Abstract P3035: Time-of-intake Regulates Glucocorticoid Effects On Heart Metabolism And Function Through Cardiomyocyte-autonomous Mechanisms

Abstract

Glucocorticoids are circadian regulators of energy balance. However, the cardiomyocyte-autonomous mechanisms of glucocorticoid action on heart metabolism remain unresolved. Also, little attention is given to the impact of circadian time of intake on the effects of these drugs in heart. Here, we investigated whether circadian time of exposure gates the effects of synthetic glucocorticoids on heart metabolism and function. In single pulse experiments, we compared the effects of the glucocorticoid prednisone in wildtype (WT) hearts through light-phase- versus dark-phase-specific injections. Light-phase pulse - but not dark-phase pulse - increased NAD + and ATP levels in murine hearts in vivo for one circadian cycle post-pulse. To ask whether this effect was replicated in chronic treatment, we used the intermittent once-weekly prednisone regimen that we previously used to boost muscle metabolism without the wasting and metabolic toxicity caused by once-daily dosing. In WT mice treated for 12 weeks with once-weekly prednisone, light-phase-specific dosing gated the positive effects of treatment on NAD + , mitochondrial respiration and abundance in heart, as compared to dark-phase-specific dosing. These processes were cardiomyocyte-autonomous as the circadian-specific treatment effects were blocked by inducible cardiomyocyte-specific ablation of the glucocorticoid receptor. To probe relevance of this treatment for the injured heart, we treated mice after induction of ischemic injury. Light-phase-specific prednisone treatment significantly improved NAD + , mitochondrial function and systolic function in injured hearts. RNA-seq showed that treatment elicited a virtuous gene program of circadian metabolism in the myocardium. Indeed, the effects of treatment on heart metabolism gene cascades were dependent on the intact heart peripheral clock, as shown by mice with inducible cardiomyocyte-specific ablation of the clock factor BMAL1. In summary, our data indicate that glucocorticoids regulate cardiomyocyte metabolism in a cell-autonomous fashion hinging upon circadian-time of intake and interaction with the peripheral clock. Our work supports a role for chrono-pharmacology of ischemic heart disease with glucocorticoids.