Causal Relationship Between Circulating Metabolites and Sarcopenia‐Related Traits: A Mendelian Randomization and Experimental Study

Sarcopenia (SP), an age-associated condition marked by muscle weakness and loss has been strongly connected with metabolic factors according to substantial evidence. Nevertheless, the causal correlation between SP and serum metabolites, and the biological signaling pathways involved, is still not well understood. We performed a bidirectional two-sample Mendelian randomization (MR) analysis to examine the causal relationships between 1091 levels and 309 ratios of metabolites with SP traits, alongside investigating the relevant biological signaling pathways. Additionally, we explored the differential expression of plasma metabolites and potential biological signaling pathways in an animal model of SP. When SP was utilized as the outcome, we identified 11 robust causal associations between seven metabolite levels/ratios and SP-related traits using Bonferroni's correction (threshold: <i>p</i> < 0.05). We verified the stable causal association of glycine levels and SP in the validation. As for the reverse MR analysis, there were 11 strong causal relationships with 11 plasma metabolite levels/ratios remaining after multiple contrast correction. Additionally, biological signaling pathway analysis showed that glycine metabolism, insulin resistance, and cAMP signaling pathways may contribute to the connection between metabolites and SP. Mendelian validation of various datasets and observations in animal serum metabolomics suggests a strong association between glycine metabolism and SP. Our results indicate that the identified metabolites and biosignaling pathways could serve as important circulatory metabolic biomarkers for the screening and prevention of SP in clinical settings. Additionally, they represent potential molecules for future exploration of mechanisms and selection of drug targets.