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.肌肉减少症（Sarcopenia），即肌肉萎缩，随衰老进程发生，与代谢功能减退、失能及死亡率升高密切相关。本研究采用衰老与年轻化的体外、体内模型，探究了成肌细胞（myoblasts）中发生的衰老相关代谢重编程。质谱分析法（Mass Spectrometry）结果显示，衰老骨骼肌存在甲硫氨酸（methionine）代谢亢进与牛磺酸（taurine）缺乏的问题。衰老骨骼肌还表现出磷酸化调控酶活性受抑，包括Akt2、丙酮酸脱氢酶（PDH）及丙酮酸激酶（PK），这些酶对糖酵解（glycolysis）激活至关重要。海马代谢分析仪分析结果显示，衰老成肌细胞存在胰岛素抵抗，通过甲硫氨酸分解代谢生成三磷酸腺苷（ATP），该过程会产生铵离子，进而诱导活性氧（reactive oxygen species, ROS）生成、引发DNA损伤并抑制肌管形成。有趣的是，表达转录因子NANOG的核纤层蛋白A（lamin A）缺陷型（早衰样）转基因小鼠，其骨骼肌生理功能得到显著改善：包括p62蛋白水平降低、胰岛素敏感性提升、甲硫氨酸分解代谢下调、糖酵解通路上调以及牛磺酸合成增加。与之相符的是，老年个体的人类成肌细胞同样通过分解甲硫氨酸生成ATP，并伴随铵离子产生。值得注意的是，补充牛磺酸可恢复胰岛素敏感性与糖酵解功能、抑制甲硫氨酸分解代谢，并恢复成肌细胞分化为可同步收缩的横纹骨骼肌的能力。本研究将代谢重编程与骨骼肌衰老及年轻化关联起来，并为改善肌肉减少症提供了潜在方案——肌肉减少症是老年人群功能衰退的最重要诱因之一。