Reprograming of Methionine Metabolism Rejuvenates Impaired Bioenergetics of Aged Myoblasts and Restores Regenerative Potential of Progeric Skeletal Muscle
Sarcopenia or muscle wasting occurs with aging and correlates with loss of metabolic function, disabilities and mortality. Here we investigated the age-related metabolic rewiring that occurs in myoblasts using in vitro and in vivo models of aging and rejuvenation. Mass spectroscopy revealed that aged skeletal muscle is afflicted with elevated methionine metabolism and taurine deficiency. Aged skeletal muscle also exhibited suppressed activity of phospho-regulated enzymes including Akt2, pyruvate dehydrogenase (PDH), and pyruvate kinase (PK), which are critical for the activation of glycolysis. Seahorse analytics revealed that senescent myoblasts are insulin resistant and generate ATP by methionine catabolism, which increased ammonium that induced reactive oxygen species, evoked DNA damage and suppressed myotube formation. Interestingly, transgenic lamin A deficient (progeroid) mice, expressing the transcription factor NANOG, exhibited marked improvements in skeletal muscle physiology including decreased p62, increased insulin sensitivity, downregulation of methionine catabolism, upregulation of glycolysis and increased taurine synthesis. In agreement, human myoblasts from older adults catabolized methionine to produce ATP with concurrent ammonium generation. Notably, taurine administration also restored insulin sensitivity and glycolysis, suppressed methionine catabolism, and restored the ability of myoblasts to differentiate into striated skeletal muscle capable of synchronized contraction. Our investigation links metabolic reprogramming to skeletal muscle aging and rejuvenation and provides possible means for addressing sarcopenia, one of the most important causes of functional decline in older adults.