PPARgamma inhibits NF-kappaB-dependent transcriptional activation in skeletal muscle

Am J Physiol Endocrinol Metab. 2009 Jul;297(1):E174-83. doi: 10.1152/ajpendo.90632.2008. Epub 2009 May 5.

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-kappaB. 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-kappaB activity in skeletal muscle. Using C(2)C(12) myotubes as an in vitro model of myofibers, we demonstrate that PPAR, and specifically PPARgamma, activation potently inhibits inflammatory mediator-induced NF-kappaB transcriptional activity in a time- and dose-dependent manner. Furthermore, PPARgamma activation by rosiglitazone strongly suppresses cytokine-induced transcript levels of the NF-kappaB-dependent genes intracellular adhesion molecule 1 (ICAM-1) and CXCL1 (KC), the murine homolog of IL-8, in myotubes. To verify whether muscular NF-kappaB activity in human subjects is suppressed by PPARgamma 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 PPARgamma 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-kappaB activation may be an interesting therapeutic avenue for treatment of several inflammation-associated skeletal muscle abnormalities.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Cells, Cultured
  • Cytokines / pharmacology
  • Down-Regulation / drug effects
  • Humans
  • Hypoglycemic Agents / pharmacology
  • Inflammation Mediators / pharmacology
  • Male
  • Mice
  • Middle Aged
  • Muscle, Skeletal / drug effects
  • Muscle, Skeletal / metabolism*
  • NF-kappa B / antagonists & inhibitors*
  • NF-kappa B / metabolism
  • NF-kappa B / physiology
  • PPAR gamma / agonists
  • PPAR gamma / physiology*
  • Pyrimidines / pharmacology
  • Rosiglitazone
  • Thiazoles / pharmacology
  • Thiazolidinediones / pharmacology
  • Transcriptional Activation / drug effects
  • Transcriptional Activation / genetics

Substances

  • Cytokines
  • GW 501516
  • Hypoglycemic Agents
  • Inflammation Mediators
  • NF-kappa B
  • PPAR gamma
  • Pyrimidines
  • Thiazoles
  • Thiazolidinediones
  • Rosiglitazone
  • pirinixic acid