Semaglutide targets muscle mitochondria to regulate glutamine metabolism, alleviating osteoarthritis in mice.

Osteoarthritis (OA) is a debilitating chronic joint disease characterized by cartilage degradation, pain, and inflammation, for which current treatments primarily manage symptoms rather than modifying disease progression. While semaglutide is well-established for its metabolic benefits in conditions like obesity and type 2 diabetes, its therapeutic potential in OA has emerged, yet the precise mechanisms remain largely unexplored. Understanding how semaglutide exerts effects beyond systemic weight loss, particularly involving peripheral tissues like muscle, is crucial for developing novel OA interventions and leveraging its pleiotropic actions.

Researchers investigated semaglutide's mechanism in OA using mice subjected to a high-fat diet and OA conditions. They employed cross-tissue single-cell RNA sequencing and multi-omics analysis to identify metabolic changes. To confirm the role of muscle mitochondria, they pre-stimulated C2C12 muscle cells with semaglutide and then performed intramuscular injections of these mitochondria into OA mice. In vitro experiments further assessed the effect of glutamine, produced by semaglutide-stimulated C2C12 cells, on chondrocyte inflammation, using an IL-1β-induced rat chondrocyte senescence model.

Multi-omics analysis revealed that semaglutide significantly improved mitochondrial metabolic disorders within muscle tissue under both high-fat diet and OA conditions in mice. The study identified that semaglutide specifically targeted muscle mitochondria to regulate glutamine metabolism during OA progression. This mitochondrial regulation was linked to systemic effects. The most compelling finding demonstrated a direct therapeutic impact:

Intramuscular injection of mitochondria from C2C12 cells, pre-stimulated by semaglutide, effectively alleviated pain symptoms and reduced cartilage damage in OA mice. This beneficial effect was achieved by inhibiting muscle glutaminase activity and consequently upregulating circulating glutamine concentration. Furthermore, in vitro experiments corroborated that glutamine produced by C2C12 cells stimulated by semaglutide had an alleviating effect on chondrocyte inflammation, highlighting a direct protective role.