β-Hydroxybutyrate inhibits FOXO3a by histone H3K9 β-Hydroxybutyrylation to ameliorate stroke-related sarcopenia

Stroke-related sarcopenia (SRS) is characterized by progressive systemic muscle loss and decreased function and is thought to be primarily affected by catabolic-anabolic imbalance, but there is a lack of specific treatment. Our study evaluated whether β-hydroxybutyrate (BHB) improves SRS through regulation in protein synthesis and proteolysis. BHB reduced infarct volume, increased muscle mass and muscle fiber cross-sectional area. Delayed administration of BHB, when the infarct volume was stable, improved the balance beam score and time of rotarod and the above SRS indicators. Mechanistically, BHB increased the total contents of H3K9bhb in gastrocnemius muscles of tMCAO mice and enhanced the endogenous binding of H3K9bhb with Foxo3a promoter in response to the transcription inhibition of Foxo3a. Our study indicated BHB alleviated SRS, which was partly mediated by H3K9bhb, and then inhibited FOXO3a. BHB also promoted protein synthesis, muscle regeneration and proliferation to maintain protein metabolic homeostasis and ultimately ameliorated SRS.