The Role of Clock Genes in Cardiometabolic Disease Anticipating anticipation: pursuing identification of cardiomyocyte circadian clock function

Young ME. Anticipating anticipation: pursuing identification of cardiomyocyte circadian clock function. J Appl Physiol 107: 1339–1347, 2009. First published July 16, 2009; doi:10.1152/japplphysiol.00473.2009.—Diurnal rhythms in myocardial physiology (e.g., metabolism, contractile function) and pathophyiology (e.g., sudden cardiac death) are well establish and have classically been ascribed to time-of-day-dependent alterations in the neurohumoral milieu. Existence of an intramyocellular circadian clock has recently been exposed. Circadian clocks enable the cell to anticipate environmental stimuli, facilitating a timely and appropriate response. Generation of genetically modified mice with a targeted disruption of the cardiomyocyte circadian clock has provided an initial means for deciphering the functions of this transcriptionally based mechanism and allowed predictions regarding which environmental stimuli the heart anticipates (i.e., “anticipating anticipation”). Recent studies show that the cardiomyocyte circadian clock influences myocardial gene expression, -adrenergic signaling, transcriptional responsiveness to fatty acids, triglyceride metabolism, heart rate, and cardiac output, as well as ischemia-reperfusion tolerance. In addition to reviewing current knowledge regarding the roles of the cardiomyocyte circadian clock, this article highlights putative frontiers in this field. The latter includes establishing molecular links between the cardiomyocyte circadian clock with identified functions, understanding the pathophysiological consequences of disruption of this mechanism, targeting resynchronization of the cardiomyocyte circadian clock for prevention/ treatment of cardiovascular disease, linking the circadian clock with the cardiobeneficial effects of caloric restriction, and determining whether circadian clock genes are subject to epigenetic regulation. Information gained from studies investigating the cardiomyocyte circadian clock will likely translate to extracardiac tissues, such as skeletal muscle, liver, and adipose tissue.