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

• Published in: Biochimica et biophysica acta Vol. 1830; no. 1; pp. 2105 - 2117
• Main Authors: Ringseis, Robert, Keller, Janine, Lukas, Isabel, Spielmann, Julia, Most, Erika, Couturier, Aline, König, Bettina, Hirche, Frank, Stangl, Gabriele I., Wen, Gaiping, Eder, Klaus
• Format: Journal Article
• Language: English
• Published: Netherlands Elsevier B.V 01.01.2013
• Subjects: agonists; Animals; Anticholesteremic Agents - adverse effects; Anticholesteremic Agents - pharmacology; Atrogin-1; clofibrate; Clofibrate - adverse effects; Clofibrate - pharmacokinetics; gels; gene expression regulation; Humans; Hyperlipidemias - drug therapy; Hyperlipidemias - genetics; Hyperlipidemias - metabolism; messenger RNA; Mice; Mice, Knockout; MuRF1; Muscle atrophy; Muscle Proteins - genetics; Muscle Proteins - metabolism; Muscle, Skeletal - metabolism; Muscle, Skeletal - pathology; muscles; muscular atrophy; Muscular Atrophy - chemically induced; Muscular Atrophy - genetics; Muscular Atrophy - metabolism; Muscular Atrophy - pathology; patients; Peroxisome proliferator-activated receptor α; PPAR alpha - antagonists & inhibitors; PPAR alpha - genetics; PPAR alpha - metabolism; proteasome endopeptidase complex; Proteasome Endopeptidase Complex - genetics; Proteasome Endopeptidase Complex - metabolism; protein degradation; proteins; Proteolysis - drug effects; Pyrimidines - adverse effects; Pyrimidines - pharmacology; Rats; reporter genes; signal transduction; Signal Transduction - drug effects; Signal Transduction - genetics; skeletal muscle; transcription (genetics); transcription factors; Transcription, Genetic - drug effects; Transcription, Genetic - genetics; ubiquitin; Ubiquitin - genetics; Ubiquitin - metabolism; Ubiquitin proteasome system; ubiquitin-protein ligase; ubiquitination; Ubiquitination - drug effects; Ubiquitination - genetics; Up-Regulation - drug effects; Up-Regulation - genetics; 3-MH; Muscle atrophy; RXRα; DTT; CPT; MuRF1; ChIP; EDL; PPARα; Peroxisome proliferator-activated receptor α; PI3K; ACOX; CTSL; Atrogin-1; PPRE; Ubiquitin proteasome system; UPS; FoxO1
• ISSN: 0304-4165; 0006-3002; 1872-8006
• DOI: 10.1016/j.bbagen.2012.09.024

Treatment 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. Rats, 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. In 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. 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 PPARα-dependent gene transcription but by PPARα-dependent inhibition of the PI3K/Akt1 signalling pathway leading to activation of FoxO1. PPARα 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.