Department of Orthopedics, Renmin Hospital of Wuhan University, Wuhan, Hubei 4300670, China.
Department of Orthopedics, Renmin Hospital of Yangxin Country, Huangshi, Hubei 435200, China.
Oxid Med Cell Longev. 2022 Apr 27;2022:9148246. doi: 10.1155/2022/9148246. eCollection 2022.
Current evidences indicate that both inflammation and oxidative stress contribute to the pathogenesis of sepsis-associated skeletal muscle atrophy. However, the interaction between inflammation and oxidative stress has not been completely understood in sepsis-associated skeletal muscle atrophy. Here in the present study, a murine model of sepsis has been established by cecal ligation and puncture (CLP) with wild-type and interleukin- (IL-) 6 knockout (KO) mice. Our results suggested that IL-6 KO largely attenuated skeletal muscle atrophy as reflected by reduced protein degradation, increased cross-sectional area (CSA) of myofibers, and improved muscle contractile function (all < 0.05). In addition, we observed that IL-6 KO promoted the expression of peroxisome proliferator-activated receptor coactivator-1alpha (PGC-1) and inhibited CLP-induced mitochondrial reactive oxygen species (ROS) production in skeletal muscles (all < 0.05). However, the knockdown of PGC-1 abolished the protective effects of IL-6 KO in CLP-induced skeletal muscle atrophy and reversed the changes in mitochondrial ROS production (all < 0.05). Ex vivo experiments found that exogenous IL-6 inhibited PGC-1 expression, promoted mitochondrial ROS production, and induced proteolysis in C2C12 cells (all < 0.05). Together, these results suggested that IL-6 deficiency attenuated skeletal muscle atrophy by inhibiting mitochondrial ROS production through the upregulation of PGC-1 expression in septic mice.
目前的证据表明，炎症和氧化应激都有助于脓毒症相关的骨骼肌萎缩的发病机制。然而，在脓毒症相关的骨骼肌萎缩中，炎症和氧化应激之间的相互作用尚未完全理解。在本研究中，通过盲肠结扎和穿刺（CLP）建立了野生型和白细胞介素-（IL-）6 敲除（KO）小鼠的脓毒症模型。我们的结果表明，IL-6 KO 极大地减轻了骨骼肌萎缩，表现为蛋白降解减少、肌纤维横截面积（CSA）增加和肌肉收缩功能改善（均<0.05）。此外，我们观察到 IL-6 KO 促进了过氧化物酶体增殖物激活受体共激活因子-1α（PGC-1）的表达，并抑制了 CLP 诱导的骨骼肌线粒体活性氧（ROS）产生（均<0.05）。然而，PGC-1 的敲低消除了 IL-6 KO 在 CLP 诱导的骨骼肌萎缩中的保护作用，并逆转了线粒体 ROS 产生的变化（均<0.05）。离体实验发现，外源性 IL-6 抑制了 PGC-1 的表达，促进了线粒体 ROS 的产生，并诱导了 C2C12 细胞的蛋白水解（均<0.05）。综上所述，这些结果表明，IL-6 缺乏通过上调 PGC-1 的表达抑制线粒体 ROS 的产生，从而减轻脓毒症小鼠的骨骼肌萎缩。
