Impact of circadian time of dosing on cardiac-autonomous effects of glucocorticoids

Abstract

Bioenergetic capacity is critical to adapt the high energy demand of the heart to circadian oscillations and diseased states. Glucocorticoids regulate the circadian cycle of energy metabolism, but little is known about how circadian timing of exogenous glucocorticoid dosing directly regulates cardiac bioenergetics through the primary receptor of these drugs, the glucocorticoid receptor (GR). While chronic once-daily intake of glucocorticoids promotes metabolic stress and heart failure, we recently discovered that intermittent once-weekly dosing of exogenous glucocorticoids promoted muscle metabolism and heart function in dystrophic mice. However, the effects of glucocorticoid intermittence on heart failure beyond muscular dystrophy remain unknown. Here we investigated the extent to which circadian time of dosing regulates the cardiac-autonomous effects of the glucocorticoid prednisone in conditions of single pulse or chronic intermittent dosing. In WT mice, we found that prednisone improved cardiac content of NAD⁺ and ATP with light-phase dosing (ZT0), while the effects were blocked by dark-phase dosing (ZT12). The effects on mitochon-drial function were cardiomyocyte-autonomous, as shown by inducible cardiomyocyte-restricted GR ablation, and depended on an intact activating clock complex, as shown by hearts from BMAL1-KO mice. Conjugating time-of-dosing with chronic intermittence, we found that once-weekly light-phase prednisone improved metabolism and function in heart after myocardial injury. Our study identifies cardiac-autonomous mechanisms through which circadian time and chronic intermittence reconvert glucocorticoid drugs to bioenergetic boosters for the heart.