Loss of functional metabolic muscle mass remains a strong and consistent predictor of mortality among people living with human immunodeficiency virus (PLWH). PLWH have a higher incidence of alcohol use disorder (AUD), and myopathy is a significant clinical comorbidity due to AUD. One mechanism of skeletal muscle (SKM) mass maintenance and repair is by differentiation and fusion of satellite cells (SCs) to existing myofibers. Previous studies demonstrated that chronic binge alcohol (CBA) administration decreases SC differentiation potential, myogenic gene expression, and miR-206 expression in simian immunodeficiency virus (SIV)-infected male rhesus macaques and that miR-206 targets the Class IIA histone deacetylase, HDAC4. The aim of this study was to determine whether alcohol-induced increases in Class IIA HDACs mediate the observed decrease in differentiation potential of SCs. Data show that CBA dysregulated HDAC gene expression in SKM and myoblasts of SIV-infected macaques. CBA and antiretroviral therapy increased HDAC activity in SKM and this was positively correlated with HDAC4 gene expression. In vitro ethanol (ETOH) treatment increased HDAC expression during differentiation and decreased differentiation potential of myoblasts. HDAC expression was negatively correlated with fusion index and myotube formation, indicators of differentiation potential. Treatment with a Class II HDAC inhibitor, TMP195, restored differentiation in ETOH-treated myoblasts. MEF2C expression at day 3 of differentiation was positively correlated with fusion index and myotube formation. These findings suggest that an alcohol-mediated increase in Class IIA HDAC expression contributes to decreased myoblast differentiation by downregulating MEF2C, a transcription factor critical for myogenesis.

中文翻译：

---

酒精诱导的骨骼肌干细胞分化受损的表观基因组机制；IIA 类组蛋白脱乙酰酶的作用。

功能性代谢肌肉质量的损失仍然是人类免疫缺陷病毒 (PLWH) 感染者死亡率的一个强有力且一致的预测指标。PLWH 的酒精使用障碍 (AUD) 发生率较高，而肌病是 AUD 引起的重要临床合并症。骨骼肌 (SKM) 大规模维持和修复的一种机制是通过卫星细胞 (SC) 与现有肌纤维的分化和融合。先前的研究表明，长期酗酒 (CBA) 给药会降低猴免疫缺陷病毒 (SIV) 感染的雄性恒河猴的 SC 分化潜能、肌原性基因表达和 miR-206 表达，并且 miR-206 靶向 IIA 类组蛋白去乙酰化酶 HDAC4 . 本研究的目的是确定酒精诱导的 IIA 类 HDAC 的增加是否介导了观察到的 SCs 分化潜能的降低。数据显示 CBA 在 SIV 感染的猕猴的 SKM 和成肌细胞中的 HDAC 基因表达失调。CBA 和抗逆转录病毒治疗增加了 SKM 中的 HDAC 活性，这与 HDAC4 基因表达呈正相关。体外乙醇 (ETOH) 处理增加了分化过程中的 HDAC 表达并降低了成肌细胞的分化潜能。HDAC表达与融合指数和肌管形成、分化潜能指标呈负相关。用 II 类 HDAC 抑制剂 TMP195 治疗恢复了 ETOH 处理的成肌细胞的分化。分化第3天的MEF2C表达与融合指数和肌管形成呈正相关。