Classical NF-κB activation impairs skeletal muscle oxidative phenotype by reducing IKK-α expression.
Biochim Biophys Acta
; 1842(2): 175-85, 2014 Feb.
Article
em En
| MEDLINE
| ID: mdl-24215713
ABSTRACT
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-ß 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.Palavras-chave
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-ß; Il-1ß; 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 1ß; nuclear factor of kappa light polypeptide gene enhancer in B-cells inhibitor alpha; peptidylprolyl isomerase A (cyclophilin A); ß-hydroxyacyl-CoA dehydrogenase; ß2m, Beta 2 microglobulin
Texto completo:
1
Coleções:
01-internacional
Base de dados:
MEDLINE
Assunto principal:
NF-kappa B
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Músculo Esquelético
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Fibras Musculares Esqueléticas
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Quinase I-kappa B
Tipo de estudo:
Prognostic_studies
Limite:
Aged
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Animals
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Female
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Humans
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Male
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Middle aged
Idioma:
En
Revista:
Biochim Biophys Acta
Ano de publicação:
2014
Tipo de documento:
Article