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

Molly S. Bray, Chad A. Shaw, Michael W S Moore, Rodrigo A P Garcia, Melissa M. Zanquetta, David J. Durgan, William J. Jeong, Ju Yun Tsai, Heiko Bugger, Dongfang Zhang, Andreas Rohrwasser, Julie H. Rennison, Jason R B Dyck, Sheldon E. Litwin, Paul E. Hardin, Chi Wing Chow, Margaret P. Chandler, E. Dale Abel, Martin E. Young

Research output: Contribution to journalArticle

190 Citations (Scopus)

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. Radio-telemetry studies reveal attenuation of heart rate diurnal variations and bradycardia in CCM mice (in the absence of conduction system abnormalities). Reduced heart rate persisted inCCMhearts 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 μMepinephrine) 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.

Original languageEnglish (US)
JournalAmerican Journal of Physiology - Heart and Circulatory Physiology
Volume294
Issue number2
DOIs
StatePublished - Feb 2008

Fingerprint

Circadian Clocks
Cardiac Myocytes
Gene Expression
Heart Rate
Telemetry
Microarray Analysis
Bradycardia
Workload
Radio
Oxygen Consumption
Echocardiography
Fatty Acids
Phenotype
Light

Keywords

  • Bradycardia
  • Carbohydrate
  • Chronobiology
  • Epinephrine
  • Fatty acids

ASJC Scopus subject areas

  • Physiology

Cite this

Disruption of the circadian clock within the cardiomyocyte influences myocardial contractile function, metabolism, and gene expression. / Bray, Molly S.; Shaw, Chad A.; Moore, Michael W S; Garcia, Rodrigo A P; Zanquetta, Melissa M.; Durgan, David J.; Jeong, William J.; Tsai, Ju Yun; Bugger, Heiko; Zhang, Dongfang; Rohrwasser, Andreas; Rennison, Julie H.; Dyck, Jason R B; Litwin, Sheldon E.; Hardin, Paul E.; Chow, Chi Wing; Chandler, Margaret P.; Abel, E. Dale; Young, Martin E.

In: American Journal of Physiology - Heart and Circulatory Physiology, Vol. 294, No. 2, 02.2008.

Research output: Contribution to journalArticle

Bray, MS, Shaw, CA, Moore, MWS, Garcia, RAP, Zanquetta, MM, Durgan, DJ, Jeong, WJ, Tsai, JY, Bugger, H, Zhang, D, Rohrwasser, A, Rennison, JH, Dyck, JRB, Litwin, SE, Hardin, PE, Chow, CW, Chandler, MP, Abel, ED & Young, ME 2008, 'Disruption of the circadian clock within the cardiomyocyte influences myocardial contractile function, metabolism, and gene expression', American Journal of Physiology - Heart and Circulatory Physiology, vol. 294, no. 2. https://doi.org/10.1152/ajpheart.01291.2007
Bray, Molly S. ; Shaw, Chad A. ; Moore, Michael W S ; Garcia, Rodrigo A P ; Zanquetta, Melissa M. ; Durgan, David J. ; Jeong, William J. ; Tsai, Ju Yun ; Bugger, Heiko ; Zhang, Dongfang ; Rohrwasser, Andreas ; Rennison, Julie H. ; Dyck, Jason R B ; Litwin, Sheldon E. ; Hardin, Paul E. ; Chow, Chi Wing ; Chandler, Margaret P. ; Abel, E. Dale ; Young, Martin E. / Disruption of the circadian clock within the cardiomyocyte influences myocardial contractile function, metabolism, and gene expression. In: American Journal of Physiology - Heart and Circulatory Physiology. 2008 ; Vol. 294, No. 2.
@article{2dc837cbb2ad4d41b4d9a5c3bfdb1e39,
title = "Disruption of the circadian clock within the cardiomyocyte influences myocardial contractile function, metabolism, and gene expression",
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. Radio-telemetry studies reveal attenuation of heart rate diurnal variations and bradycardia in CCM mice (in the absence of conduction system abnormalities). Reduced heart rate persisted inCCMhearts 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 μMepinephrine) 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.",
keywords = "Bradycardia, Carbohydrate, Chronobiology, Epinephrine, Fatty acids",
author = "Bray, {Molly S.} and Shaw, {Chad A.} and Moore, {Michael W S} and Garcia, {Rodrigo A P} and Zanquetta, {Melissa M.} and Durgan, {David J.} and Jeong, {William J.} and Tsai, {Ju Yun} and Heiko Bugger and Dongfang Zhang and Andreas Rohrwasser and Rennison, {Julie H.} and Dyck, {Jason R B} and Litwin, {Sheldon E.} and Hardin, {Paul E.} and Chow, {Chi Wing} and Chandler, {Margaret P.} and Abel, {E. Dale} and Young, {Martin E.}",
year = "2008",
month = "2",
doi = "10.1152/ajpheart.01291.2007",
language = "English (US)",
volume = "294",
journal = "American Journal of Physiology - Renal Fluid and Electrolyte Physiology",
issn = "1931-857X",
publisher = "American Physiological Society",
number = "2",

}

TY - JOUR

T1 - Disruption of the circadian clock within the cardiomyocyte influences myocardial contractile function, metabolism, and gene expression

AU - Bray, Molly S.

AU - Shaw, Chad A.

AU - Moore, Michael W S

AU - Garcia, Rodrigo A P

AU - Zanquetta, Melissa M.

AU - Durgan, David J.

AU - Jeong, William J.

AU - Tsai, Ju Yun

AU - Bugger, Heiko

AU - Zhang, Dongfang

AU - Rohrwasser, Andreas

AU - Rennison, Julie H.

AU - Dyck, Jason R B

AU - Litwin, Sheldon E.

AU - Hardin, Paul E.

AU - Chow, Chi Wing

AU - Chandler, Margaret P.

AU - Abel, E. Dale

AU - Young, Martin E.

PY - 2008/2

Y1 - 2008/2

N2 - 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. Radio-telemetry studies reveal attenuation of heart rate diurnal variations and bradycardia in CCM mice (in the absence of conduction system abnormalities). Reduced heart rate persisted inCCMhearts 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 μMepinephrine) 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.

AB - 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. Radio-telemetry studies reveal attenuation of heart rate diurnal variations and bradycardia in CCM mice (in the absence of conduction system abnormalities). Reduced heart rate persisted inCCMhearts 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 μMepinephrine) 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.

KW - Bradycardia

KW - Carbohydrate

KW - Chronobiology

KW - Epinephrine

KW - Fatty acids

UR - http://www.scopus.com/inward/record.url?scp=39149108483&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=39149108483&partnerID=8YFLogxK

U2 - 10.1152/ajpheart.01291.2007

DO - 10.1152/ajpheart.01291.2007

M3 - Article

C2 - 18156197

AN - SCOPUS:39149108483

VL - 294

JO - American Journal of Physiology - Renal Fluid and Electrolyte Physiology

JF - American Journal of Physiology - Renal Fluid and Electrolyte Physiology

SN - 1931-857X

IS - 2

ER -