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

Background: Impairments in skeletal muscle oxidative phenotype (OXPHEN) have been linked to the development of insulin resistance, metabolic inflexibility and progression of the metabolic syndrome and have been associated with progressive disability in diseases associated with chronic systemic inflammation. We previously showed that the inflammatory cytokine tumour necrosis factor-alpha (TNF-alpha) directly impairs muscle OXPHEN but underlying molecular mechanisms remained unknown. Interestingly, the inflammatory signalling pathway classical nuclear factor-kappa B (NF-kappa B) is activated in muscle in abovementioned disorders. Therefore, we hypothesised that muscle activation of classical NF-kappa B signalling is sufficient and required for inflammation-induced impairment of muscle OXPHEN. Methods: Myotubes from mouse and human muscle cell lines were subjected to activation or blockade of the classical NF-kappa B pathway. In addition, wild-type and MISR (muscle-specific inhibition of classical NF-kappa B) mice were injected intra-muscularly with TNF-alpha. Markers and key regulators of muscle OXPHEN were investigated. Results: Classical NF-kappa B activation diminished expression of oxidative phosphorylation (OXPHOS) sub-units, slow myosin heavy chain expression, activity of mitochondrial enzymes and potently reduced intra-cellular ATP levels. Accordingly, PGC-1/PPAR/NRF-1/Tfam signalling, the main pathway controlling muscle OXPHEN, was impaired upon classical NF-kappa B activation which required intact p65 trans-activation domains and depended on de novo gene transcription. Unlike wild-type myotubes, I kappa B alpha-SR myotubes (blocked classical NF-kappa B signalling) were refractory 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-kappa B blockade in vivo abrogated TNF-alpha-induced reductions in PGC-1 alpha expression. Conclusion: Classical NF-kappa B activation impairs skeletal muscle OXPHEN. (C) 2013 Elsevier B.V. All rights reserved.