Histone β‐hydroxybutyrylation is critical in reversal of sarcopenia

Abstract Sarcopenia, a leading cause for global disability and mortality, is an age‐related muscular disorder, characterized by accelerated muscle mass loss and functional decline. It is known that caloric restriction (CR), ketogenic diet or endurance exercise lessen sarcopenia and elevate circulating β‐hydroxybutyrate (β‐HB) levels. Whether the elevated β‐HB is essential to the reversal of sarcopenia, however, remains unclear. Here we show in both Caenorhabditis elegans and mouse models that an increase of β‐HB reverse myofiber atrophy and improves motor functions at advanced ages. β‐HB‐induced histone lysine β‐hydroxybutyrylation (Kbhb) is indispensable for the reversal of sarcopenia. Histone Kbhb enhances transcription of genes associated with mitochondrial pathways, including oxidative phosphorylation, ATP metabolic process and aerobic respiration. This ultimately leads to improve mitochondrial integrity and enhance mitochondrial respiration. The histone Kbhb are validated in mouse model with CR. Thus, we demonstrate that β‐HB induces histone Kbhb, increases mitochondrial function, and reverses sarcopenia.