ARS | Publication request: The intrinsic circadian clock within the cardiomyocyte directly regulates myocardial gene expression, metabolism, and function

Submitted to: Keystone Symposia
Publication Type: Abstract Only
Publication Acceptance Date: April 13, 2007
Publication Date: May 25, 2007
Citation: Bray, M.S., Shaw, C.A., Garcia, R.A.P., Zanquetta, M.M., Dyck, J.R.B., Chow, C., Abel, E.D., Young, M.E. 2007. The intrinsic circadian clock within the cardiomycyte directly regulates myocardial gene expression, metabolism, and function [abstract]. Keystone Symposia: Nuclear Receptor Pathways and Metabolic Syndrome, March 27-April 1, 2007, Steamboat Springs, Colorado. 165.

Technical Abstract: Circadian rhythms have been firmly established in both cardiovascular physiology (e.g., heart rate, cardiac output) and pathophysiology (e.g., arrhythmias). These phenomena have been attributed primarily to circadian rhythms in neurohumoral influences, such as sympathetic activity. Virtually every mammalian cell possesses an intrinsic circadian clock, a transcriptionally based molecular mechanism capable of regulating multiple cellular functions. CLOCK mutant mice exhibit altered circadian rhythms in behavior (e.g., locomotion, feeding), and increased susceptibility to development of features of the Metabolic Syndrome. We have recently generated a cardiomyocyte-specific circadian clock mutant (CCM) mouse, to identify the influences that this molecular mechanism has on myocardial physiology and pathophysiology. Through the use of microarray analysis, we identified 1077 and 350 direct circadian clock regulated genes in atria and ventricles, respectively. These genes cluster into 6 major categories: regulation of metabolism, signal transduction, transcription, protein turnover, cytoskeleton, and ion homeostasis. Consistent with a greater number of circadian clock regulated genes within atria (compared to ventricles), continuous radiotelemetric monitoring exposed decreased heart rate in CCM mice (compared to wild-type littermates). Furthermore, electrocardiographic telemetry exposed reduced heart rate of CCM hearts in the absence of electrical abnormalities, consistent with sinus bradycardia. Reduced heart rate persists in CCM hearts perfused ex vivo, highlighting the intrinsic nature of this phenotype. Furthermore, consistent with a role of the circadian clock within the cardiomyocyte in regulation of myocardial metabolism, we find that CCM mouse hearts exhibit decreased rates of glucose utilization (as measured ex vivo) and decreased fasting-induced myocardial triglyceride accumulation. These studies are the first to identify roles for the circadian clock within the cardiomyocyte, exposing direct influences on myocardial gene expression, metabolism (i.e., glucose and triglyceride metabolism), and function (i.e., heart rate). These studies suggest that chronic impairment of this molecular mechanism may contribute towards cardiovascular disease development.