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

Frontiers in endocrinology 2026

["Youngho Son", "Hye-Eun Byeon", "Sung-E Choi", "Youngha Kim", "Yu Jung Heo", "Soon Beom Kwon", "Jaemyung Choi", "Seung Jin Han", "Jayoung Jeon", "Hae Jin Kim", "Nami Lee", "Kwan-Woo Lee"]

Abstract

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.

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