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Cardiomyocyte-Specific BMAL1 Plays Critical Roles in Metabolism, Signaling, and Maintenance of Contractile Function of the Heart
Open accessAbstract
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.
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“For instance, Bmal1 knockout in mice causes dilated cardiomyopathy (62) and selective Bmal1 knockout in cardiomyocytes eliminates much of the rhythmic transcriptome (63), reduces stroke volume and ejection fraction, and causes heart failure and early mortality in mice (63,64).”
From Role of the circadian system in cardiovascular disease (2018) · cites this paper as [63]
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Metadata
- Authors
- Young, M. E., Brewer, R. A., Peliciari-Garcia, R. A., Collins, H. E., He, L., Birky, T. L., Peden, B. W., Thompson, E. G., Ammons, B.-J., Bray, M. S., Chatham, J. C., Wende, A. R., Yang, Q., Chow, C.-W., Martino, T. A., & Gamble, K. L.
- Affiliations
- University of Alabama at Birmingham (US)
- Division of Cardiovascular Diseases, Department of Medicine, University of Alabama at Birmingham, Birmingham, Alabama, USA
- Albert Einstein College of Medicine (US)
- University of Guelph (CA)
- Corresponding author
- Young, Martin E.
- ORCID
- Venue
- Journal of Biological Rhythms
- Publisher
- SAGE Publications
- Published
- 2014-08
- Volume
- 29
- Issue
- 4
- Pages
- 257-276
- ISSN
- 0748-7304 (ISSN-L)
- 1552-4531
- PMC
- PMC4260630
- OpenAlex
- W2080300476
- Cited by
- 220
- References
- 68
- Citations by year
- 2026: 10 · 2025: 20 · 2024: 27 · 2023: 18 · 2022: 26 · 2021: 21 · 2020: 21 · 2019: 17 · 2018: 13 · 2017: 18 · 2016: 15 · 2015: 13 · 2014: 1
- FWCI
- 7.53
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Journal of Biological Rhythms (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- Funders
- University of Alabama at Birmingham
- National Institutes of Health (5ul1rr025777-04, 5p60dk079626-05)
- National Heart, Lung, and Blood Institute (HL-074259, HL‑106199, R21HL106199, R21HL107709, HL-107709, R01HL074259, R01HL123574)
- National Institute of Diabetes and Digestive and Kidney Diseases (P60-DK-079626, DK11015, P30DK056336, P30DK079626)
- National Institute of Neurological Disorders and Stroke (R01NS082413)
- National Center for Research Resources (UL1-RR-025777)
- Topics
- Life Sciences › Neuroscience › Endocrine and Autonomic Systems › Circadian rhythm and melatonin
- Health Sciences › Medicine › Cardiology and Cardiovascular Medicine › Cardiac electrophysiology and arrhythmias
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Congenital heart defects research
- Keywords
- Bmal1, circadian clock, cardiomyocytes, cardiomyocyte-specific knockout mice, BDH1, PIK3R1, ketone body metabolism, glucose utilization, fasting response, dilated cardiomyopathy, myocardial metabolism, direct transcriptional targets, lifespan
- MeSH terms
- Animals, Circadian Rhythm, Glucose, Heart, Ketone Bodies, Male, Mice, Inbred C57BL, Signal Transduction, Mice, Knockout, Myocytes, Cardiac, Mice, ARNTL Transcription Factors, Circadian Clocks
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