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1 Pediatrics, Baylor College of Medicine, Houston, Texas, United States
2 Molecular and Human Genetics, Baylor College of Medicine, Houston, Texas, United States
3 Division of Endocrinology, Metabolism and Diabetes, University of Utah, Salt Lake City, Utah, United States
4 Division of Cardiology, University of Utah, Salt Lake City, Utah, United States
5 Human Genetics, University of Utah, Salt Lake City, Utah, United States
6 Physiology and Biophysics, Case Western Reserve University, Cleveland, Ohio, United States
7 Pediatrics, University of Alberta, Edmonton, Canada
8 Biology, Texas A and M University, College Station, Texas, United States
9 Department of Molecular Pharmacology, Albert Einstein College of Medicine, Bronx, New York, United States
* To whom correspondence should be addressed. E-mail: meyoung{at}bcm.edu.
Virtually every mammalian cell, including cardiomyocytes, possesses an intrinsic circadian clock. The role of this transcriptionally-based molecular mechanism in cardiovascular biology is poorly understood. We hypothesized that the circadian clock within the cardiomyocyte influences diurnal variations in myocardial biology. We therefore generated a cardiomyocyte-specific circadian clock mutant (CCM) mouse, in order to test this hypothesis. At 12 weeks of age, CCM mice exhibit normal myocardial contractile function in vivo, as assessed by echocardiography. Radiotelemetry studies reveal attenuation of heart rate diurnal variations and bradycardia in CCM mice (in the absence of conduction system abnormalities). Reduced heart rate persisted in CCM hearts perfused ex vivo in the working mode, highlighting the intrinsic nature of this phenotype. Wild-type, but not CCM, hearts exhibited a marked diurnal variation in responsiveness to an elevation in workload (80mmHg plus 1µM epinephrine) ex vivo, with a greater increase in cardiac power and efficiency during the dark (active) phase versus the light (inactive) phase. Moreover, myocardial oxygen consumption and fatty acid oxidation rates were increased, while cardiac efficiency was decreased, in CCM hearts. These observations were associated with no alterations in mitochondrial content or structure, and modest mitochondrial dysfunction, in CCM hearts. Gene expression microarray analysis identified 548 and 176 genes in atria and ventricles, respectively, whose normal diurnal expression patterns were altered in CCM mice. These studies suggest that the cardiomyocyte circadian clock influences myocardial contractile function, metabolism, and gene expression.
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