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 nuclear factor kappa B (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 if 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 intra-cellular adhesion molecule 1 (ICAM-1) and CXCL1 (KC), the murine homologue of interleukin 8 (IL-8), in myotubes. To verify if muscular NF-B activity in human subjects is suppressed by PPAR- activation, we examined the effect of 8 weeks 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 towards 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.