title: Cardiomyocyte-specific BMAL1 plays critical roles in metabolism, signaling, and maintenance of contractile function of the heart.
abstract: Circadian clocks are cell autonomous, transcriptionally based, molecular mechanisms that confer the selective advantage of anticipation, enabling cells/organs to respond to environmental factors in a temporally appropriate manner. Critical to circadian clock function are 2 transcription factors, CLOCK and BMAL1. The purpose of the present study was to reveal novel physiologic functions of BMAL1 in the heart, as well as to determine the pathologic consequences of chronic disruption of this circadian clock component. To address this goal, we generated cardiomyocyte-specific Bmal1 knockout (CBK) mice. Following validation of the CBK model, combined microarray and in silico analyses were performed, identifying 19 putative direct BMAL1 target genes, which included a number of metabolic (e.g., β-hydroxybutyrate dehydrogenase 1 [Bdh1]) and signaling (e.g., the p85α regulatory subunit of phosphatidylinositol 3-kinase [Pik3r1]) genes. Results from subsequent validation studies were consistent with regulation of Bdh1 and Pik3r1 by BMAL1, with predicted impairments in ketone body metabolism and signaling observed in CBK hearts. Furthermore, CBK hearts exhibited depressed glucose utilization, as well as a differential response to a physiologic metabolic stress (i.e., fasting). Consistent with BMAL1 influencing critical functions in the heart, echocardiographic, gravimetric, histologic, and molecular analyses revealed age-onset development of dilated cardiomyopathy in CBK mice, which was associated with a severe reduction in life span. Collectively, our studies reveal that BMAL1 influences metabolism, signaling, and contractile function of the heart.
authors.affiliation: Division of Cardiovascular Diseases, Department of Medicine, University of Alabama at Birmingham, Birmingham, Alabama, USA meyoung@uab.edu.
authors.forename: Martin E
authors.initials: ME
authors.lastname: Young
authors.affiliation: Division of Cardiovascular Diseases, Department of Medicine, University of Alabama at Birmingham, Birmingham, Alabama, USA.
authors.forename: Rachel A
authors.initials: RA
authors.lastname: Brewer
authors.affiliation: Division of Cardiovascular Diseases, Department of Medicine, University of Alabama at Birmingham, Birmingham, Alabama, USA Institute of Biomedical Sciences-I, Department of Physiology and Biophysics, University of Sao Paulo, Sao Paulo, Brazil.
authors.forename: Rodrigo A
authors.initials: RA
authors.lastname: Peliciari-Garcia
authors.affiliation: Division of Molecular and Cellular Pathology, Department of Pathology, University of Alabama at Birmingham, Birmingham, Alabama, USA.
authors.forename: Helen E
authors.initials: HE
authors.lastname: Collins
authors.affiliation: Department of Nutrition Sciences, University of Alabama at Birmingham, Birmingham, Alabama, USA.
authors.forename: Lan
authors.initials: L
authors.lastname: He
authors.affiliation: Division of Cardiovascular Diseases, Department of Medicine, University of Alabama at Birmingham, Birmingham, Alabama, USA.
authors.forename: Tana L
authors.initials: TL
authors.lastname: Birky
authors.affiliation: Division of Cardiovascular Diseases, Department of Medicine, University of Alabama at Birmingham, Birmingham, Alabama, USA.
authors.forename: Bradley W
authors.initials: BW
authors.lastname: Peden
authors.affiliation: Division of Cardiovascular Diseases, Department of Medicine, University of Alabama at Birmingham, Birmingham, Alabama, USA.
authors.forename: Emily G
authors.initials: EG
authors.lastname: Thompson
authors.affiliation: Division of Cardiovascular Diseases, Department of Medicine, University of Alabama at Birmingham, Birmingham, Alabama, USA.
authors.forename: Billy-Joe
authors.initials: BJ
authors.lastname: Ammons
authors.affiliation: Department of Epidemiology, University of Alabama at Birmingham, Birmingham, Alabama, USA.
authors.forename: Molly S
authors.initials: MS
authors.lastname: Bray
authors.affiliation: Division of Molecular and Cellular Pathology, Department of Pathology, University of Alabama at Birmingham, Birmingham, Alabama, USA.
authors.forename: John C
authors.initials: JC
authors.lastname: Chatham
authors.affiliation: Division of Molecular and Cellular Pathology, Department of Pathology, University of Alabama at Birmingham, Birmingham, Alabama, USA.
authors.forename: Adam R
authors.initials: AR
authors.lastname: Wende
authors.affiliation: Department of Nutrition Sciences, University of Alabama at Birmingham, Birmingham, Alabama, USA.
authors.forename: Qinglin
authors.initials: Q
authors.lastname: Yang
authors.affiliation: Department of Molecular Pharmacology, Albert Einstein College of Medicine, Bronx, New York, USA.
authors.forename: Chi-Wing
authors.initials: CW
authors.lastname: Chow
authors.affiliation: Department of Biomedical Science, University of Guelph, Guelph, Ontario, Canada.
authors.forename: Tami A
authors.initials: TA
authors.lastname: Martino
authors.affiliation: Division of Behavioral Neurobiology, Department of Psychiatry, University of Alabama at Birmingham, Birmingham, Alabama, USA.
authors.forename: Karen L
authors.initials: KL
authors.lastname: Gamble
mesh_terms: D056930:ARNTL Transcription Factors / Q000378:metabolism*; D000818:Animals; D057906:Circadian Clocks / Q000502:physiology; D002940:Circadian Rhythm / Q000502:physiology; D005947:Glucose / Q000378:metabolism; D006321:Heart / Q000502:physiology*; D007657:Ketone Bodies / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D032383:Myocytes, Cardiac / Q000378:metabolism*; D015398:Signal Transduction / Q000502:physiology*
chemical_list: D056930:ARNTL Transcription Factors; C538961:Bmal1 protein, mouse; D007657:Ketone Bodies; D005947:Glucose
keywords: chronobiology; circadian; metabolism; signaling; transcriptome