An integrated drug repositioning analysis identifies rosiglitazone as a repurposing candidate for sarcopenia

Sarcopenia is characterized by age-related muscle/strength loss and is becoming a highly important public health issue. The development of sarcopenia increases the risk of various adverse health outcomes, including falls, functional decline, frailty, and mortality. Despite its significance, there are no approved drugs to prevent or treat age-related sarcopenia. In this study, we used an integrated drug repurposing approach to repurpose approved drugs for the treatment of sarcopenia. We first used a network-based proximity score to quantify the relationship between disease-gene and drug-gene modules and identify potential repurposing candidates. Then we used summary-data-based Mendelian randomization analysis to explore the potential causal association between drug targets and sarcopenia. In an aging mouse model, we demonstrated that rosiglitazone, an insulin sensitizer used to treat diabetes, could improve endurance exercise performance, and increase grip strength, muscle fiber area, and hind limb muscle mass. Furthermore, we conducted transcriptomics, metabolomics analyses, and 16s RNA sequencing analysis in mice to explore the underlying mechanism of action for rosiglitazone. The results suggested that rosiglitazone may be a promising therapeutic option for alleviating or treating age-related sarcopenia, although additional clinical validation is still needed. Overall design: After the age of 17 months, mice in the experimental group received a commercially purified diet (AIN-93M) that contained rosiglitazone, while control mice received a standard purified diet (AIN-93M) without rosiglitazone.