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

Dec 25, 2007American journal of physiology. Heart and circulatory physiology

Disrupting the heart muscle’s internal clock affects its contraction, metabolism, and gene activity

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Abstract

At 12 weeks of age, cardiomyocyte-specific circadian clock mutant (CCM) mice exhibit bradycardia and altered heart rate variations.

CCM mice show attenuation of diurnal variations in heart rate without conduction system abnormalities.
In CCM hearts, reduced heart rate persists even when perfused ex vivo, indicating an intrinsic phenomenon.
Wild-type hearts demonstrate significant diurnal variations in response to increased workload, unlike CCM hearts.
CCM hearts have increased myocardial oxygen consumption and fatty acid oxidation rates, but decreased cardiac efficiency.
No changes in mitochondrial content or structure were observed in CCM hearts, but modest mitochondrial dysfunction was noted.
Gene expression analysis revealed that 548 atrial and 176 ventricular genes had altered diurnal expression patterns in CCM mice.

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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 microM 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.

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

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