Inhibiting Glutaminase Reverses Senescence-Associated Mitochondrial Dysfunction and Skeletal Muscle Decline

Age-associated loss of skeletal muscle mass and function, also known as sarcopenia, is closely linked to mitochondrial dysfunction. In this study, we report that senescent skeletal muscle myoblasts exhibit elevated activity and expression of the enzyme glutaminase (GLS1), which is mediated by p38 MAPK signaling and leads to intracellular urea accumulation that impairs mitochondrial function. Pharmacological inhibition of GLS1 with CB-839 reduced urea levels, restored the expression of electron transport chain (ETC) complexes, and improved mitochondrial function. Consistent with our in vitro findings, CB-839 administration to progeroid mice similarly upregulated ETC complexes and enhanced mitochondrial respiratory capacity in skeletal muscle, leading to improved structural integrity and enhanced muscle strength. Together, these findings suggest that targeting glutamine metabolism via GLS1 inhibition may represent a promising therapeutic strategy to ameliorate age-related skeletal muscle decline by restoring mitochondrial health.