(252d) Metabolic Rewiring of Aged Myoblasts and Restores Regenerative Potential of Progeric Skeletal Muscle

Skeletal muscle (SkM) comprises approximately 40% of total body mass and plays essential physiological roles in the body such as enabling skeletal movements and regulating metabolism. Age-related muscle loss, sarcopenia is a major medical problem facing the elderly and correlates with loss of metabolic function, falls leading to cranial fractures, type II diabetes, and cardiac insufficiency. Here we investigate the age-related metabolic rewiring that occurs in myoblasts using in vitro and in vivo models of aging and rejuvenation. RNA sequencing and pathway analysis data revealed that several metabolic pathways changed significantly upon senescence. We also provided evidence aged myoblasts have less glycolysis and insulin sensitivity, which leads to utilize a different source of energy to generate ATP. Our results suggested that aged myoblasts preferred to catabolize amino acids mostly methionine for ATP production and this came at the expense of accumulation of ammonium that leads to DNA damage and impaired cellular function, compromising regenerative capacity and myotube formation. Interestingly, we found that expression of the embryonic transcription factor, NANOG, in senescent cells restored insulin sensitivity, Akt2 signaling, glucose uptake and utilization of glucose for ATP production. In addition, NANOG decreased expression of methionine adenosyl-transferase (MAT) 2A and ammonium levels. Interestingly, inhibiting MAT2A using shRNA showed similar results as NANOG, including restoration of insulin sensitivity, Akt2 signaling and increased glycolysis. Most notably, decreasing methionine catabolism by NANOG expression or MAT2A inhibition led to dramatic improvements in skeletal muscle strength in a mouse model of premature aging.