Treatment with pharmacological PPARα agonists stimulates the ubiquitin proteasome pathway and myofibrillar protein breakdown in skeletal muscle of rodents

Background: Treatment of hyperlipidemic patients with fibrates, agonists of peroxisome proliferator-activated receptor alpha (PPAR alpha), provokes muscle atrophy as a side effect. The molecular mechanism underlying this phenomenon is still unknown. We tested the hypothesis that activation of PPAR alpha leads to an up-regulation of the ubiquitin proteasome system (UPS) which plays a major role in protein degradation in muscle. Methods: Rats, wild-type and PPAR alpha-deficient mice (PPAR alpha(-/-)) were treated with synthetic PPAR alpha agonists (clofibrate, WY-14,643) to study their effect on the UPS and myofibrillar protein breakdown in muscle. Results: In rats and wild-type mice but not PPAR alpha(-/-) mice, clofibrate or WY-14,643 caused increases in mRNA and protein levels of the ubiquitin ligases atrogin-1 and MuRF1 in muscle. Wild-type mice treated with WY-14,643 had a greater 3-methylhistidine release from incubated muscle and lesser muscle weights. In addition, wild-type mice but not PPAR alpha(-/-) mice treated with WY-14,643 had higher amounts of ubiquitin-protein conjugates, a decreased activity of PI3K/Akt1 signalling, and an increased activity of FoxO1 transcription factor in muscle. Reporter gene and gel shift experiments revealed that the atrogin-1 and MuRF1 promoter do not contain functional PPAR alpha DNA-binding sites. Conclusions: These findings indicate that fibrates stimulate ubiquitination of proteins in skeletal muscle which in turn stimulates protein degradation. Up-regulation of ubiquitin ligases is probably not mediated by PPAR alpha-dependent gene transcription but by PPAR alpha-dependent inhibition of the PI3K/Akt1 signalling pathway leading to activation of FoxO1. General significance: PPAR alpha plays a role in the regulation of the ubiquitin proteasome system. (C) 2012 Elsevier B.V. All rights reserved.