Sarcopenia is associated with mortality in patients with nonalcoholic steatohepatitis (NASH). Angiotensin II receptor blocker (ARB) has been suggested to prevent sarcopenia, but reports on its effect on NASH-derived skeletal muscle atrophy in conjunction with insulin-like growth factor 1 (IGF-1)-mediated muscle homeostasis are few. Our aim was to examine the combined effect of the ARB losartan and IGF-1 replacement on skeletal muscle atrophy in a methionine–choline deficient (MCD) diet-fed murine steatohepatitis model. The MCD-fed mice developed steatohepatitis and skeletal muscle atrophy, as indicated by the reduction of psoas muscle mass and attenuation of forelimb and hindlimb grip strength. Significantly suppressed steatohepatitis and skeletal muscle atrophy was observed after single treatment with ARB or IGF-1, and these effects were augmented after combination treatment. Treatment with ARB and IGF-1 effectively inhibited ubiquitin proteasome-mediated protein degradation by reducing forkhead box protein O1 (FOXO1) and FOXO3a transcriptional activity in the skeletal muscle. Combined ARB and IGF-1 decreased the intramuscular expression of proinflammatory cytokines (i.e., TNFα, IL6, and IL1β) and increased the Trolox equivalent antioxidant capacity and antioxidant enzymes (CAT, GPX1, SOD2, and CYTB). This antioxidant effect was based on downregulation of NADPH oxidase (NOX) 2, normalization of mitochondrial biogenesis and dynamics. Moreover, ARB increased the hepatic and plasma IGF-1 levels and improved steatohepatitis, leading to enhanced skeletal muscle protein synthesis mediated by IGF-1/ AKT/ mechanistic target of rapamycin signaling. Collectively, combined ARB and IGF-1 replacement could be a promising new therapeutic target for NASH-derived skeletal muscle wasting.

肌肉减少症与非酒精性脂肪性肝炎 (NASH) 患者的死亡率相关。血管紧张素 II 受体阻滞剂 (ARB) 被认为可以预防肌肉减少症，但有关其对 NASH 衍生骨骼肌萎缩以及胰岛素样生长因子 1 (IGF-1) 介导的肌肉稳态的影响的报道很少。我们的目的是在甲硫氨酸胆碱缺乏 (MCD) 饮食喂养的小鼠脂肪性肝炎模型中检查 ARB 氯沙坦和 IGF-1 替代品对骨骼肌萎缩的综合作用。喂食MCD的小鼠出现了脂肪性肝炎和骨骼肌萎缩，腰肌质量减少以及前肢和后肢握力减弱表明了这一点。 ARB或IGF-1单独治疗后观察到脂肪性肝炎和骨骼肌萎缩得到显着抑制，并且在联合治疗后这些效果得到增强。 ARB 和 IGF-1 治疗通过降低骨骼肌中叉头盒蛋白 O1 (FOXO1) 和 FOXO3a 转录活性，有效抑制泛素蛋白酶体介导的蛋白质降解。 ARB 和 IGF-1 联合使用可降低促炎细胞因子（即 TNFα、IL6 和 IL1β）的肌内表达，并增加 Trolox 等效抗氧化能力和抗氧化酶（CAT、GPX1、SOD2 和 CYTB）。这种抗氧化作用基于 NADPH 氧化酶 (NOX) 2 的下调、线粒体生物发生和动力学的正常化。此外，ARB 增加肝脏和血浆 IGF-1 水平并改善脂肪性肝炎，从而增强 IGF-1/AKT/雷帕霉素信号传导机制靶标介导的骨骼肌蛋白合成。 总的来说，联合 ARB 和 IGF-1 替代疗法可能成为 NASH 所致骨骼肌萎缩的一个有前景的新治疗靶点。