Fasting induces a highly resilient deep quiescent (DQ) state in MuSCs
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DQ is characterized by delayed cell-cycle entry but heightened stress resistance
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The ketone body β-hydroxybutyrate (BHB) can directly promote DQ in MuSCs
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The effects of BHB are due to its role as an HDAC inhibitor and are mediated by p53
Summary
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.
Graphical abstract
Keywords
MuSC
HDAC
p53
fasting
ketosis
muscle
BHB
quiescence
stem cells
diet
Data and code availability
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The data that support the findings of this study are available from the corresponding author upon request. RNA-Seq data have been deposited in the NCBI Gene Expression Omnibus with the accession code GSE184821. Raw data used to generate graphs and western blots used to are included in Data S1.
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This paper does not report original code.
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Any additional information required to reanalyze the data reported in this paper is available from the lead contact upon request.