Premium
TNF‐α impairs regulation of muscle oxidative phenotype: implications for cachexia?
Author(s) -
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.
Publication year - 2010
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fj.09.150714
Subject(s) - mitochondrial biogenesis , endocrinology , cachexia , wasting , tfam , medicine , myosin , dysferlin , copd , biology , inflammation , oxidative phosphorylation , gastrocnemius muscle , tumor necrosis factor alpha , muscle atrophy , myostatin , skeletal muscle , mitochondrion , microbiology and biotechnology , biochemistry , cancer
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, fi‐hydroxya‐cyl‐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, mitochon‐drial 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 mito‐chondrial 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 mitochon‐drial 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., 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‐α impairs regulation of muscle oxidative phenotype: implications for cachexia? FASEBJ. 24, 5052–5062 (2010). www.fasebj.org