Semaglutide targets muscle mitochondria to regulate glutamine metabolism and treat osteoarthritis

As a metabolic regulatory drug for lowering body weight, semaglutide has shown additional therapeutic effects in osteoarthritis (OA), but the underlying mechanism requires further investigation. Here, we employed cross-tissue single-cell RNA sequencing analysis and found that semaglutide improved mitochondrial metabolic disorders in muscle tissue under high-fat diet and OA conditions in mice. The results of multi-omics analysis indicated that semaglutide targeted muscle mitochondria to regulate glutamine metabolism during OA. Intramuscular injection of mitochondria from C2C12 cells, pre-stimulated by semaglutide, could alleviate pain symptoms and cartilage damage of OA, which was achieved by inhibiting muscle glutaminase activity and upregulating circulating glutamine concentration. In vitro experiments confirmed the alleviating effect of glutamine produced by C2C12 cells stimulated by semaglutide on chondrocyte inflammation. These findings reveal the mitochondrial regulatory mechanism in the muscle-cartilage axis and provide a perspective for the application of semaglutide in OA treatment.