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This Article Full Text Full Text (PDF) All Versions of this Article: 297/1/E174    most recent 90632.2008v1 Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Google Scholar Articles by Remels, A. H. V. Articles by Schols, A. M. W. J. PubMed PubMed Citation Articles by Remels, A. H. V. Articles by Schols, A. M. W. J.

PPAR inhibits NF-B-dependent transcriptional activation in skeletal muscle

Departments of ¹Respiratory Medicine, ²Human Biology, and ³Molecular Genetics, Maastricht University, the Netherlands; and ⁴Centre for Physical Activity and Nutrition Research, School of Exercise and Nutrition Sciences, Deakin University, Melbourne, Australia

Submitted 26 July 2008 ; accepted in final form 25 April 2009

Skeletal muscle pathology associated with a chronic inflammatory disease state (e.g., skeletal muscle atrophy and insulin resistance) is a potential consequence of chronic activation of NF-B. It has been demonstrated that peroxisome proliferator-activated receptors (PPARs) can exert anti-inflammatory effects by interfering with transcriptional regulation of inflammatory responses. The goal of the present study, therefore, was to evaluate whether PPAR activation affects cytokine-induced NF-B activity in skeletal muscle. Using C₂C₁₂ myotubes as an in vitro model of myofibers, we demonstrate that PPAR, and specifically PPAR, activation potently inhibits inflammatory mediator-induced NF-B transcriptional activity in a time- and dose-dependent manner. Furthermore, PPAR activation by rosiglitazone strongly suppresses cytokine-induced transcript levels of the NF-B-dependent genes intracellular adhesion molecule 1 (ICAM-1) and CXCL1 (KC), the murine homolog of IL-8, in myotubes. To verify whether muscular NF-B activity in human subjects is suppressed by PPAR activation, we examined the effect of 8 wk of rosiglitazone treatment on muscular gene expression of ICAM-1 and IL-8 in type 2 diabetes mellitus patients. In these subjects, we observed a trend toward decreased basal expression of ICAM-1 mRNA levels. Subsequent analyses in cultured myotubes revealed that the anti-inflammatory effect of PPAR activation is not due to decreased RelA translocation to the nucleus or reduced RelA DNA binding. These findings demonstrate that muscle-specific inhibition of NF-B activation may be an interesting therapeutic avenue for treatment of several inflammation-associated skeletal muscle abnormalities.

peroxisome proliferator-activated receptor-; nuclear factor-B; rosiglitazone; inflammation; type 2 diabetes mellitus; skeletal muscle atrophy