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 μM 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.
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Selective Bmal1 knockout in cardiomyocytes eliminates much of the rhythmic transcriptome, reduces stroke volume and ejection fraction, and causes heart failure and early mortality in mice.
“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 [64]
Mice lacking the Clock gene specifically within cardiomyocytes have brachycardia, greater myocardial oxygen consumption, and decreased cardiac efficiency.
“Moreover, mice lacking the Clock gene specifically within cardiomyocytes have brachycardia, greater myocardial oxygen consumption, and decreased cardiac efficiency (Bray et al., 2008).”
From The impact of the circadian timing system on cardiovascular and metabolic function (2012) · cites this paper as Bray et al., 2008
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- Authors
- 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.-Y., Bugger, H., Zhang, D., Rohrwasser, A., Rennison, J. H., Dyck, J. R. B., Litwin, S. E., Hardin, P. E., Chow, C.-W., Chandler, M. P., Abel, E. D., & Young, M. E.
- Affiliations
- Agricultural Research Service (US)
- Baylor College of Medicine (US)
- Universidade de São Paulo (BR)
- University of Utah (US)
- Case Western Reserve University (US)
- University of Alberta (CA)
- Texas A&M University (US)
- ORCID
- Venue
- American Journal of Physiology-Heart and Circulatory Physiology
- Publisher
- American Physiological Society
- Published
- 2008-02
- Volume
- 294
- Issue
- 2
- Pages
- H1036-H1047
- ISSN
- 0363-6135 (ISSN-L)
- 1522-1539
- OpenAlex
- W2122453474
- Cited by
- 384
- References
- 53
- Citations by year
- 2026: 13 · 2025: 18 · 2024: 20 · 2023: 25 · 2022: 32 · 2021: 28 · 2020: 22 · 2019: 19 · 2018: 23 · 2017: 22 · 2016: 20 · 2015: 20 · 2014: 28 · 2013: 14 · 2012: 22
- FWCI
- 5.58
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- American Journal of Physiology-Heart and Circulatory Physiology (publishedVersion)
- PubMed (publishedVersion)
- Scientific Electronic Library Online (São Paulo Research Foundation, Latin American and Caribbean Center on Health Sciences Information, Conselho Nacional de Desenvolvimento Científico e Tecnológico) (publishedVersion)
- Funders
- National Heart, Lung, and Blood Institute (HL-074259, HL 070070, R01HL070070, R01HL074259)
- Topics
- Life Sciences › Neuroscience › Endocrine and Autonomic Systems › Circadian rhythm and melatonin
- Health Sciences › Medicine › Cardiology and Cardiovascular Medicine › Cardiac electrophysiology and arrhythmias
- Health Sciences › Medicine › Cardiology and Cardiovascular Medicine › Cardiovascular Function and Risk Factors
- Keywords
- circadian clock, cardiomyocytes, cardiac contractility, myocardial metabolism, diurnal variation, heart rate, cardiac efficiency, myocardial oxygen consumption, fatty acid oxidation, mitochondrial dysfunction, circadian gene expression, epinephrine response
- MeSH terms
- Animals, Circadian Rhythm, DNA, Echocardiography, Electrocardiography, Heart Rate, Mitochondria, Heart, Muscle Proteins, Myocardial Contraction, Myocardium, Perfusion, Telemetry, Signal Transduction, Gene Expression, Reverse Transcriptase Polymerase Chain Reaction, Oligonucleotide Array Sequence Analysis, Myocytes, Cardiac, Mice, In Vitro Techniques
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