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Disruption of the circadian clock within the cardiomyocyte influences myocardial contractile function, metabolism, and gene expression

¹US Department of Agriculture/Agricultural Research Service Children's Nutrition Research Center, Department of Pediatrics, and ²Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, Texas; ³Department of Physiology and Biophysics, Institute of Biomedical Sciences, University of Sao Paulo, Sao Paulo, Brazil; ⁴Division of Endocrinology, Metabolism and Diabetes and Program in Human Molecular Biology, ⁵Division of Cardiology, and ⁶Department of Human Genetics, University of Utah, Salt Lake City, Utah; ⁷Department of Physiology and Biophysics, Case Western Reserve University, Cleveland, Ohio; ⁸Cardiovascular Research Group, Department of Pediatrics and Pharmacology, Faculty of Medicine and Dentistry, University of Alberta, Edmonton, Alberta, Canada; ⁹Department of Biology, Texas A&M University, College Station, Texas; and ¹⁰Department of Molecular Pharmacology, Albert Einstein College of Medicine, Bronx, New York

Submitted 2 November 2007 ; accepted in final form 17 December 2007

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 to test this hypothesis. At 12 wk 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 (80 mmHg plus 1 µM epinephrine) ex vivo, with a greater increase in cardiac power and efficiency during the dark (active) phase vs. the light (inactive) phase. Moreover, myocardial oxygen consumption and fatty acid oxidation rates were increased, whereas 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.

bradycardia; carbohydrate; chronobiology; epinephrine; fatty acids

This article has been cited by other articles:

				M. S. Bray and M. E. Young Diurnal variations in myocardial metabolism Cardiovasc Res, July 15, 2008; 79(2): 228 - 237. [Abstract] [Full Text] [PDF]