Evidence Suggesting that the Cardiomyocyte Circadian Clock Modulates Responsiveness of the Heart to Hypertrophic Stimuli in Mice

Apr 2, 2011Chronobiology international

The heart’s internal clock may influence how heart cells respond to growth signals in mice

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Abstract

Chronic dyssynchrony of the cardiomyocyte circadian clock is associated with increased biventricular weight and hypertrophy markers in mice.

Circadian misalignment due to phase shifts in the light-dark cycle may lead to maladaptation in myocardial function.
Cardiomyocyte Clock Mutant mice show increased heart size and hypertrophy markers regardless of aging or simulated shiftwork exposure.
A second genetic model with disrupted cardiomyocyte circadian rhythms also exhibits similar heart growth and hypertrophy markers.
Wild-type mice display a diurnal variation in cardiac growth response to the hypertrophic agent isoproterenol, which is absent in CCM mice.
The cardiomyocyte circadian clock may play a role in how the heart responds to hypertrophic stimuli.

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Circadian dyssynchrony of an organism (at the whole-body level) with its environment, either through light-dark (LD) cycle or genetic manipulation of clock genes, augments various cardiometabolic diseases. The cardiomyocyte circadian clock has recently been shown to influence multiple myocardial processes, ranging from transcriptional regulation and energy metabolism to contractile function. The authors, therefore, reasoned that chronic dyssychrony of the cardiomyocyte circadian clock with its environment would precipitate myocardial maladaptation to a circadian challenge (simulated shiftwork; SSW). To test this hypothesis, 2- and 20-month-old wild-type and CCM (Cardiomyocyte Clock Mutant; a model with genetic temporal suspension of the cardiomyocyte circadian clock at the active-to-sleep phase transition) mice were subjected to chronic (16-wks) biweekly 12-h phase shifts in the LD cycle (i.e., SSW). Assessment of adaptation/maladaptation at whole-body homeostatic, gravimetric, humoral, histological, transcriptional, and cardiac contractile function levels revealed essentially identical responses between wild-type and CCM littermates. However, CCM hearts exhibited increased biventricular weight, cardiomyocyte size, and molecular markers of hypertrophy (anf, mcip1), independent of aging and/or SSW. Similarly, a second genetic model of selective temporal suspension of the cardiomyocyte circadian clock (Cardiomyocyte-specific BMAL1 Knockout [CBK] mice) exhibits increased biventricular weight and mcip1 expression. Wild-type mice exhibit 5-fold greater cardiac hypertrophic growth (and 6-fold greater anf mRNA induction) when challenged with the hypertrophic agonist isoproterenol at the active-to-sleep phase transition, relative to isoproterenol administration at the sleep-to-active phase transition. This diurnal variation was absent in CCM mice. Collectively, these data suggest that the cardiomyocyte circadian clock likely influences responsiveness of the heart to hypertrophic stimuli.

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Evidence Suggesting that the Cardiomyocyte Circadian Clock Modulates Responsiveness of the Heart to Hypertrophic Stimuli in Mice

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