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Comprehensive transcriptomic profiling reveals impaired polyamine metabolism as a contributor to age-related muscle decline.

ABSTRACT: Sarcopenia, the age-associated decline in skeletal muscle mass and function, remains mechanistically poorly understood, particularly at the spatial and fiber type-specific levels. Here, we present a spatial transcriptomic atlas of skeletal muscle from young and aged mice, resolving age-associated transcriptional reprogramming across distinct myofiber types and tissue compartments. Our analyses uncover coordinated alterations in sarcomeric organization, excitation-contraction coupling, and oxidative stress responses, together with fiber type-specific metabolic rewiring toward glycolytic or oxidative programs. We also delineate conserved molecular signatures across muscles and species, highlighting Car3 as a potential pan-muscle biomarker of sarcopenia. In this context, we identify selective downregulation of key enzymes in the polyamine biosynthetic pathway, including Amd1 and Smox, resulting in reduced spermidine levels in aged muscle. This decline in polyamine availability also impacts muscle-resident cell populations. Indeed, pharmacological inhibition of Amd1 in fibro-adipogenic progenitors (FAPs) recapitulates aging-associated phenotypes, including myofibroblast differentiation, extracellular matrix dysregulation, and impaired support for satellite cell-mediated myogenesis. Collectively, our work reveals spatially organized, fiber type-specific, and polyamine-linked mechanisms of muscle aging and highlights the polyamine pathway as a promising therapeutic target to counteract sarcopenia.

ORGANISM(S): Mus musculus

PROVIDER: GSE308816 | GEO | 2026/07/13

REPOSITORIES: GEO

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Project description: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.

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Comprehensive transcriptomic profiling reveals impaired polyamine metabolism as a contributor to age-related muscle decline.

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