Epigenetic inhibition of class I histone deacetylases by MS-275 attenuates diabetic skeletal muscle atrophy via Akt/ARK5–FoxO and myostatin–Smad signaling

Background Sarcopenia is highly prevalent in individuals with diabetes and is associated with impaired physical function and increased mortality. Diabetes-associated skeletal muscle atrophy is driven by chronic inflammation, dysregulated anabolic–catabolic signaling, and activation of ubiquitin–proteasome–mediated protein degradation. Emerging evidence suggests that histone deacetylases (HDACs) act as epigenetic regulators of metabolic and inflammatory pathways; however, their role in diabetic sarcopenia remains incompletely understood. Methods Male db/db mice were used as a model of diabetes-associated muscle atrophy and treated with MS-275 (entinostat), a selective class I HDAC inhibitor, for 4 weeks. Skeletal muscle mass and fiber cross-sectional area were assessed by magnetic resonance imaging and histological analysis. Inflammatory responses, myostatin signaling, and Akt/ARK5–FoxO–mediated catabolic pathways were evaluated using immunohistochemistry, quantitative PCR, ELISA, and western blotting. Results MS-275 treatment significantly restored skeletal muscle mass and myofiber size in db/db mice. These effects were accompanied by marked reductions in macrophage infiltration, pro-inflammatory cytokine expression, and NF-κB activation. MS-275 also suppressed circulating myostatin levels and attenuated downstream Smad2/3 signaling. Furthermore, MS-275 restored Akt and ARK5 phosphorylation and promoted FoxO1/3 phosphorylation, resulting in decreased expression of the muscle-specific E3 ubiquitin ligases MuRF1 and atrogin-1. Conclusion Our findings demonstrate that epigenetic inhibition of class I HDACs by MS-275 attenuates diabetes-associated skeletal muscle atrophy by coordinately suppressing inflammatory signaling and myostatin-driven catabolic pathways while restoring Akt/ARK5–FoxO signaling. These results suggest that class I HDACs are key epigenetic regulators of diabetic muscle wasting and that targeting their activity provides important mechanistic insights for preserving skeletal muscle mass in diabetic sarcopenia.