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

BackgroundTreatment of hyperlipidemic patients with fibrates, agonists of peroxisome proliferator-activated receptor α (PPARα), provokes muscle atrophy as a side effect. The molecular mechanism underlying this phenomenon is still unknown. We tested the hypothesis that activation of PPARα leads to an up-regulation of the ubiquitin proteasome system (UPS) which plays a major role in protein degradation in muscle.MethodsRats, wild-type and PPARα-deficient mice (PPARα−/−) were treated with synthetic PPARα agonists (clofibrate, WY-14,643) to study their effect on the UPS and myofibrillar protein breakdown in muscle.ResultsIn rats and wild-type mice but not PPARα−/− 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 PPARα−/− 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 PPARα DNA-binding sites.ConclusionsThese 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 PPARα-dependent gene transcription but by PPARα-dependent inhibition of the PI3K/Akt1 signalling pathway leading to activation of FoxO1.General significancePPARα plays a role in the regulation of the ubiquitin proteasome system.

► PPARα activators increase expression of ubiquitin ligases in muscle of rodents. ► PPARα activators enhance 3-methylhistidine release from incubated muscle in mice. ► PPARα activators decrease muscle weights in mice. ► PPARα activators increase amounts of ubiquitin–protein conjugates in muscle of mice. ► PPARα activators reduce activity of PI3K/Akt1 signalling in muscle of mice.