Agonists of the peroxisome proliferator-activated receptor alpha induce a fiber-type-selective transcriptional response in rat skeletal muscle

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 beta-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.