Submitted to: Meeting Abstract
Publication Type: Abstract Only
Publication Acceptance Date: 3/17/2008
Publication Date: 5/17/2008
Citation: Tsai, J., Moore, M.W.S., Young, M.E. 2008. Role of cardiomyocyte circadian clock in myocardial metabolic adaptation [abstract]. Proceeding, Society for Research on Biological Rhythms. May 17-21, 2008, San Delia, Florida. p. 65. Interpretive Summary:
Technical Abstract: Marked circadian rhythmicities in cardiovascular physiology and pathophysiology exist. The cardiomyocyte circadian clock has recently been linked to circadian rhythms in myocardial gene expression, metabolism, and contractile function. For instance, the cardiomyocyte circadian clock is essential for the acute transcriptional response of the heart to elevated circulating fatty acids. When fatty acid availability exceeds the oxidative capacity of the myocardium, excess fatty acids spill-over into "lipotoxic" pathways, potentially causing contractile dysfunction. These observations led us to hypothesize that disruption of the cardiomyocyte circadian clock impairs metabolic adaptation of the heart to chronic elevation of fatty acids. Wild type (WT) and cardiomyocyte-specific circadian clock mutant (CCM) mice were fed either a control or Western (high fat) diet for 16 weeks. Hearts were perfused ex vivo in the working mode for assessment of myocardial metabolism and contractile function, while a second set of hearts were used for transcriptional analysis. Western diet feeding induced anticipated alterations in myocardial metabolism (e.g. reduced carbohydrate metabolism; p<0.01) and impaired contractile function (p<0.01) for WT, but not CCM, mice. During assessment of myocardial metabolism with elevated fatty acids ex vivo (1.2mM), CCM hearts do not decrease reliance on endogenous substrate utilization (unlike WT hearts), suggesting abnormal triglyceride metabolism. Consistent with this, diurnal variations in expression of adiponutrin (adpn) and diacylglycerol acyltransferase 2 (dgat2), regulators of triglyceride metabolism, were abolished in CCM hearts (p<0.05). These data demonstrate that the cardiomyocyte circadian clock is essential for the metabolic adaptation of the heart to chronic elevation in fatty acids.