TNF-alpha impairs regulation of muscle oxidative phenotype: implications for cachexia?
Chronic obstructive pulmonary disease (COPD) is characterized by weight loss, muscle wasting (in advanced disease ultimately resulting in cachexia), and loss of muscle oxidative phenotype (oxphen). This study investigates the effect of inflammation (as a determinant of muscle wasting) on muscle oxphen by using cell studies combined with analyses of muscle biopsies of patients with COPD and control participants. We analyzed markers (citrate synthase, β-hydroxyacyl-CoA dehydrogenase, and cytochrome c oxidase IV) and regulators (PGC-1α, PPAR-α, and Tfam) of oxphen in vastus lateralis muscle biopsies of patients with advanced COPD and healthy smoking control participants. Here 17 of 73 patients exhibited elevated muscle TNF-α mRNA levels. In these patients, significantly lower mRNA levels of all oxidative markers/regulators were found. Interestingly, these patients also had a significantly lower body mass index and tended to have less muscle mass. In cultured muscle cells, mitochondrial protein content and myosin heavy chain isoform I (but not II) protein and mRNA levels were reduced on chronic TNF-α stimulation. TNF-α also reduced mitochondrial respiration in a nuclear factor kappaB (NF-κB) -dependent manner. Importantly, TNF-α-induced NF-κB activation decreased promoter transactivation and transcriptional activity of regulators of mitochondrial biogenesis and muscle oxphen. In conclusion, these results demonstrate that TNF-α impairs muscle oxphen in a NF-κB-dependent manner.
Remels
A H V
AH
Department of Respiratory Medicine, Maastricht University Medical Centre, Maastricht, The Netherlands.
Gosker
H R
HR
Schrauwen
P
P
Hommelberg
P P H
PP
Sliwinski
P
P
Polkey
M
M
Galdiz
J
J
Wouters
E F M
EF
Langen
R C J
RC
Schols
A M W J
AM
D000818:Animals; D015153:Blotting, Western; D002100:Cachexia / Q000378:metabolism*; D002460:Cell Line; D002950:Citrate (si)-Synthase / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000378:metabolism; D003576:Electron Transport Complex IV / Q000378:metabolism; D024202:Electrophoretic Mobility Shift Assay; D004797:Enzyme-Linked Immunosorbent Assay; D006360:Heat-Shock Proteins / Q000378:metabolism; D006801:Humans; D006836:Hydro-Lyases / Q000378:metabolism; D051379:Mice; D024101:Mitochondrial Proteins / Q000378:metabolism; D018482:Muscle, Skeletal / Q000187:drug effects / Q000378:metabolism*; D016328:NF-kappa B / Q000235:genetics / Q000378:metabolism; D047493:PPAR alpha / Q000378:metabolism; D000071248:Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha; D029424:Pulmonary Disease, Chronic Obstructive / Q000378:metabolism; D014157:Transcription Factors / Q000378:metabolism; D014409:Tumor Necrosis Factor-alpha / Q000235:genetics / Q000378:metabolism* / Q000494:pharmacology*
D004268:DNA-Binding Proteins; D006360:Heat-Shock Proteins; D024101:Mitochondrial Proteins; D016328:NF-kappa B; D047493:PPAR alpha; C486497:PPARGC1A protein, human; D000071248:Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha; C499631:TFAM protein, human; D014157:Transcription Factors; D014409:Tumor Necrosis Factor-alpha; D003576:Electron Transport Complex IV; D002950:Citrate (si)-Synthase; C065185:D-3-hydroxyacyl CoA dehydratase; D006836:Hydro-Lyases