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Title: DIURNAL VARIATIONS IN THE RESPONSIVENESS OF CARDIAC AND SKELETAL MUSCLE TO FATTY ACIDS

Author
item STAVINOHA, MELISSA - UT HEALTH SCI CENTER
item RAYSPELLICY, JOSEPH - UT HEALTH SCI CENTER
item HART-SAILORS, MARY - UT HEALTH SCI CENTER
item Mersmann, Harry
item BRAY, MOLLY - UT HEALTH SCI CENTER
item YOUNG, MARTIN - UT HEALTH SCI CENTER

Submitted to: American Journal of Physiology - Endocrinology and Metabolism
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: 7/26/2004
Publication Date: 11/1/2004
Citation: Stavinoha, M.A., Rayspellicy, J.W., Hart-Sailors, M.L., Mersmann, H.J., Bray, M.S., Young, M.E. 2004. Diurnal variations in the responsiveness of cardiac and skeletal muscle to fatty acids. American Journal of Physiology - Endocrinology and Metabolism. 287(5):E878-E887.

Interpretive Summary: Fatty acids are a major source of energy to mammals including humans. Fatty acids are available from the fat in the diet and from fat stores within the body. We hypothesized that fatty acid utilization by the heart and skeletal muscle varied during the day and night to maximize use during periods of greatest fatty acid availability. Expression of muscle genes associated with regulation of fatty acid utilization were synchronized with the highest blood fatty acids (during the light period). However, heart genes were highest in the dark when fatty acids were lower. When fatty acids were elevated by feeding diets high in fat, by fasting or by diabetes, the genes were increased in both muscle and heart. Mice without one of the key regulators of the fatty acid utilization genes (PPARalpha) maintained the daily variation in gene expression observed in normal mice. These observations indicate the complexity of the regulation of the daily variation in fatty acid utilization, suggest that part of the regulation is independent from PPARalpha, and indicate that the daily variation must be factored into the design of experiments to measure the role of fatty acid utilization and its regulation.

Technical Abstract: 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-alpha (PPAR alpha). 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 alpha-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 alpha 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 alpha-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 alpha 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.