Submitted to: Journal of Biological Chemistry
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: 6/6/2006
Publication Date: 6/22/2006
Citation: Durgan, D.J., Trexler, N.A., Egbejimi, O., McElfresh, T.A., Suk, H.Y., Petterson, L.E., Shaw, C.A., Hardin, P.E., Bray, M., Chandler, M.P., Chow, C., Young, M.E. 2006. The circadian clock within the cardiomyocyte is essential for responsiveness of the heart to fatty acids. Journal of Biological Chemistry. 281(34):24254-24269. Interpretive Summary: Though fats are an excellent fuel source for many cells and organs, if they are not used for fuel, the fats will accumulate in the liver and in skeletal muscle where they can promote the development of resistance to the effect of insulin. We proposed that a mechanism for making sure that the cells are ready to use the fats when they are needed (for example, during sleeping) is the circadian clock within the cells. We focused our study on the cells of the heart. We report that both the circadian clock within the cells of the heart and the genes that control the use of fats for fuel demonstrate a rhythmic pattern, even when the cells are removed from the animal. Reversal of the light/dark cycle was associated with a re-setting of the circadian clock within the rat heart, which took 5 to 8 days for completion. When the circadian clock in the heart was disturbed and/or out of coordination with the light/dark cycle, the genes needed to process fats were not responsive. These studies suggest that the circadian clock within the cells of the heart influences the heart's ability to process fats.
Technical Abstract: Cells/organs must respond both rapidly and appropriately to increased fatty acid availability; failure to do so is associated with the development of skeletal muscle and hepatic insulin resistance, pancreatic beta-cell dysfunction, and myocardial contractile dysfunction. Here we tested the hypothesis that the intrinsic circadian clock within the cardiomyocytes of the heart allows rapid and appropriate adaptation of this organ to fatty acids, by investigating whether: 1) circadian rhythms in fatty acid responsiveness persist in isolated adult rat cardiomyocytes (ARCs); and 2) manipulation of the circadian clock within the heart, through either light/dark (L/D) cycle or genetic disruptions, impairs responsiveness of the heart to fasting in vivo. We report that both the intramyocellular circadian clock and diurnal variations in fatty acid responsiveness observed in the intact rat heart in vivo, persist in ARCs. Reversal of the 12h/12h L/D cycle was associated with a re-entrainment of the circadian clock within the rat heart, which required 5 to 8 days for completion. Fasting rats resulted in the induction of fatty acid responsive genes, an effect that was dramatically attenuated 2 days after L/D cycle reversal. Similarly, a targeted disruption of the circadian clock within the heart, through overexpression of a dominant negative CLOCK mutant, severely attenuated induction of myocardial fatty acid responsive genes during fasting. These studies expose a causal relationship between the circadian clock within the cardiomyocyte with: 1) responsiveness of the heart to fatty acids; and 2) myocardial triglyceride metabolism.