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ToxSci Advance Access originally published online on May 17, 2006
Toxicological Sciences 2006 92(2):578-586; doi:10.1093/toxsci/kfl019
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© The Author 2006. Published by Oxford University Press on behalf of the Society of Toxicology. All rights reserved. For Permissions, please email: journals.permissions@oxfordjournals.org

Agonists of the Peroxisome Proliferator–Activated Receptor Alpha Induce a Fiber-Type–Selective Transcriptional Response in Rat Skeletal Muscle

Angus T. De Souza1, Paul D. Cornwell, Xudong Dai, Michelle J. Caguyong and Roger G. Ulrich

Rosetta Inpharmatics LLC, Merck & Co, Inc, Seattle, Washington 98109

Received January 20, 2006; accepted April 11, 2006

In rodents, treatment with peroxisome proliferator–activated receptor alpha (PPAR{alpha}) agonists results in peroxisome proliferation, hepatocellular hypertrophy, and hepatomegaly. Drugs in the fibrate class of PPAR{alpha} agonists have also been reported to produce rare skeletal muscle toxicity. Although target-driven hepatic effects of PPAR{alpha} treatment have been extensively studied, a characterization of the transcriptional effects of this nuclear receptor/transcription factor on skeletal muscle responses has not been reported. In this study we investigated the effects of PPAR{alpha} agonists on skeletal muscle gene transcription in rats. Further, since statins have been reported to preferentially effect type II muscle fibers, we compared PPAR{alpha} signaling effects between type I and type II muscles. By comparing the transcriptional responses of agonists that signal through different nuclear receptors and using a selection/deselection analytical strategy based on ANOVA, we identified a PPAR{alpha} activation signature that is evident in type I (soleus), but not type II (quadriceps femoris), skeletal muscle fibers. The fiber-type–selective nature of this response is consistent with increased fatty acid uptake and ß-oxidation, which represent the major clinical benefits of the hypolipidemic compounds used in this study, but does not reveal any obvious off-target pathways that may drive adverse effects.

Key Words: peroxisome proliferator–activated receptor alpha (PPAR{alpha}); microarray; fenofibrate; Wy-14,643; liver.


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