Role of oxidative stress in impaired insulin signaling associated with exercise-induced muscle damage

Abstract

Skeletal muscle is a major tissue that utilizes blood glucose. A single bout of exercise improves glucose uptake in skeletal muscle through insulin-dependent and insulin-independent signal transduction mechanisms. However, glucose utilization is decreased in muscle damage induced by acute, unaccustomed, or eccentric exercise. The decrease in glucose utilization is caused by decreased insulin-stimulated glucose uptake in damaged muscles with inhibition of the membrane translocation of glucose transporter 4 through phosphatidyl 3-kinase/Akt signaling. In addition to inflammatory cytokines, reactive oxygen species including 4-hydroxy-2-nonenal and peroxynitrate can induce degradation or inactivation of signaling proteins through posttranslational modification, thereby resulting in a disturbance in insulin signal transduction. In contrast, treatment with factors that attenuate oxidative stress in damaged muscle suppresses the impairment of insulin sensitivity. Muscle-damaging exercise may thus lead to decreased endurance capacity and muscle fatigue in exercise, and it may decrease the efficiency of exercise therapy for metabolic improvement.

Keywords: 4-HNE; 4-Hydroxynonenal; 4-hydroxy-2-nonenal; AMP-activated kinase; AMPK; CK; Ca(2+)/calmodulin-dependent protein kinase; CaMK; Delayed-onset muscle damage; GLUT4; IKK; IL; IRS; Insulin signal transduction; IκB kinase; MAPK; Muscle-damaging exercise; NF-κB; PGC-1α; PI3-K; ROS; SOD; TNF-α; creatine kinase; glucose transporter 4; insulin receptor substrate; interleukin; mitogen-activated protein kinase; nuclear factor-κB; peroxisome proliferator-activated receptor γ coactivator-1α; phosphatidylinositol 3-kinase; reactive oxygen species; superoxide dismutase; tumor necrosis factor-α.