Imeglimin Attenuates Skeletal Muscle Atrophy in Mouse Models of Obesity and Ageing

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BACKGROUND: Sarcopenia is a major contributor to frailty and mortality in ageing and obesity and is tightly linked to metabolic dysfunction. Imeglimin is a first-in-class oral hypoglycaemic agent targeting mitochondrial function; however, despite the central role of mitochondria in skeletal muscle homeostasis, its effects on skeletal muscle under sarcopenia-relevant conditions remain unclear. METHODS: Imeglimin was administered to male C57BL/6 mice with high-fat diet (HFD)-induced obesity for 6 weeks and to naturally aged (18 months old) male mice for 12 weeks. Skeletal muscle fibre morphology and transcriptomic profiles were analysed in fast- and slow-twitch muscles. In parallel, C2C12 myotubes were exposed to palmitate with or without imeglimin, and inflammatory gene expression and reactive oxygen species (ROS) generation were assessed. RESULTS: Imeglimin significantly increased the cross-sectional area (CSA) of Type II fibres in the extensor digitorum longus (EDL) muscle of HFD-fed mice (+66%, p < 0.01 vs. controls). Transcriptomic analyses revealed suppression of conserved molecular signatures of muscle atrophy, including activation of immediate-early genes and inflammatory pathways (-62% to -79%, p < 0.05 vs. HFD-fed mice). In palmitate-treated C2C12 myotubes, imeglimin attenuated lipotoxicity-induced inflammatory gene expression (-28% to -72%, p < 0.05 vs. controls) with reduced ROS generation, consistent with its cell-autonomous effect on myocytes. Notably, in naturally aged mice, 12-week imeglimin treatment preserved EDL muscle fibre size (+14%, p < 0.05 vs. controls) without altering systemic glucose tolerance, accompanied by transcriptomic changes overlapping with those observed in the HFD model (-27% to -82%, p < 0.05 vs. aged controls). CONCLUSIONS: Imeglimin attenuates skeletal muscle atrophy in obesity and ageing, accompanied by coordinated suppression of stress- and inflammation-associated transcriptional programmes. These findings indicate that pharmacological regulation of mitochondrial stress responses influences skeletal muscle vulnerability under chronic metabolic stress and identify skeletal muscle as a previously underappreciated target of imeglimin action.

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