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Semaglutide targets muscle mitochondria to regulate glutamine metabolism and treat osteoarthritis

ABSTRACT:

Metabolic and inflammatory diseases often coexist, and become important challenges facing global health, and obesity has shown to be a susceptibility factor for osteoarthritis (OA). As a metabolic regulatory drug for lowering blood sugar and body weight, semaglutide has shown additional therapeutic effects in OA, but the underlying mechanism requires further investigation. Here we employed cross-tissue single-cell RNA sequencing (scRNA-seq) analysis, and found that semaglutide significantly improved mitochondrial metabolic disorders in muscle tissue under high-fat diet (HFD) and OA conditions in mice. The results of metabolome and mitochondrial proteomics indicated that semaglutide targeted muscle mitochondria to regulate glutamine metabolism during OA. Intramuscular injection of semaglutide pre-stimulated mitochondria from myoblasts could significantly alleviate OA inflammation and pain symptoms, which was achieved by inhibiting muscle glutaminase activity, upregulating circulating glutamine concentration, and thereby alleviating cartilage inflammation. In vitro experiments further confirmed the alleviating effect of glutamine produced by myoblasts stimulated by semaglutide on chondrocyte inflammation. These findings reveal the mitochondrial regulatory mechanism in the muscle-OA axis, and provide a new perspective for the application of semaglutide in OA treatment.

INSTRUMENT(S): Liquid Chromatography MS - negative - reverse-phase, Liquid Chromatography MS - positive - reverse-phase

PROVIDER: MTBLS14295 | MetaboLights | 2026-05-06

REPOSITORIES: MetaboLights

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			Action	DRS
	a_MTBLS14295_LC-MS_negative_reverse-phase.txt	Txt
	a_MTBLS14295_LC-MS_positive_reverse-phase.txt	Txt
	i_Investigation.txt	Txt
	m_MTBLS14295_LC-MS_negative_reverse-phase_v2_maf.tsv	Tabular
	m_MTBLS14295_LC-MS_positive_reverse-phase_v2_maf.tsv	Tabular

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Project description:Idiopathic inflammatory myopathies (IIMs) are severe autoimmune diseases whose pathogenetic mechanisms are still poorly understood. Invalidation of the inducible T cell co-stimulator (Icos) gene on the diabetes-prone NOD mouse background leads to spontaneous autoimmune myositis, providing a tool for studying the pathophysiological mechanisms involved in muscle inflammation. Myositis in Icos-/- NOD mice is characterized by progressive muscle weakness with immune cell infiltration and expression of IFN-associated genes, thus resembling human myositis. Proteomic and spatial transcriptomic analysis of Icos-/- NOD mice muscle brought to light a profound metabolic dysregulation in myofibers. Electron microscopy analysis, mitochondrial respiration assessment and histoenzymology stainings revealed dramatic structural abnormalities and severe dysfunction of muscle mitochondria in diseased Icos-/- NOD mice. Consequently, muscle from these mice exhibited elevated reactive oxygen species (ROS) production and an oxidative stress-transcriptomic signature. Blocking IFN in Icos-/- NOD mice diminished immune cell infiltration and ROS production. Transcriptomic analysis of muscle biopsies from IIMs patients revealed a negative correlation between IFN and mitochondrial gene expression levels, and treatment of human myoblasts with IFN reduced the expression of mitochondrial respiratory chain genes, suggesting a link between IFN production and mitochondrial dysfunction. Sustaining a relevant pathogenic role for oxidative stress in the disease, preventive and therapeutic ROS-buffer treatments also significantly alleviated myositis while preserving mitochondrial ultrastructure and restoring muscle mitochondrial respiration in mice. Notably, preventive ROS-buffer treatment also reduced muscle inflammation. Together, our results suggest that ROS, mitochondrial dysfunction and inflammation are interconnected in a self-maintenance loop, opening perspectives for ROS targeting drugs and/or mitochondria therapy in myositis.

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Semaglutide targets muscle mitochondria to regulate glutamine metabolism and treat osteoarthritis

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