Zuo Xinrong, Zhao Rui, Wu Minming, Wang Yanyan, Wang Shisheng, Tang Kuo, Wang Yang, Chen Jie, Yan Xiaoxiang, Cao Yang, Li Tao
Department of Anesthesiology, Laboratory of Mitochondrial Metabolism and Perioperative Medicine, National Clinical Research Center for Geriatrics, West China Hospital of Sichuan University, Chengdu, China.
Division of Gastrointestinal Surgery, Department of General Surgery, West China Hospital of Sichuan University, Chengdu, China.
Nat Aging. 2025 Mar;5(3):419-436. doi: 10.1038/s43587-024-00797-8. Epub 2025 Feb 5.
Sarcopenia is a geriatric disorder characterized by a gradual loss of muscle mass and function. Despite its prevalence, the underlying mechanisms remain unclear, and there are currently no approved treatments. In this study, we conducted a comprehensive analysis of the molecular and metabolic signatures of skeletal muscle in patients with impaired muscle strength and sarcopenia using multi-omics approaches. Across discovery and replication cohorts, we found that disrupted branched-chain amino acid (BCAA) catabolism is a prominent pathway in sarcopenia, which leads to BCAA accumulation and decreased muscle health. Machine learning analysis further supported the causal role of BCAA catabolic dysfunction in sarcopenia. Using mouse models, we validated that defective BCAA catabolism impairs muscle mass and strength through dysregulated mTOR signaling, and enhancing BCAA catabolism by BT2 protects against sarcopenia in aged mice and in mice lacking Ppm1k, a positive regulator of BCAA catabolism in skeletal muscle. This study highlights improving BCAA catabolism as a potential treatment of sarcopenia.
肌肉减少症是一种老年疾病，其特征是肌肉质量和功能逐渐丧失。尽管其患病率很高，但其潜在机制仍不清楚，目前尚无获批的治疗方法。在本研究中，我们使用多组学方法对肌肉力量受损和肌肉减少症患者的骨骼肌分子和代谢特征进行了全面分析。在发现队列和复制队列中，我们发现支链氨基酸（BCAA）分解代谢紊乱是肌肉减少症中的一个突出途径，这会导致BCAA积累并降低肌肉健康。机器学习分析进一步支持了BCAA分解代谢功能障碍在肌肉减少症中的因果作用。使用小鼠模型，我们验证了有缺陷的BCAA分解代谢通过失调的mTOR信号传导损害肌肉质量和力量，并且通过BT2增强BCAA分解代谢可预防老年小鼠和缺乏Ppm1k（骨骼肌中BCAA分解代谢的正向调节因子）的小鼠的肌肉减少症。这项研究强调改善BCAA分解代谢作为肌肉减少症的一种潜在治疗方法。
