title: Treatment with pharmacological PPARα agonists stimulates the ubiquitin proteasome pathway and myofibrillar protein breakdown in skeletal muscle of rodents.
abstract: BACKGROUND
  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.
  
  
  METHODS
  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.
  
  
  RESULTS
  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.
  
  
  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 PPARα-dependent gene transcription but by PPARα-dependent inhibition of the PI3K/Akt1 signalling pathway leading to activation of FoxO1.
  
  
  CONCLUSIONS
  PPARα plays a role in the regulation of the ubiquitin proteasome system.
authors.affiliation: Institute of Animal Nutrition and Nutritional Physiology, Justus-Liebig-University, Giessen, Germany.
authors.forename: Robert
authors.initials: R
authors.lastname: Ringseis
authors.forename: Janine
authors.initials: J
authors.lastname: Keller
authors.forename: Isabel
authors.initials: I
authors.lastname: Lukas
authors.forename: Julia
authors.initials: J
authors.lastname: Spielmann
authors.forename: Erika
authors.initials: E
authors.lastname: Most
authors.forename: Aline
authors.initials: A
authors.lastname: Couturier
authors.forename: Bettina
authors.initials: B
authors.lastname: König
authors.forename: Frank
authors.initials: F
authors.lastname: Hirche
authors.forename: Gabriele I
authors.initials: GI
authors.lastname: Stangl
authors.forename: Gaiping
authors.initials: G
authors.lastname: Wen
authors.forename: Klaus
authors.initials: K
authors.lastname: Eder
mesh_terms: D000818:Animals; D000924:Anticholesteremic Agents / Q000009:adverse effects* / Q000494:pharmacology; D002994:Clofibrate / Q000009:adverse effects* / Q000493:pharmacokinetics; D006801:Humans; D006949:Hyperlipidemias / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D009124:Muscle Proteins / Q000235:genetics / Q000378:metabolism*; D018482:Muscle, Skeletal / Q000378:metabolism* / Q000473:pathology; D009133:Muscular Atrophy / Q000139:chemically induced / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D047493:PPAR alpha / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D046988:Proteasome Endopeptidase Complex / Q000235:genetics / Q000378:metabolism*; D059748:Proteolysis / Q000187:drug effects*; D011743:Pyrimidines / Q000009:adverse effects* / Q000494:pharmacology; D051381:Rats; D015398:Signal Transduction / Q000187:drug effects / Q000235:genetics; D014158:Transcription, Genetic / Q000187:drug effects / Q000235:genetics; D025801:Ubiquitin / Q000235:genetics / Q000378:metabolism*; D054875:Ubiquitination / Q000187:drug effects* / Q000235:genetics; D015854:Up-Regulation / Q000187:drug effects / Q000235:genetics
chemical_list: D000924:Anticholesteremic Agents; D009124:Muscle Proteins; D047493:PPAR alpha; D011743:Pyrimidines; D025801:Ubiquitin; C006253:pirinixic acid; D046988:Proteasome Endopeptidase Complex; D002994:Clofibrate