An integrated drug repositioning analysis identifies rosiglitazone as a treatment for sarcopenia.

Age-related sarcopenia is a growing global health challenge with no approved pharmacotherapies. Here, we integrate network-based drug repurposing and Mendelian randomization to identify rosiglitazone, a PPARγ agonist used in diabetes, as a potential therapeutic candidate for sarcopenia. In aged male C57BL/6JRj murine models, rosiglitazone administration significantly improved muscle strength, mass, and endurance. Multi-omics profiling revealed its mechanism involves gut microbiota remodeling, activation of skeletal muscle Igf1 signaling, suppression of atrophy-related ubiquitin ligases (Atrogin-1/MuRF1), and modulation of protein metabolism, suggesting a coordinated "gut-muscle-metabolism" axis. Genetic analyses further support the causal role of Clostridiaceae/Clostridium in grip strength. Our findings nominate rosiglitazone as a promising intervention for sarcopenia, warranting further clinical investigation.