Journal article

Authors list: Ringseis, R; Keller, J; Lukas, I; Spielmann, J; Most, E; Couturier, A; König, B; Hirche, F; Stangl, GI; Wen, GP; Eder, K

Publication year: 2013

Pages: 2105-2117

Journal: Biochimica et Biophysica Acta (BBA) - General Subjects

Volume number: 1830

Issue number: 1

ISSN: 0304-4165

DOI Link: https://doi.org/10.1016/j.bbagen.2012.09.024

Publisher: Elsevier

Abstract: 

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.

Harvard Citation style: Ringseis, R., Keller, J., Lukas, I., Spielmann, J., Most, E., Couturier, A., et al. (2013) Treatment with pharmacological PPARα agonists stimulates the ubiquitin proteasome pathway and myofibrillar protein breakdown in skeletal muscle of rodents, Biochimica et Biophysica Acta (BBA) - General Subjects, 1830(1), pp. 2105-2117. https://doi.org/10.1016/j.bbagen.2012.09.024

APA Citation style: Ringseis, R., Keller, J., Lukas, I., Spielmann, J., Most, E., Couturier, A., König, B., Hirche, F., Stangl, G., Wen, G., & Eder, K. (2013). Treatment with pharmacological PPARα agonists stimulates the ubiquitin proteasome pathway and myofibrillar protein breakdown in skeletal muscle of rodents. Biochimica et Biophysica Acta (BBA) - General Subjects. 1830(1), 2105-2117. https://doi.org/10.1016/j.bbagen.2012.09.024