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

Remels AH, Langen RC, Gosker HR, Russell AP, Spaapen F, Voncken JW, Schrauwen P, Schols AM. PPAR gamma inhibits NF-kappa B-dependent transcriptional activation in skeletal muscle. Am J Physiol Endocrinol Metab 297: E174-E183, 2009. First published May 5, 2009; doi: 10.1152/ajpendo.90632.2008.-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-kappa 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-kappa B activity in skeletal muscle. Using C2C12 myotubes as an in vitro model of myofibers, we demonstrate that PPAR, and specifically PPAR gamma, activation potently inhibits inflammatory mediator-induced NF-kappa B transcriptional activity in a time- and dose-dependent manner. Furthermore, PPAR gamma activation by rosiglitazone strongly suppresses cytokine-induced transcript levels of the NF-kappa 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-kappa B activity in human subjects is suppressed by PPAR gamma 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 gamma 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-kappa B activation may be an interesting therapeutic avenue for treatment of several inflammation-associated skeletal muscle abnormalities.