p27(Kip1) is implicated in MuSC aging, its precise role and molecular mechanism have not been elucidated. Age-related MuSC dysfunction was associated with reduced autophagy, increased apoptosis, and hypophosphorylation of AMPK and its downstream target p27(Kip1). AMPK activation or ectopic expression of a phosphomimetic p27(Kip1) mutant was sufficient to suppress in vitro apoptosis, increase proliferation, and improve in vivo transplantation efficiency of aged MuSCs. Moreover, activation of the AMPK/p27(Kip1) pathway reduced markers of cell senescence in aged cells, which was, in part, dependent on p27(Kip1) phosphorylation. Thus, the AMPK/p27(Kip1) pathway likely regulates the autophagy/apoptosis balance in aged MuSCs and may be a potential target for improving muscle regeneration in older individuals.