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

Network-based drug repurposing analysis identified rosiglitazone, a PPARγ agonist, as a candidate therapeutic for sarcopenia.

• The approach integrated network-based drug repurposing with Mendelian randomization.
• Rosiglitazone is an existing diabetes medication classified as a PPARγ agonist.
• The drug was nominated from a systematic repositioning framework rather than de novo discovery.

Rosiglitazone administration significantly improved muscle strength, mass, and endurance in aged male C57BL/6JRj mice.

• The murine model used was aged male C57BL/6JRj mice.
• Outcomes measured included muscle strength, muscle mass, and endurance.
• Improvements were described as statistically significant.

Rosiglitazone's mechanism of action involves gut microbiota remodeling in aged mice.

• Multi-omics profiling was used to characterize the mechanistic pathway.
• Gut microbiota composition was altered following rosiglitazone treatment.
• This microbiota remodeling was identified as part of a coordinated 'gut-muscle-metabolism' axis.

Rosiglitazone activated skeletal muscle Igf1 signaling and suppressed atrophy-related ubiquitin ligases.

• Multi-omics profiling revealed activation of skeletal muscle Igf1 signaling.
• Atrophy-related ubiquitin ligases Atrogin-1 and MuRF1 were suppressed following treatment.
• Modulation of protein metabolism was also observed as part of the mechanism.

Genetic analyses support a causal role of Clostridiaceae/Clostridium in grip strength.

• Mendelian randomization was used to assess causal relationships.
• The gut bacterial family Clostridiaceae and genus Clostridium were specifically implicated.
• Grip strength was used as the outcome measure for the genetic causal analysis.

Age-related sarcopenia currently has no approved pharmacotherapies, representing an unmet clinical need.

• Sarcopenia is described as a growing global health challenge.
• No approved pharmacotherapies exist for sarcopenia at the time of publication.
• This gap motivates the drug repositioning approach used in the study.