Integrated Multi-Omics Analysis Identifies Disrupted Branched-Chain Amino Acid Catabolism as Causal for Sarcopenia

Abstract Sarcopenia is a geriatric skeletal muscle disorder with a gradual loss of skeletal muscle mass and function. Despite its prevalence, the underlying mechanisms of sarcopenia are not yet fully understood, and there are currently no approved treatments. In this study, we conduct a comprehensive analysis of the molecular and metabolic signatures of skeletal muscle in early and late stages of sarcopenia using multi-omics approaches. We found substantial metabolic and mitochondrial dysfunction in sarcopenia. Our results reveal that disrupted BCAA catabolism is a prominent pathway in sarcopenia, which leads to BCAA accumulation and decreased muscle strength and mass. Machine learning analysis further supports the causal role of BCAA catabolic dysfunction in sarcopenia. We further validate our results using separate cohorts of sarcopenia patients and muscle-specific Ppm1k knockout mice. The study highlights the importance of improving BCAA catabolism as a potential strategy for slowing down the progression of sarcopenia.