Effects of Urolithin A supplementation on muscle health outcomes in humans from randomized controlled trials.

BACKGROUND: Urolithin A (UA), a gut microbiota-derived metabolite, has been proposed to improve skeletal muscle function, but evidence from randomized controlled trials has not been systematically summarized. This systematic review and meta-analysis aimed to evaluate the effects of UA supplementation on muscle performance as well as biochemical and mitochondrial biomarkers in humans. METHODS: Randomized controlled trials published up to December 2025 were identified through systematic searches of four electronic databases: PubMed, Embase, Web of Science, and Scopus. Trials comparing oral UA supplementation with placebo and reporting muscle-related outcomes were included. Risk of bias was assessed using the Cochrane Risk of Bias 2 (RoB 2) tool, and the certainty of evidence for the primary quantitatively synthesized outcome was rated using the GRADE approach. Quantitative meta-analysis was feasible only for the 6-min walk test (6MWT); remaining outcomes were synthesized narratively. For multi-arm trials with a shared comparator, intervention arms were combined into a single group following Cochrane Handbook guidance to avoid unit-of-analysis errors. Pooled mean differences with 95% confidence intervals were calculated using inverse-variance weighting, with both fixed-effect and random-effects sensitivity analyses. RESULTS: Five randomized controlled trials (n = 236) were included. Quantitative synthesis was feasible only for the 6MWT (k = 2). After combining the 500 mg and 1,000 mg Urolithin A arms of Singh et al. (5) against the shared placebo group, the pooled mean difference was +17.03 m (95% CI -5.33 to 39.40 m; p = 0.135; I 2 = 0%); a sensitivity analysis using placebo-group splitting yielded a comparable estimate (+18.80 m; 95% CI -3.24 to 40.85 m; p = 0.095). The certainty of evidence for the 6MWT outcome was rated as low (GRADE). Non-6MWT outcomes - muscle strength, endurance, aerobic capacity, and biochemical or mitochondrial biomarkers - were heterogeneous across populations, doses, and assessment modalities, were not quantitatively pooled, and are reported as exploratory signals rather than reproducible effects. CONCLUSION: The currently available randomized human evidence is limited to five small, short-term trials in clinically heterogeneous populations. Quantitative pooling was feasible for a single outcome (6MWT) based on two trials and showed a directionally favorable but statistically inconclusive effect with low GRADE certainty. Narrative findings on strength, endurance, and mitochondrial-related biomarkers are exploratory and hypothesis-generating, not reproducible evidence of efficacy. Larger, longer, and methodologically standardized trials in better-defined populations are required before firm clinical recommendations can be made. SYSTEMATIC REVIEW REGISTRATION: https://www.crd.york.ac.uk/PROSPERO/view/CRD420251270987, identifier: PROSPERO 2025 CRD420251270987.