TNF-α-Induced NF-κB Activation Stimulates Skeletal Muscle Glycolytic Metabolism Through Activation of HIF-1α

A shift in quadriceps muscle metabolic profile toward decreased oxidative metabolism and increased glycolysis is a consistent finding in chronic obstructive pulmonary disease (COPD). Chronic inflammation has been proposed as a trigger of this pathological metabolic adaptation. Indeed, the proinflammatory cytokine TNF-alpha impairs muscle oxidative metabolism through activation of the nuclear factor-kappa B (NF-kappa B) pathway. Putative effects on muscle glycolysis, however, are unclear. We hypothesized that TNF-alpha-induced NF-kappa B signaling stimulates muscle glycolytic metabolism through activation of the glycolytic regulator hypoxia-inducible factor-1 alpha (HIF-1 alpha). Wild-type C2C12 and C2C12-I kappa B alpha-SR (blocked NF-kappa B signaling) myotubes were stimulated with TNF-alpha, and its effects on glycolytic metabolism and involvement of the HIF pathway herein were investigated. As proof of principle, expression of HIF signaling constituents was investigated in quadriceps muscle biopsies of a previously well-characterized cohort of clinically stable patients with severe COPD and healthy matched controls. TNF-alpha increased myotube glucose uptake and lactate production and enhanced the activity and expression levels of multiple effectors of muscle glycolytic metabolism in a NF-kappa B-dependent manner. In addition, TNF-alpha activated HIF signaling, which required classical NF-kappa B activation. Moreover, the knockdown of HIF-1 alpha largely attenuated TNF-alpha-induced increases in glycolytic metabolism. Accordingly, the mRNA levels of HIF-1 alpha and the HIF-1 alpha target gene, vascular endothelial growth factor (VEGF), were increased in muscle biopsies of COPD patients compared with controls, which was most pronounced in the patients with high levels of muscle TNF-alpha. In conclusion, these data show that TNF-alpha-induced classical NF-kappa B activation enhances muscle glycolytic metabolism in a HIF-1 alpha-dependent manner.