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

ABSTRACT: 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.

ORGANISM(S): Mus musculus

PROVIDER: GSE184821 | GEO | 2022/09/28

REPOSITORIES: GEO

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Project description:Regeneration of skeletal muscle is dependent on the function of tissue-resident muscle stem cells (MuSC), known as satellite cells. MuSC dysfunction is central to muscle pathophysiology, including in age-associated loss of muscle regenerative capacity and congenital disorders such as Duchenne muscular dystrophy. Despite the central role of satellite cells in muscle regeneration, the signals controlling the balance between muscle stem cell quiescence, proliferation, and differentiation remain incompletely understood. Knowledge of the signals that maintain a quiescent state is particularly lacking, yet such cues are crucial to maintaining a stem cell reservoir that can meet the needs of regeneration throughout life. Here we identify Oncostatin M (OSM), a member of the interleukin-6 family of cytokines, as a potent and essential trans-acting regulator of satellite cell quiescence. Key to this discovery is the development of a novel in vivo imaging-based screening strategy allowing identification of proteins that do not induce in vitro proliferation, but instead maintain MuSCs in a non-mitotic state, poised for rapid robust expansion upon transplantation. We demonstrate that OSM induces reversible exit from the cell cycle and induction of a global transcriptional program significantly enriched within a newly established satellite cell “quiescence signature”. Genetic ablation of the OSM receptor in mice demonstrates that signaling via OSM/R is essential for maintenance of satellite cell quiescence, and for proper skeletal muscle regeneration in vivo. Given that aberrant activation and exhaustion of stem cells is seen in a variety of disorders, OSM constitutes an attractive therapeutic target in muscle disease states. Microarray profiling was used to directly test the hypothesis that OSMR signaling in muscle stem cells promotes their engraftment by inducing a global transcriptional state equivalent to that of quiescent, freshly isolated, non-activated MuSC.

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

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