Glutamine deficiency enhances nuclear localization of TCA cycle enzymes and epigenetic modifications, impairing...

Extracellular glutamine (Gln) is essential for muscle progenitor cell (MPC) function and skeletal muscle regeneration/development, especially under physiological stress like aging or catabolic conditions. Gln availability regulates MPC proliferation by modulating intracellular metabolic and epigenetic states. Gln deficiency reduces cell viability, induces G0/G1 cell cycle arrest, and downregulates MyoD expression, collectively inhibiting myogenesis in human primary myoblasts (human skeletal muscle myoblast) and mouse C2C12 cells. Mechanistically, Gln deficiency enhances nuclear localization of tricarboxylic acid cycle enzyme, α-ketoglutarate dehydrogenase complex, components (i.e., DLST and OGDH), elevates histone succinylation, and reduces chromatin accessibility at the myogenic regulatory regions (Myod1 locus). These changes establish a direct link between Gln availability and an epigenetic-metabolic axis crucial for myogenic gene regulation. Thus, extracellular Gln acts as a key regulator of MPC proliferation through metabolic-mediated control of chromatin state.NEW & NOTEWORTHY This study revealed that extracellular Gln regulates MPC proliferation through metabolic-epigenetic axis. Gln deficiency impairs myogenesis, enhances the nuclear localization of TCA cycle enzyme, increases histone succinylation, and reduces chromatin accessibility at the myogenic regulatory regions. These findings establish Gln as a critical modulator of chromatin state via intermediary metabolic mediators during myogenesis.