TNF-alpha-Induced NF-kappa B Activation Stimulates Skeletal Muscle Glycolytic Metabolism Through Activation of HIF-1 alpha

A shift in quadriceps muscle metabolic profile towards 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 pro-inflammatory cytokine tumor necrosis factor alpha (TNF-alpha) impairs muscle oxidative metabolism through activation of the nuclear factor kappa B (NF-kappaB) pathway. Putative effects on muscle glycolysis however are unclear. We hypothesized that TNF-alpha-induced NF-kappaB signaling stimulates muscle glycolytic metabolism through activation of the glycolytic regulator hypoxia-inducible factor-1alpha (HIF-1alpha). Wild-type C2C12 and C2C12-IkappaBalpha-SR (blocked NF-kappaB 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-kappaB-dependent manner. In addition, TNF-alpha activated HIF signaling, which required classical NF-kappaB activation. Moreover, knock-down of HIF-1alpha largely attenuated TNF-alpha-induced increases in glycolytic metabolism. Accordingly, mRNA levels of HIF-1alpha and of the HIF-1alpha target gene vascular endothelial growth factor (VEGF) were increased in muscle biopsies of COPD patients compared to controls which was most pronounced in patients with high levels of muscle TNF-alpha. TNF-alpha-induced classical NF-kappaB activation enhances muscle glycolytic metabolism in a HIF-1alpha dependent manner.