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. 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.
authors.affiliation: US Department of Agriculture, Agricultural Research Service Children's Nutrition Research Center, Department of Pediatrics, Houston, TX 77030, USA.
authors.forename: Molly S
authors.initials: MS
authors.lastname: Bray
authors.forename: Chad A
authors.initials: CA
authors.lastname: Shaw
authors.forename: Michael W S
authors.initials: MW
authors.lastname: Moore
authors.forename: Rodrigo A P
authors.initials: RA
authors.lastname: Garcia
authors.forename: Melissa M
authors.initials: MM
authors.lastname: Zanquetta
authors.forename: David J
authors.initials: DJ
authors.lastname: Durgan
authors.forename: William J
authors.initials: WJ
authors.lastname: Jeong
authors.forename: Ju-Yun
authors.initials: JY
authors.lastname: Tsai
authors.forename: Heiko
authors.initials: H
authors.lastname: Bugger
authors.forename: Dongfang
authors.initials: D
authors.lastname: Zhang
authors.forename: Andreas
authors.initials: A
authors.lastname: Rohrwasser
authors.forename: Julie H
authors.initials: JH
authors.lastname: Rennison
authors.forename: Jason R B
authors.initials: JR
authors.lastname: Dyck
authors.forename: Sheldon E
authors.initials: SE
authors.lastname: Litwin
authors.forename: Paul E
authors.initials: PE
authors.lastname: Hardin
authors.forename: Chi-Wing
authors.initials: CW
authors.lastname: Chow
authors.forename: Margaret P
authors.initials: MP
authors.lastname: Chandler
authors.forename: E Dale
authors.initials: ED
authors.lastname: Abel
authors.forename: Martin E
authors.initials: ME
authors.lastname: Young
mesh_terms: D000818:Animals; D002940:Circadian Rhythm / Q000235:genetics* / Q000502:physiology*; D004247:DNA / Q000096:biosynthesis / Q000235:genetics; D004452:Echocardiography; D004562:Electrocardiography; D015870:Gene Expression / Q000502:physiology*; D006339:Heart Rate / Q000502:physiology; D066298:In Vitro Techniques; D051379:Mice; D008929:Mitochondria, Heart / Q000502:physiology; D009124:Muscle Proteins / Q000378:metabolism; D009200:Myocardial Contraction / Q000235:genetics / Q000502:physiology*; D009206:Myocardium / Q000378:metabolism*; D032383:Myocytes, Cardiac / Q000502:physiology*; D020411:Oligonucleotide Array Sequence Analysis; D010477:Perfusion; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction / Q000502:physiology; D013686:Telemetry
chemical_list: D009124:Muscle Proteins; D004247:DNA