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

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 (HSMM) and mouse C2C12 cells. Mechanistically, Gln deficiency enhances nuclear localization of TCA cycle enzyme, KGDHC, 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.