Despite improvements in clinical treatments, cardiovascular disease (CVD) remains the primary cause of mortality in the United States. CVDs, as with multiple common diseases, are the product of a complex gene- environment interaction, wherein genetic information intrinsically influences the responsiveness of an individual to environmental stimuli/stresses. We have recently highlighted the cardiomyocyte circadian clock as a cell autonomous molecular mechanism that facilitates temporally-appropriate cardiac responses to various stimuli/stresses (e.g., epinephrine, fatty acids, pro-hypertrophic stimuli). Disruption of the circadian clock mechanism, through either genetic (e.g., polymorphisms in clock component genes) or environmental (e.g., shift work, sleep and eating behavior modulation) means, is associated with increased CVD risk in humans. Recently, we have observed development of dilated cardiomyopathy (and reduced lifespan) in mice following cardiomyocyte-restricted deletion of the circadian clock transcription factor BMAL1 (termed CBK mice). Transcriptome and bioinformatic approaches (in young mice, prior to cardiac pathology) identified 9 putative direct BMAL1 target genes. Subsequent validation studies confirmed that BMAL1 directly binds to multiple E- boxes in the Pik3r1 (p85? regulatory subunit of PI3K) promoter, resulting in time-of-day-dependent oscillations in mRNA and protein levels of this insulin signaling component in control, but not CBK, hearts. Our preliminary studies also suggest impaired myocardial insulin signaling following cardiomyocyte circadian clock disruption, and that circadian clock dysfunction observed in Zucker Diabetic Fatty rat hearts (an obesity and type 2 diabetes model) is partially normalized through time-of-day-dependent restricted feeding. Collectively, these observations have led us to hypothesize that the cardiomyocyte circadian clock modulates myocardial insulin sensitivity in a time-of-day-dependent manner (through regulation of p85?), and that dysfunction of the clock following diet-induced obesity disrupts myocardial insulin signaling, thereby contributing to contractile dysfunction. The following specific aims will test this hypothesis: 1) Determine whether the cardiomyocyte circadian clock modulates myocardial insulin signaling and critical insulin- mediated processes (e.g., metabolism, autophagy) in a time-of-day-dependent manner;2) Determine the mechanism for cardiomyopathy in BMAL1 deficient hearts by testing the hypothesis that dysfunction is secondary to decreased p85?;and 3) Determine if normalization of the cardiomyocyte circadian clock will attenuate cardiac contractile dysfunction in a mouse model of insulin resistance (i.e., diet-induced obesity). Successful completion of the proposed studies will likely identify the cardiomyocyte circadian clock as a novel intrinsic mechanism that modulates myocardial insulin sensitivity, and provide a foundation for future translational studies targeting the cardiomyocyte circadian clock for obesity/diabetic cardiomyopathy prevention and/or treatment.
Previous studies have established close links between perturbations in cardiac insulin signaling and contractile dysfunction of the heart during obesity and diabetes. Our preliminary studies have identified a putative novel mechanism (i.e., the cardiomyocyte circadian clock) that directly regulates cardiac insulin signaling, and we provide evidence suggesting that this mechanism is dysfunctional in the heart during obesity and type 2 diabetes. Successful completion of the proposed studies will likely provide a foundation for future translational studies targeting the cardiomyocyte circadian clock for obesity/diabetic cardiomyopathy prevention and/or treatment.
|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|