Fasting Induces a Highly Resilient Deep Quiescent State in Muscle Stem Cells via Ketone Body Signaling. Fasting Induces a Highly Resilient Deep Quiescent State in Muscle Stem Cells via Ketone Body Signaling

Short-term fasting is beneficial for the regeneration of multiple tissue types. However, the effects of fasting on muscle regeneration are largely unknown. Here we report that fasting slows muscle repair both immediately after the conclusion of fasting as well as after multiple days of refeeding. We show that ketosis, either endogenously produced during fasting or a ketogenic diet, or exogenously administered, promotes a deep quiescent state in MuSCs. Although deep quiescent MuSCs are less poised to activate, slowing muscle regeneration, they have markedly improved survival when facing sources of cellular stress. Further, we show that ketone bodies, specifically b- hydroxybutyrate, directly promote MuSC deep quiescence via a non‐metabolic mechanism. We show that b-hydroxybutyrate functions as an HDAC inhibitor within MuSCs leading to acetylation and activation of an HDAC1 target protein p53. Finally, we demonstrate that p53 activation contributes to the deep quiescence and enhanced resilience observed during fasting. Overall design: Skeletal muscle stem cells (MuSCs) were isolated by FACS from wild type mice that were treated with either ketone bodies or PBS processed for RNA-seq.

短期禁食对多种组织类型的再生具有积极作用。然而，禁食对肌肉再生的影响目前仍鲜有明确研究。本研究发现，禁食不仅会在禁食结束后即刻延缓肌肉修复进程，还会在复饲数日后持续产生该效应。我们证实，酮症——涵盖禁食期间内源性生成的酮症、生酮饮食诱导的酮症，以及外源性给药诱导的酮症——可促使骨骼肌干细胞 (MuSCs) 进入深度静息状态。尽管深度静息的MuSCs激活准备度降低，进而延缓肌肉再生，但它们在遭遇各类细胞应激时的存活能力显著提升。此外，我们发现酮体，尤其是β-羟基丁酸，可通过非代谢机制直接诱导MuSCs进入深度静息状态。我们证实，β-羟基丁酸在MuSCs中可作为组蛋白去乙酰化酶 (HDAC) 抑制剂，介导组蛋白去乙酰化酶1 (HDAC1) 的靶蛋白p53发生乙酰化并激活。最后，我们证实p53的激活是禁食期间观察到的MuSCs深度静息状态与抗逆性增强的关键促成因素。整体实验设计：通过荧光激活细胞分选术 (FACS) 从分别经酮体或磷酸盐缓冲液 (PBS) 处理的野生型小鼠体内分离得到骨骼肌干细胞 (MuSCs)，并对其进行RNA测序 (RNA-seq) 分析。