IL‐6 Deficiency Attenuates Skeletal Muscle Atrophy by Inhibiting Mitochondrial ROS Production through the Upregulation of PGC‐1<i>α</i> in Septic Mice

Abstract

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 P &lt; 0.05). In addition, we observed that IL‐6 KO promoted the expression of peroxisome proliferator‐activated receptor γ coactivator–1alpha (PGC–1 α ) and inhibited CLP‐induced mitochondrial reactive oxygen species (ROS) production in skeletal muscles (all P &lt; 0.05). However, the knockdown of PGC–1 α abolished the protective effects of IL‐6 KO in CLP‐induced skeletal muscle atrophy and reversed the changes in mitochondrial ROS production (all P &lt; 0.05). Ex vivo experiments found that exogenous IL‐6 inhibited PGC–1 α expression, promoted mitochondrial ROS production, and induced proteolysis in C2C12 cells (all P &lt; 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 α expression in septic mice.

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