Effects of local Interleukin‐6 on Skeletal Muscle Mitochondrial Physiology

Abstract

Skeletal muscle is vital to metabolic health and physical function. Skeletal muscle mitochondria have been extensively interrogated as organelles whose function and dysfunction are closely tied with chronic diseases such as diabetes and sarcopenia. There is accumulating evidence suggesting that chronic inflammation that is prevalent with aging and obesity is associated with skeletal muscle abnormalities such as functional impairments in mitochondria. Despite compelling links between inflammation, oxidative stress, and skeletal muscle dysfunction, the local effects of inflammatory cytokines on skeletal muscle mitochondrial physiology are currently not well‐understood. The purpose of this study was to determine how the inflammatory cytokine interleukin‐6 (IL‐6) influences skeletal muscle mitochondrial function. To determine the acute effects of IL‐6, mitochondria were isolated from skeletal muscle of healthy male mice (C57BL6) and were exposed to IL‐6 (IL6+,50 ng/ml) or vehicle (CTRL) for one hour. Multiplexed measurements of mitochondrial respiration (high‐resolution respirometry) and reactive oxygen species production (ROS, fluorometry) revealed that IL‐6 significantly increased ROS production as a percent of oxygen (4.14%±0.40) compared to CTRL (2.74%±0.34). Similarly, IL‐6 increased ROS production in differentiated C2C12 myotubes that were incubated for 18 hrs with 50 ng/mL IL‐6 (4.71%±.57) compared to CTRL (2.21%±.34). To evaluate the possibility that IL‐6 triggers ROS production by stimulating the mitochondrial transition pore (mPTP), isolated mitochondria were ale treated with cyclosporin A (CsA), a mPTP inhibitor in the presence or absence of IL‐6. Inhibition of mPTP attenuated IL‐6 induced ROS production (IL6+ (4.14%±0.40) vs. IL6+/CsA (2.78%±0.58). These results suggest that IL‐6 triggers an increase in mitochondrial ROS production that appears to be mediated by opening of the mPTP. Prolonged opening of the mPTP caused by chronically elevated IL‐6 may contribute to increased oxidative stress that is evident in skeletal muscle with aging and obesity.This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.