Journal article
Genetic disruption of the cardiomyocyte circadian clock differentially influences insulin-mediated processes in the heart
Journal of molecular and cellular cardiology, Vol.110, pp.80-95
09/2017
DOI: 10.1016/j.yjmcc.2017.07.005
PMCID: PMC5586500
PMID: 28736261
Abstract
Cardiovascular physiology exhibits time-of-day-dependent oscillations, which are mediated by both extrinsic (e.g., environment/behavior) and intrinsic (e.g., circadian clock) factors. Disruption of circadian rhythms negatively affects multiple cardiometabolic parameters. Recent studies suggest that the cardiomyocyte circadian clock directly modulates responsiveness of the heart to metabolic stimuli (e.g., fatty acids) and stresses (e.g., ischemia/reperfusion). The aim of this study was to determine whether genetic disruption of the cardiomyocyte circadian clock impacts insulin-regulated pathways in the heart. Genetic disruption of the circadian clock in cardiomyocyte-specific Bmal1 knockout (CBK) and cardiomyocyte-specific Clock mutant (CCM) mice altered expression (gene and protein) of multiple insulin signaling components in the heart, including p85α and Akt. Both baseline and insulin-mediated Akt activation was augmented in CBK and CCM hearts (relative to littermate controls). However, insulin-mediated glucose utilization (both oxidative and non-oxidative) and AS160 phosphorylation were attenuated in CBK hearts, potentially secondary to decreased Inhibitor-1. Consistent with increased Akt activation in CBK hearts, mTOR signaling was persistently increased, which was associated with attenuation of autophagy, augmented rates of protein synthesis, and hypertrophy. Importantly, pharmacological inhibition of mTOR (rapamycin; 10days) normalized cardiac size in CBK mice. These data suggest that disruption of cardiomyocyte circadian clock differentially influences insulin-regulated processes, and provide new insights into potential pathologic mediators following circadian disruption.
•Cardiomyocyte clock disruption differentially influences insulin signaling proteins.•Cardiomyocyte clock disruption attenuates glucose utilization.•Cardiomyocyte clock disruption attenuates autophagy.•Cardiomyocyte clock disruption augments protein synthesis.
Details
- Title: Subtitle
- Genetic disruption of the cardiomyocyte circadian clock differentially influences insulin-mediated processes in the heart
- Creators
- Graham R McGinnis - Division of Cardiovascular Disease, Department of Medicine, University of Alabama at Birmingham, Birmingham, AL, USAYawen Tang - Division of Cardiovascular Disease, Department of Medicine, University of Alabama at Birmingham, Birmingham, AL, USARachel A Brewer - Division of Cardiovascular Disease, Department of Medicine, University of Alabama at Birmingham, Birmingham, AL, USAManoja K Brahma - Division of Molecular Cellular Pathology, Department of Pathology, University of Alabama at Birmingham, Birmingham, AL, USAHaley L Stanley - Division of Cardiovascular Disease, Department of Medicine, University of Alabama at Birmingham, Birmingham, AL, USAGobinath Shanmugam - Division of Molecular Cellular Pathology, Department of Pathology, University of Alabama at Birmingham, Birmingham, AL, USANamakkal Soorappan Rajasekaran - Division of Molecular Cellular Pathology, Department of Pathology, University of Alabama at Birmingham, Birmingham, AL, USAGlenn C Rowe - Division of Cardiovascular Disease, Department of Medicine, University of Alabama at Birmingham, Birmingham, AL, USAStuart J Frank - Department of Medicine, Division of Endocrinology, Diabetes, and Metabolism, University of Alabama at Birmingham, Birmingham, AL, USAAdam R Wende - Division of Molecular Cellular Pathology, Department of Pathology, University of Alabama at Birmingham, Birmingham, AL, USAE. Dale Abel - Division of Endocrinology and Metabolism, Department of Medicine and Fraternal Order of Eagles Diabetes Research Center, University of Iowa, Iowa City, IA, USAHeinrich Taegtmeyer - Division of Cardiology, Department of Internal Medicine, McGovern Medical School UT Health Science Center, Houston, TX, USASilvio Litovsky - Division of Molecular Cellular Pathology, Department of Pathology, University of Alabama at Birmingham, Birmingham, AL, USAVictor Darley-Usmar - Division of Molecular Cellular Pathology, Department of Pathology, University of Alabama at Birmingham, Birmingham, AL, USAJianhua Zhang - Division of Molecular Cellular Pathology, Department of Pathology, University of Alabama at Birmingham, Birmingham, AL, USAJohn C Chatham - Division of Molecular Cellular Pathology, Department of Pathology, University of Alabama at Birmingham, Birmingham, AL, USAMartin E Young - Division of Cardiovascular Disease, Department of Medicine, University of Alabama at Birmingham, Birmingham, AL, USA
- Resource Type
- Journal article
- Publication Details
- Journal of molecular and cellular cardiology, Vol.110, pp.80-95
- DOI
- 10.1016/j.yjmcc.2017.07.005
- PMID
- 28736261
- PMCID
- PMC5586500
- NLM abbreviation
- J Mol Cell Cardiol
- ISSN
- 0022-2828
- eISSN
- 1095-8584
- Publisher
- Elsevier Ltd
- Grant note
- DOI: 10.13039/100000050, name: National Heart, Lung, and Blood Institute, award: HL106199, HL074259, HL123574, HL122975, HL118067; DOI: 10.13039/100000062, name: National Institute of Diabetes and Digestive and Kidney Diseases, award: DK107441; name: Veterans Association, award: 5 I01 BX003718; DOI: 10.13039/100008333, name: UAB; DOI: 10.13039/100000002, name: National Institutes of Health, award: T32HD071866; DOI: 10.13039/100000968, name: American Heart Association, award: 16POST27010009
- Language
- English
- Date published
- 09/2017
- Academic Unit
- Roy J. Carver Department of Biomedical Engineering; Fraternal Order of Eagles Diabetes Research Center; Biochemistry and Molecular Biology; Endocrinology and Metabolism; Internal Medicine
- Record Identifier
- 9984025264902771
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