Circadian Mechanisms Governing Cardiac Growth - The incidences of co-morbidities, such as obesity and diabetes, continue to rise, undoubtedly contributing to increased cardiovascular disease. This includes rising cases of heart failure (particularly HFpEF), for which in-depth understanding of the mechanisms involved in disease etiology, as well as treatment strategies, remain unmet needs. With respect to the current application, cardiac processes fluctuate dramatically over the course of the day, at molecular, cellular, and organ levels; these rhythms are mediated in large part by the cardiomyocyte circadian clock. We have recently unveiled the beginning of the sleep phase as a period of accelerated cellular constituent turnover, which is critical for cardiac growth and repair. Significance of this phenomenon is underscored by realization that cardiac growth only occurs when the heart is acutely challenged with prohypertrophic stimuli/stresses at the beginning of the sleep period. Moreover, repetitive challenge of the heart with a prohypertrophic stimulus at the beginning of the sleep period accelerates adverse cardiac remodeling and contractile dysfunction in models of heart disease. These studies highlight the importance of temporally coordinating extra-cardiac (e.g., behaviors) and intra-cardiac (e.g., circadian clocks) influences for the maintenance of normal cardiac function. The precise mechanisms promoting cardiac growth at the beginning of the sleep period remain unknown. Here, we provide evidence in support of two distinct contributing mechanisms. Our studies suggest that the cardiomyocyte circadian clock augments branched chain amino acid (BCAA) catabolism in the middle of the active period, when cardiac protein synthesis is lowest. This has led us to hypothesize that increased BCAA catabolism limits BCAA-mediated activation of mTOR and cardiac protein synthesis during the active period (Aim 1). We also provide evidence that the cardiomyocyte circadian clock activates the integrated stress response (ISR; an established translation inhibitor) in the middle of the active period. These data have led us to hypothesize that ISR activation during the active period attenuates cardiac protein synthesis at this time (Aim 2). Surprisingly, 24hr rhythms in cardiac growth appear to be antiphase during HFpEF, peaking during the active period, leading to the hypothesis that aberrant 24hr rhythms in growth mechanisms contribute to adverse cardiac remodeling and HFpEF development during cardiometabolic diseases (Aim 3). Collectively, these novel observations have led to the overarching hypothesis that temporal governance of pathways orchestrating cardiac growth (BCAA signaling and ISR) are impaired during cardiometabolic disease, leading to adverse remodeling of the myocardium, such that reinstatement of normal rhythms will attenuate HFpEF development. Successful completion of the proposed studies will reveal the mechanisms temporally governing cardiac growth, the extent to which these rhythms are impacted by cardiometabolic disease, and the efficacy of chronopharmacologic strategies for the treatment of HFpEF.
