Elevated trimethylamine levels characterize impaired muscle mass response to leucine-enriched protein supplementation in older adults at risk of sarcopenia

Leucine-enriched supplementation is a primary intervention for sarcopenia, yet individual responses vary. We integrated 1H-NMR metabolomics with clinical assessments in 47 older adults at high sarcopenia risk to identify metabotypes associated with improvements in muscle mass and strength. Following a 12-week intervention, distinct metabolic trajectories emerged between responders and non-responders. Notably, urinary levels of the gut-derived metabolite trimethylamine (TMA) and phenylpyruvic acid exhibited divergent trends across outcome-defined groups. Elevated TMA was associated with a blunted muscle mass response to leucine supplementation and with impaired myogenic differentiation and compromised myotube integrity in vitro, supporting a potential role in limiting myogenic capacity. These findings highlight the gut-muscle axis as a key modulator of heterogeneous responses to nutritional intervention and provide a metabolic framework for stratifying individuals in sarcopenia prevention strategies.