PPARγ inhibits NF-κB-dependent transcriptional activation in skeletal muscle

Author:

Remels A. H. V.,Langen R. C. J.,Gosker H. R.,Russell A. P.,Spaapen F.,Voncken J. W.,Schrauwen P.,Schols A. M. W. J.

Abstract

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-κB. 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-κB activity in skeletal muscle. Using C2C12 myotubes as an in vitro model of myofibers, we demonstrate that PPAR, and specifically PPARγ, activation potently inhibits inflammatory mediator-induced NF-κB transcriptional activity in a time- and dose-dependent manner. Furthermore, PPARγ activation by rosiglitazone strongly suppresses cytokine-induced transcript levels of the NF-κB-dependent genes intracellular adhesion molecule 1 (ICAM-1) and CXCL1 (KC), the murine homolog of IL-8, in myotubes. To verify whether muscular NF-κB activity in human subjects is suppressed by PPARγ 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 PPARγ 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-κB activation may be an interesting therapeutic avenue for treatment of several inflammation-associated skeletal muscle abnormalities.

Publisher

American Physiological Society

Subject

Physiology (medical),Physiology,Endocrinology, Diabetes and Metabolism

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