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

Abstract Background Sarcopenia is a major contributor to frailty and mortality in aging and obesity and is tightly linked to metabolic dysfunction. Imeglimin is a first-in-class oral hypoglycemic 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 six weeks and to naturally aged (18-month-old) male mice for 12 weeks. Skeletal muscle fiber morphology and transcriptomic profiles were analyzed 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 fibers 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 fiber 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 aging, accompanied by coordinated suppression of stress- and inflammation-associated transcriptional programs. 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.