Regulation of skeletal muscle oxidative phenotype by classical NF-κB signalling.

BACKGROUND: Impairments in skeletal muscle oxidative phenotype (OXPHEN) linked to the development of insulin resistance, metabolic inflexibility progression of the metabolic syndrome and have been associated with disability in diseases associated with chronic systemic inflammation. We previously showed that the inflammatory cytokine tumour necrosis factor- (TNF-alpha) directly impairs muscle OXPHEN but underlying molecular remained unknown. Interestingly, the inflammatory signalling pathway nuclear factor-kappaB (NF-kappaB) is activated in muscle in disorders. Therefore, we hypothesised that muscle activation of NF-kappaB signalling is sufficient and required for inflammation-induced impairment of muscle OXPHEN. METHODS: Myotubes from mouse and human lines were subjected to activation or blockade of the classical NF- pathway. In addition, wild-type and MISR (muscle-specific inhibition of NF-kappaB) mice were injected intra-muscularly with TNF-alpha. Markers regulators of muscle OXPHEN were investigated. RESULTS: Classical NF- activation diminished expression of oxidative phosphorylation (OXPHOS) slow myosin heavy chain expression, activity of mitochondrial enzymes potently reduced intra-cellular ATP levels. Accordingly, PGC-1/PPAR/NRF- signalling, the main pathway controlling muscle OXPHEN, was impaired classical NF-kappaB activation which required intact p65 trans- and depended on de novo gene transcription. Unlike wild-type myotubes, IkappaBalpha-SR myotubes (blocked classical NF-kappaB signalling) were to TNF-alpha-induced impairments in OXPHEN and its regulation by the PGC-1/PPAR/NRF-1/Tfam cascade. In line with in vitro data, NF-kappaB vivo abrogated TNF-alpha-induced reductions in PGC-1alpha expression. Classical NF-kappaB activation impairs skeletal muscle OXPHEN.