Classical NF-kappaB activation impairs skeletal muscle oxidative phenotype by reducing IKK-alpha expression

Background: Loss of quadriceps muscle oxidative phenotype (OXPHEN) is an evident and debilitating feature of chronic obstructive pulmonary disease (COPD). We recently demonstrated involvement of the inflammatory classical NF-kappaB pathway in inflammation-induced impairments in muscle OXPHEN. The exact underlying mechanisms however are unclear. Interestingly, IkappaB kinase alpha (IKK-alpha: a key kinase in the alternative NF-kappaB pathway) was recently identified as a novel positive regulator of skeletal muscle OXPHEN. We hypothesised that inflammation-induced classical NF-kappaB activation contributes to loss of muscle OXPHEN in COPD by reducing IKK-alpha expression. Methods: Classical NF-kappaB signalling was activated (molecularly or by tumour necrosis factor alpha: TNF-alpha) in cultured myotubes and the impact on muscle OXPHEN and IKK-alpha levels was investigated. Moreover, the alternative NF-kappaB pathway was modulated to investigate the impact on muscle OXPHEN in absence or presence of an inflammatory stimulus. As a proof of concept, quadriceps muscle biopsies of COPD patients and healthy controls were analysed for expression levels of IKK-alpha, OXPHEN markers and TNF-alpha. Results: IKK-alpha knock-down in cultured myotubes decreased expression of OXPHEN markers and key OXPHEN regulators. Moreover, classical NF-kappaB activation (both by TNF-alpha and IKK-beta over-expression) reduced IKK-alpha levels and IKK-alpha over-expression prevented TNF-alpha-induced impairments in muscle OXPHEN. Importantly, muscle IKK-alpha protein abundance and OXPHEN was reduced in COPD patients compared to controls, which was more pronounced in patients with increased muscle TNF-alpha mRNA levels. Conclusion: Classical NF-kappaB activation impairs skeletal muscle OXPHEN by reducing IKK-alpha expression. TNF-alpha-induced reductions in muscle IKK-alpha may accelerate muscle OXPHEN deterioration in COPD.