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

Abstract

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. (Author correspondence: [email protected])

Keywords:

• Aging
• Cardiac hypertrophy
• Circadian clocks
• Heart
• Shiftwork
• Cardiomyocyte

ACKNOWLEDGMENTS

This work was supported by the National Heart, Lung, and Blood Institute (HL-074259 [M.E.Y.]) and support from the Pennington Biomedical Research Foundation (J.M.G.). Ju-Yun Tsai was supported by the DeBakey Heart Fund at Baylor College of Medicine. David J. Durgan was supported by the NSF GK-12 Fellowship. We wish to acknowledge the DRTC-funded (P30DK56336, P30NS057098, P60DK079626) Small Animal Physiology Core at UAB (Dr. Timothy Nagy, Director) for help with the MRI analysis. We also wish to thank Dr. Michael Schneider for providing MHCα-CRE mice.

Declaration of Interest: The authors report no conflicts of interest. The authors alone are responsible for the content and writing of the paper.