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.