The PPARα agonists fenofibrate and CP-778875 cause increased β-oxidation, leading to oxidative injury in skeletal and cardiac muscle in the rat.
Weak peroxisome proliferator-activated receptor (PPAR) α agonists (fibrates) are used to treat dyslipidemia. This study compared the effects of the potent and selective PPARα agonist CP-778875 on peroxisomal β-oxidation and cardiac and/or skeletal muscle injury with those of the weak PPARα agonist fenofibrate. We hypothesized that these muscle effects are mediated through the PPARα receptor, leading to increased β-oxidation and consequent oxidative stress. CP-778875 (5 or 500 mg/kg) and fenofibrate (600 or 2,000→1,200 mg/kg, dose lowered because of intolerance) were administered to rats for six weeks. Standard end points, serum troponin I, heart and skeletal muscle β-oxidation of palmitoyl-CoA, and acyl co-oxidase (AOX) mRNA were assessed. Both compounds dose-dependently increased the incidence and/or severity of cardiomyocyte degeneration and necrosis, heart weight, troponin I, and skeletal muscle degeneration. Mean heart β-oxidation (3.4- to 5.1-fold control) and AOX mRNA (2.4- to 3.2-fold control) were increased with CP-778875 500 mg/kg and both doses of fenofibrate. β-Oxidation of skeletal muscle was not affected by either compound; however, a significant increase in AOX mRNA (1.6- to 2.1-fold control) was observed with CP-778875 500 mg/kg and both doses of fenofibrate. Taken together, these findings were consistent with PPARα agonism and support the link between increased cardiac and skeletal muscle β-oxidation and resultant muscle injury in the rat.
Pfizer Worldwide Research and Development, Groton Laboratory, Pfizer, Inc., Groton, Connecticut 06340, USA. john.c.pettersen@pfizer.com
John C
JC
Pettersen
Ingrid
I
Pruimboom-Brees
Omar L
OL
Francone
David E
DE
Amacher
Sherri E
SE
Boldt
Roy L
RL
Kerlin
William E
WE
Ballinger
D000818:Animals; D001774:Blood Chemical Analysis; D001835:Body Weight; D004305:Dose-Response Relationship, Drug; D005260:Female; D011345:Fenofibrate / Q000493:pharmacokinetics / Q000633:toxicity*; D006321:Heart / Q000187:drug effects*; D008099:Liver / Q000737:chemistry / Q000187:drug effects / Q000201:enzymology / Q000473:pathology; D008297:Male; D009124:Muscle Proteins / Q000378:metabolism; D018482:Muscle, Skeletal / Q000737:chemistry / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D009135:Muscular Diseases / Q000139:chemically induced / Q000378:metabolism; D009206:Myocardium / Q000737:chemistry / Q000378:metabolism / Q000473:pathology; D009243:NAD / Q000378:metabolism; D018384:Oxidative Stress / Q000187:drug effects*; D047493:PPAR alpha / Q000819:agonists*; D020675:Peroxisomes / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D018675:Toxicity Tests; D019210:Troponin I / Q000097:blood / Q000378:metabolism
D009124:Muscle Proteins; D047493:PPAR alpha; D019210:Troponin I; D009243:NAD; D011345:Fenofibrate