The health and homeostasis of skeletal muscle are preserved by a population of tissue-resident muscle stem cells (MuSCs) that maintain a state of mitotic and metabolic quiescence in adult tissues. The capacity of MuSCs to preserve the quiescent state declines with aging and metabolic insults, promoting premature activation and stem cell exhaustion. 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. 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. Aged SESTRIN1,2 knockout mice exhibited loss of MuSCs and a reduced ability to regenerate injured muscle. These findings demonstrate that Sestrins help maintain metabolic pathways in MuSCs that protect quiescence against aging.

骨骼肌的健康和稳态由一群组织驻留肌肉干细胞 (MuSC) 维持，这些干细胞维持成体组织中的有丝分裂和代谢静止状态。MuSC 保持静止状态的能力会随着衰老和代谢损伤而下降，从而促进过早激活和干细胞耗竭。Sestrins 是一类应激诱导蛋白，可作为抗氧化剂并抑制哺乳动物雷帕霉素靶点复合物 1 (mTORC1) 信号复合物的激活。尽管具有这些关键作用，但 Sestrins 在成体干细胞中的作用尚未得到探索。我们发现 SESTRIN1,2 缺失会导致 mTORC1 复合物过度激活、进入细胞周期的倾向增加以及代谢通量的变化。老年 SESTRIN1,2 基因敲除小鼠表现出 MuSC 损失和受损肌肉再生能力下降。这些发现表明，Sestrins 有助于维持 MuSC 中的代谢途径，从而防止衰老。