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1 Brown Foundation Institute of Molecular Medicine, University of Texas Health Science Center at Houston, Houston, Texas, USA
2 School of Public Health, Human Genetics Center, University of Texas Health Science Center at Houston, Houston, Texas, USA
3 USDA/ARS Children's Nutrition Research Center, Baylor College of Medicine, Houston, Texas, USA
* To whom correspondence should be addressed. E-mail: Martin.E.Young{at}uth.tmc.edu.
Cardiac and skeletal muscle both respond to elevated fatty acid availability by increasing
fatty acid oxidation, an effect mediated in large part by peroxisome proliferator-activated
receptor 
(PPAR). We hypothesized that cardiac and skeletal muscle alter their
responsiveness to fatty acids over the course of the day, allowing optimal adaptation
when availability of this substrate increases. In the current study, pyruvate
dehydrogenase kinase 4 (pdk4) was utilized as a representative PPAR-regulated gene.
Opposing diurnal variations in pdk4 expression were observed in cardiac and skeletal
muscle isolated from the ad libitum fed rat; pdk4 expression peaked in the middle of the
dark and light phases, respectively. Elevation of circulating fatty acid levels by high fat
feeding, fasting, and streptozotocin-induced diabetes increased pdk4 expression in both
heart and soleus muscle. Highest levels of induction were observed during the dark
phase, regardless of muscle type or intervention. Specific activation of PPAR with
WY-14,643 rapidly induced pdk4 expression in heart and soleus muscle. Highest levels
of induction were again observed during the dark phase. The same pattern of induction
was observed for the PPAR-regulated genes malonyl-CoA decarboxylase and
uncoupling protein 3. Investigation into the potential mechanism(s) for these
observations exposed a coordinated up-regulation of transcriptional activators of the
PPAR system during the night, with a concomitant down-regulation of transcriptional
repressors in both muscle types. In conclusion, responsiveness of cardiac and skeletal
muscle to fatty acids exhibits a marked diurnal variation. These observations have
important physiologic and pathophysiologic implications, ranging from experimental
design to pharmacological treatment of patients.
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