Reactive Oxygen Species and p38 Mitogen-activated Protein Kinase Mediate Exercise-induced Skeletal Muscle-derived Interleukin-6 Expression

Interleukin-6 (IL-6) is a pleiotropic cytokine secreted by many different cell types, and skeletal muscle is an important source of IL-6 during exercise. Here, we studied the effects of glucose deprivation in vitro on skeletal muscle-derived IL-6 expression and release in C2C12 myocytes, as well as its regulation by p38 mitogen-activated protein kinase (p38MAPK) and reactive oxygen species (ROS). C2C12 myotubes were cultured in DMEM medium containing 4.5 g · L−1 glucose (glucose control, GC) or DMEM medium containing no glucose (glucose deprivation, GD) for 0, 6, 12, 18 and 24 hours, and then incubated with 10mM NAC (a ROS scavenger) or 10 μM SB203580 (a p38MAPK inhibitor) under either GC or GD conditions for 24 hours. IL-6 expression levels were subsequently analyzed using RT–PCR, and IL-6 protein levels in the medium were measured using ELISA. Glucose deprivation significantly enhanced IL-6 expression at 18 and 24 hours compared to the glucose control, and caused IL-6 protein levels to increase significantly over the entire 24-hour measurement period. The ROS scavenger NAC inhibited the glucose deprivation-induced release of IL-6 protein almost completely, while the p38MAPK inhibitor SB203580 inhibited glucose deprivation-induced IL-6 protein release to a lesser extent. Our study suggests that glucose deprivation in C2C12 myocytes induces IL-6 expression and release, and that this IL-6 release is mainly mediated via ROS signaling. Skeletal muscle-derived IL-6 may thus play an important role in energy metabolism during exercise.