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

Authors: Bray, Molly; SHAW, CHAD - BAYLOR COLLEGE MED; MOORE, MICHAEL - BAYLOR COLLEGE MED; GARCIA, RODRIGO - BAYLOR COLLEGE MED; ZANQUETTA, MELISSA - BAYLOR COLLEGE MED; DURGAN, DAVID - BAYLOR COLLEGE MED; JEONG, WILLIAM - BAYLOR COLLEGE MED; TSAI, JU-YUN - BAYLOR COLLEGE MED; BUGGER, HEIKO - UNIV UTAH, SLT LK CTY, UT; ZHANG, DONGFANG - UNIV UTAH, SLT LK CTY, UT; ROHRWASSER, ANDREAS - UNIV UTAH, SLT LK CTY, UT; RENNISON, JULIE - CASE WSTRN, CLEVELAND, OH; DYCK, JASON - UNIV ALBERTA, ALBERTA, CA; LITWIN, SHELDON - UNIV UTAH, SLT LK CTY, UT; HARDIN, PAUL - TAMU, COLLEGE STATION, TX; CHOW, CHI-WING - EINSTN COL MED, BRONX,NY; CHANDLER, MARGARET - CASE WSTRN, CLEVELAND, OH; ABEL, E - UNIV UTAH, SLT LK CTY, UT; Young, Martin

Submitted to: American Journal of Physiology - Heart and Circulatory Physiology
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: 12/21/2007
Publication Date: 2/1/2008
Citation: Bray, M.S., Shaw, C.A., Moore, M.W.S., Garcia, R.A.P., Zanquetta, M.M., Durgan, D.J., Jeong, W.J., Tsai, J., Bugger, H., Zhang, D., Rohrwasser, A., Rennison, J.H., Dyck, J.R.B., Litwin, S.E., Hardin, P.E., Chow, C., Chandler, M.P., Abel, E.D., Young, M.E. 2008. Disruption of the circadian clock within the cardiomyocyte influences mycardial contractile function, metabolism, and gene expression. American Journal of Physiology - Heart and Circulatory Physiology. 294(2):H1036-H1047.

Interpretive Summary: Nearly every cell in the body contains a set of molecules that regulate daily rhythms in many cellular functions – together these molecules comprise the circadian clock. In heart cells, these circadian clocks appear to regulate some aspects of heart function ,but how this regulation takes place is not known. We, therefore, created a mouse model that lacks a functional circadian clock but only in the heart cells (CCM mice). At 12 weeks of age, the hearts of CCM mice contract normally but at a much slower rate compared to normal mice. The hearts of CCM mice also do not respond as well to the stress of simulated exercise during certain times of the day as normal mice, and their usage of fuel sources like fats and sugars was also altered compared to normal mice. Based on our experiments, many different genes related to heart function appear to be regulated by the circadian clock within the heart.

Technical Abstract: 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.