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1Brown Foundation Institute of Molecular Medicine and 2School of Public Health, Human Genetics Center, University of Texas Health Science Center at Houston; and 3United States Department of Agriculture/Agricultural Research Service Children's Nutrition Research Center, Department of Pediatrics, Baylor College of Medicine, Houston, Texas 77030
Submitted 30 April 2004 ; accepted in final form 26 July 2004
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-14643 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 upregulation of transcriptional activators of the PPAR system during the night, with a concomitant downregulation 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 physiological and pathophysiological implications, ranging from experimental design to pharmacological treatment of patients.
diabetes; fasting; high-fat feeding; peroxisome proliferator-activated receptor-; pyruvate dehydrogenase kinase 4
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