Methionine adenosyltransferase2A inhibition decreases insulin resistance and restores the regenerative capacity and strength of aged skeletal muscle
We investigated the age-related metabolic changes that occur in aged and rejuvenated myoblasts using in vitro and in vivo models of aging. Metabolic and signaling experiments revealed that human senescent myoblasts (SM) and myoblasts from a mouse model of premature aging suffer from impaired glycolysis, insulin resistance, and generate ATP by catabolizing methionine via a methionine adenosyl-transferase (MAT) 2A-dependant mechanism, producing significant levels of ammonium that may further contribute to cellular senescence. Expression of the pluripotency factor NANOG downregulated MAT2A, decreased ammonium, restored insulin sensitivity, increased glucose uptake, and enhanced muscle regeneration post-injury. Similarly, selective inhibition of MAT2A activated Akt2 signaling, repaired pyruvate kinase, restored glycolysis, and induced regeneration, which led to significant enhancement of muscle strength in a mouse model of premature aging. Collectively, our investigation indicates that inhibiting methionine metabolism may restore age-associated impairments with significant gain in muscle function.