2. Academic Validation
  3. Multi-omic profiling of sarcopenia identifies disrupted branched-chain amino acid catabolism as a causal mechanism and therapeutic target

Multi-omic profiling of sarcopenia identifies disrupted branched-chain amino acid catabolism as a causal mechanism and therapeutic target

  • Nat Aging. 2025 Feb 5. doi: 10.1038/s43587-024-00797-8.
Xinrong Zuo # 1,  Rui Zhao # 1 2,  Minming Wu # 1,  Yanyan Wang # 3,  Shisheng Wang # 4,  Kuo Tang 1,  Yang Wang 1 2,  Jie Chen 5,  Xiaoxiang Yan 6,  Yang Cao 7 8,  Tao Li 9
Affiliations

Affiliations

  • 1 Department of Anesthesiology, Laboratory of Mitochondrial Metabolism and Perioperative Medicine, National Clinical Research Center for Geriatrics, West China Hospital of Sichuan University, Chengdu, China.
  • 2 Division of Gastrointestinal Surgery, Department of General Surgery, West China Hospital of Sichuan University, Chengdu, China.
  • 3 Innovation Center of Nursing Research, Nursing Key Laboratory of Sichuan Province & School of Nursing, West China Hospital, Sichuan University, Chengdu, China.
  • 4 Liver Surgery and Liver Transplant Center and NHC Key Lab of Transplant Engineering and Immunology, West China Hospital, Sichuan University, Chengdu, China.
  • 5 Department of Rheumatology and Immunology, The Affiliated Hospital, Southwest Medical University, Luzhou, China.
  • 6 Department of Cardiovascular Medicine, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China. cardexyanxx@hotmail.com.
  • 7 Department of Cardiology, Division of Life Sciences and Medicine, The First Affiliated Hospital of USTC, University of Science and Technology of China, Hefei, China. yangcao208@ustc.edu.cn.
  • 8 Division of Life Sciences and Medicine, School of Basic Medical Sciences, University of Science and Technology of China, Hefei, China. yangcao208@ustc.edu.cn.
  • 9 Department of Anesthesiology, Laboratory of Mitochondrial Metabolism and Perioperative Medicine, National Clinical Research Center for Geriatrics, West China Hospital of Sichuan University, Chengdu, China. scutaoli1981@scu.edu.cn.
  • # Contributed equally.
PMID: 39910243 DOI: 10.1038/s43587-024-00797-8
Abstract

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.

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