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 muscle stem cells (MuSCs). Although deep quiescent MuSCs are less poised to activate, slowing muscle regeneration, they have markedly improved survival when facing sources of cellular stress. Furthermore, we show that ketone bodies, specifically β-hydroxybutyrate, directly promote MuSC deep quiescence via a nonmetabolic mechanism. We show that β-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. [Display omitted] •Fasting induces a highly resilient deep quiescent (DQ) state in MuSCs•DQ is characterized by delayed cell-cycle entry but heightened stress resistance•The ketone body β-hydroxybutyrate (BHB) can directly promote DQ in MuSCs•The effects of BHB are due to its role as an HDAC inhibitor and are mediated by p53 Dietary interventions have emerged as critical modulators of stem cell function and tissue repair. Here, Benjamin and Both et al. report how various states of ketosis influence muscle regeneration by altering the quiescent state of MuSCs. They discover that the ketone body BHB promotes a deep quiescent state in MuSCs that enhances cellular resilience.