TNF-alpha impairs regulation of muscle oxidative phenotype: implications for cachexia?

A.H.V. Remels, H.R. Gosker, P. Schrauwen, P.P. Hommelberg, P. Sliwinski, M. Polkey, J. Galdiz, E.F.M. Wouters, R.C.J. Langen, A.M.W.J. Schols

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Abstract

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, beta-hydroxyacyl-CoA dehydrogenase, and cytochrome c oxidase IV) and regulators (PGC-1alpha, PPAR-alpha, 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-alpha 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-alpha stimulation. TNF-alpha also reduced mitochondrial respiration in a nuclear factor kappaB (NF-kappaB) -dependent manner. Importantly, TNF-alpha-induced NF-kappaB activation decreased promoter transactivation and transcriptional activity of regulators of mitochondrial biogenesis and muscle oxphen. In conclusion, these results demonstrate that TNF-alpha impairs muscle oxphen in a NF-kappaB-dependent manner.-Remels, A. H. V., Gosker, H. R., Schrauwen, P., Hommelberg, P. P. H., Sliwinski, P., Polkey, M., Galdiz, J., Wouters, E. F. M., Langen, R. C. J., Schols, A. M. W. J. TNF-alpha impairs regulation of muscle oxidative phenotype: implications for cachexia?
Original languageEnglish
Pages (from-to)5052-5062
Number of pages11
JournalFaseb Journal
Volume24
Issue number12
DOIs
Publication statusPublished - Dec 2010

Keywords

  • inflammation
  • nuclear factor kappa B
  • peroxisome proliferator-activated receptors
  • mitochondrial transcription factor A
  • OBSTRUCTIVE PULMONARY-DISEASE
  • TUMOR-NECROSIS-FACTOR
  • NF-KAPPA-B
  • SKELETAL-MUSCLE
  • MITOCHONDRIAL BIOGENESIS
  • SYSTEMIC INFLAMMATION
  • NUTRITIONAL DEPLETION
  • VASTUS LATERALIS
  • CANCER CACHEXIA
  • COPD PATIENTS

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