The HIF‐1α Pathway Regulates Satellite Cell Fate During Aging Through Histone Lactylation

ABSTRACT Aging‐associated sarcopenia is driven in part by the progressive loss of type II glycolytic fibers and the functional decline of their resident stem cells, the satellite cells (SCs). We show here that these defects result from attenuation of the hypoxia‐inducible factor‐1α (HIF‐1α) signaling pathway and can be reversed by pharmacological HIF‐1α reactivation. In the tibialis anterior muscle of 18‐month‐old C57BL/6J mice, HIF‐1α protein abundance decreased by ≈46% and canonical targets ( Vegf a, Egln1 ) were downregulated in freshly isolated SCs. Treatment of aged SCs with the prolyl hydroxylase inhibitor roxadustat (FG‐4592) for 48 h restored HIF signaling, upregulated glycolytic enzymes (HK2, GAPDH, ALDO) and the lactate transporter MCT4, and increased intracellular lactate by 1.9‐fold. Increased lactate enhanced global histone lactylation, an epigenetic mark that decreased with age. The effect was attenuated by the LDHA inhibitor oxamate, establishing a link between HIF‐driven metabolism and chromatin remodeling. HIF‐1α activation slowed old SC proliferation (S phase −60%), but decreased the senescence marker p16Ink4a (−54%) and increased the stem cell factor Pax7 (+1.8‐fold), indicating a shift from senescence to a quiescent, regenerative state. When differentiation was induced without drugs, pretreated aged SCs formed hypertrophic myotubes (differentiation index +1.7), exhibited higher ATP content (+1.54‐fold), and activated the IGF‐1/PI3K–Akt–mTOR pathway, leading to an increase in tropomyosin ( Tpm1 ) in fast fibers. These results suggest a HIF‐1α‐lactate‐lactylation axis that rejuvenates aged satellite cells and enhances myogenic performance, providing a mechanistic rationale for repurposing roxadustat to alleviate sarcopenia.