Classical NF-κB activation impairs skeletal muscle oxidative phenotype by reducing IKK-α expression

Biochim Biophys Acta. 2014 Feb;1842(2):175-85. doi: 10.1016/j.bbadis.2013.11.001. Epub 2013 Nov 8.


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-κB pathway in inflammation-induced impairments in muscle OXPHEN. The exact underlying mechanisms however are unclear. Interestingly, IκB kinase α (IKK-α: a key kinase in the alternative NF-κB pathway) was recently identified as a novel positive regulator of skeletal muscle OXPHEN. We hypothesised that inflammation-induced classical NF-κB activation contributes to loss of muscle OXPHEN in COPD by reducing IKK-α expression.

Methods: Classical NF-κB signalling was activated (molecularly or by tumour necrosis factor α: TNF-α) in cultured myotubes and the impact on muscle OXPHEN and IKK-α levels was investigated. Moreover, the alternative NF-κB 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-α, OXPHEN markers and TNF-α.

Results: IKK-α knock-down in cultured myotubes decreased expression of OXPHEN markers and key OXPHEN regulators. Moreover, classical NF-κB activation (both by TNF-α and IKK-β over-expression) reduced IKK-α levels and IKK-α over-expression prevented TNF-α-induced impairments in muscle OXPHEN. Importantly, muscle IKK-α protein abundance and OXPHEN was reduced in COPD patients compared to controls, which was more pronounced in patients with increased muscle TNF-α mRNA levels.

Conclusion: Classical NF-κB activation impairs skeletal muscle OXPHEN by reducing IKK-α expression. TNF-α-induced reductions in muscle IKK-α may accelerate muscle OXPHEN deterioration in COPD.

Keywords: 3-monooxygenase/tryptophan 5-monooxygenase activation protein, zeta polypeptide; 50S ribosomal subunit protein L15; 60S ribosomal protein L13a; ACTB; ALAS1; ATP; Ad; Adenosine triphosphate; Adenoviral; B2M; BMI; Beta Cytoskeletal Actin; Body mass index; CA; COPD; COXIV; CS; Chronic obstructive pulmonary disease; Citrate synthase; Classical NF-κB; Constitutively active; Cytochrome c oxidase 4; DMEM; Delta-aminolevulinate synthase 1; Dulbecco's Modified Eagle Medium; FEV1; FVC; Forced expiratory volume in one second; Forced vital capacity; GAPDH; GUSB; Gapdh, Glyceraldehyde-3-phosphate dehydrogenase; Gfp; Glucuronidase, bèta; Green fluorescent protein; HAD; HBSS; HCBP; HMBS; HPRT; Hank's Balanced Salt solution; Hprt, Hypoxanthine phosphoribosyltransferase 1; Human carnitine-palmitoyl transferase B; Hydroxymethylbilane Synthase; IKK-α; Icam-1; Ikk-α, IκB kinase alpha; Ikk-β; Il-1β; Intra-cellular adhesion molecule 1; IκB kinase beta; IκBα; Mlc; Myhc; Myosin heavy chain; Myosin light chain; NF-κB; NS; Not significant; Nrf; Nuclear factor kappa B; Nuclear respiratory factor; OXPHEN; Oxidative metabolism; Oxidative phenotype; Oxidative phosphorylation; Oxphos; PBS; PGC-1; PPAR; PPIA; Pgc-1, Peroxisome proliferator-activated receptor gamma co-activator 1; Phosphate-buffered saline; Ppar, Peroxisome proliferator-activated receptor; RPL13A; RPLO; SD; SEM; SR; Skeletal muscle; Standard deviation; Standard equality of the mean; Super repressor; TFAM; TNF-α; Tfam, Mitochondrial transcription factor A; Tnf-α, Tumour necrosis factor alpha; UBC; Ubiquitin C; WT; Wild-type; YWHAZ; interleukin 1β; nuclear factor of kappa light polypeptide gene enhancer in B-cells inhibitor alpha; peptidylprolyl isomerase A (cyclophilin A); β-hydroxyacyl-CoA dehydrogenase; β2m, Beta 2 microglobulin.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Aged
  • Animals
  • Blotting, Western
  • Cell Line
  • Female
  • Gene Expression Regulation / drug effects
  • Humans
  • I-kappa B Kinase / genetics
  • I-kappa B Kinase / metabolism*
  • Male
  • Mice
  • Middle Aged
  • Muscle Fibers, Skeletal / drug effects
  • Muscle Fibers, Skeletal / metabolism*
  • Muscle, Skeletal / drug effects
  • Muscle, Skeletal / metabolism*
  • NF-kappa B / genetics
  • NF-kappa B / metabolism*
  • Oxidation-Reduction / drug effects
  • Phenotype
  • Pulmonary Disease, Chronic Obstructive / genetics
  • Pulmonary Disease, Chronic Obstructive / metabolism
  • Pulmonary Disease, Chronic Obstructive / physiopathology
  • Quadriceps Muscle / metabolism
  • Quadriceps Muscle / physiopathology
  • RNA Interference
  • Reverse Transcriptase Polymerase Chain Reaction
  • Signal Transduction / drug effects
  • Signal Transduction / genetics
  • Signal Transduction / physiology
  • Tumor Necrosis Factor-alpha / genetics
  • Tumor Necrosis Factor-alpha / metabolism
  • Tumor Necrosis Factor-alpha / pharmacology


  • NF-kappa B
  • Tumor Necrosis Factor-alpha
  • I-kappa B Kinase