Humans exhibit marked circadian rhythms in multiple cardiovascular (CV) parameters, including heart rate, cardiac output, and blood pressure. To date, circadian rhythms in physiological CV parameters have been attributed to the same neurohumoral stimuli (e.g. sympathetic activity) believed to be responsible for fatal CV events (e.g. myocardial infarctions, arrhythmias, and sudden cardiac death). Our studies expose a novel molecular mechanism within cardiomyocytes that directly regulates myocardial gene expression, metabolism, and function over the course of the day. This mechanism is the intramyocellular circadian clock. Circadian clocks are transcriptionally-based mechanisms that confer the selective advantage of anticipation, enabling the cardiomyocyte/heart to respond rapidly and appropriately to environmental stimuli upon their onset. The broad objective of this proposal is to test the hypothesis that the circadian clock within the cardiomyocyte synchronizes responsiveness of the heart to the environment, and that impairment of this mechanism results in an inability of the heart to respond appropriately to its environment (i.e. maladaptation). Altered myocardial metabolism plays a central role in the pathogenesis of contractile dysfunction associated with hypertrophic, diabetic, and ischemic heart disease, conditions in which the circadian clock within the cardiomyocyte is impaired. We therefore intend to address the following specific aims: 1) identify the mechanisms by which the circadian clock within the cardiomyocyte modulates myocardial metabolism;and 2) determine the pathophysiological consequences of impairment of the circadian clock within the cardiomyocyte. For these studies, we will utilize our unique mouse model in which the circadian clock is specifically impaired within cardiomyocytes.
For Specific Aim 1, we will utilize isolated working mouse hearts to identify the mechanisms by which the circadian clock within the cardiomyocyte channels fatty acids and glucose into oxidative versus non-oxidative pathways.
For Specific Aim 2, we will investigate whether impairment of the circadian clock within the cardiomyocyte augments ischemia/reperfusion-, diabetes mellitus-, pressure overload-, aging-, and/or simulated shift work- mediated contractile dysfunction. Our long-term objectives are to establish causal links between impairment of the circadian clock within the cardiomyocyte with development of CV disease in humans.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL074259-09
Application #
8013811
Study Section
Myocardial Ischemia and Metabolism Study Section (MIM)
Program Officer
Evans, Frank
Project Start
2003-07-01
Project End
2013-01-31
Budget Start
2011-02-01
Budget End
2012-01-31
Support Year
9
Fiscal Year
2011
Total Cost
$366,250
Indirect Cost
Name
University of Alabama Birmingham
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
063690705
City
Birmingham
State
AL
Country
United States
Zip Code
35294
Young, Martin E (2016) Temporal partitioning of cardiac metabolism by the cardiomyocyte circadian clock. Exp Physiol 101:1035-9
Peliciari-Garcia, Rodrigo A; Goel, Mehak; Aristorenas, Jonathan A et al. (2016) Altered myocardial metabolic adaptation to increased fatty acid availability in cardiomyocyte-specific CLOCK mutant mice. Biochim Biophys Acta 1860:1579-95
McGinnis, Graham R; Young, Martin E (2016) Circadian regulation of metabolic homeostasis: causes and consequences. Nat Sci Sleep 8:163-80
Martino, Tami A; Young, Martin E (2015) Influence of the cardiomyocyte circadian clock on cardiac physiology and pathophysiology. J Biol Rhythms 30:183-205
Bailey, Shannon M; Udoh, Uduak S; Young, Martin E (2014) Circadian regulation of metabolism. J Endocrinol 222:R75-96
Podobed, Peter; Pyle, W Glen; Ackloo, Suzanne et al. (2014) The day/night proteome in the murine heart. Am J Physiol Regul Integr Comp Physiol 307:R121-37
Young, Martin E; Brewer, Rachel A; Peliciari-Garcia, Rodrigo A et al. (2014) Cardiomyocyte-specific BMAL1 plays critical roles in metabolism, signaling, and maintenance of contractile function of the heart. J Biol Rhythms 29:257-76
Gamble, Karen L; Berry, Ryan; Frank, Stuart J et al. (2014) Circadian clock control of endocrine factors. Nat Rev Endocrinol 10:466-75
Tsai, Ju-Yun; Villegas-Montoya, Carolina; Boland, Brandon B et al. (2013) Influence of dark phase restricted high fat feeding on myocardial adaptation in mice. J Mol Cell Cardiol 55:147-55
Bray, M S; Ratcliffe, W F; Grenett, M H et al. (2013) Quantitative analysis of light-phase restricted feeding reveals metabolic dyssynchrony in mice. Int J Obes (Lond) 37:843-52

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