| First Author | Ringseis R | Year | 2013 |
| Journal | Biochim Biophys Acta | Volume | 1830 |
| Issue | 1 | Pages | 2105-17 |
| PubMed ID | 23041501 | Mgi Jnum | J:192038 |
| Mgi Id | MGI:5463842 | Doi | 10.1016/j.bbagen.2012.09.024 |
| Citation | Ringseis R, et al. (2013) Treatment with pharmacological PPARalpha agonists stimulates the ubiquitin proteasome pathway and myofibrillar protein breakdown in skeletal muscle of rodents. Biochim Biophys Acta 1830(1):2105-17 |
| abstractText | BACKGROUND: Treatment of hyperlipidemic patients with fibrates, agonists of peroxisome proliferator-activated receptor alpha (PPARalpha), provokes muscle atrophy as a side effect. The molecular mechanism underlying this phenomenon is still unknown. We tested the hypothesis that activation of PPARalpha 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 PPARalpha-deficient mice (PPARalpha(-/-)) were treated with synthetic PPARalpha 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 PPARalpha(-/-) 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 PPARalpha(-/-) 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 PPARalpha 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 PPARalpha-dependent gene transcription but by PPARalpha-dependent inhibition of the PI3K/Akt1 signalling pathway leading to activation of FoxO1. GENERAL SIGNIFICANCE: PPARalpha plays a role in the regulation of the ubiquitin proteasome system. |
