Sestrins regulate age-induced deterioration of muscle stem cell homeostasis

The health and homeostasis of skeletal muscle is preserved by a population of tissue resident stem cells called satellite cells. Young healthy satellite cells maintain a state of quiescence, but aging or metabolic insults results in reduced capacity to prevent premature activation and stem cell exhaustion. As such, understanding genes and pathways that protect satellite cell maintenance of quiescence are needed. Sestrins are a class of stress-inducible proteins that act as antioxidants and inhibit the activation of the mammalian target of rapamycin complex 1 (mTORC1) signaling complex. Despite these pivotal roles, the role of Sestrins has not been explored in adult stem cells. Herein, we show that Sestrin1,2 loss results in hyperactivation of the mTORC1 complex, increased propensity to enter the cell cycle and shifts in metabolic flux. Aging of Sestrin1,2 knockout mice demonstrated a loss of MuSCs and reduced ability to regenerate. These findings demonstrate Sestrins function to help maintain MuSC metabolism that supports quiescence and against aging. HighlightsO_LISestrin deficiency alters mTORC1 signaling in muscle stem cells (MuSCs). C_LIO_LIIn young mice, Sestrins are dispensable for regenerative responses of MuSCs. C_LIO_LISestrin deficiency accelerates age-dependent loss and dysfunction of MuSCs. C_LI