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

Wintzinger, Michelle; Panta, Manoj; Miz, Karen; Prabakaran, Ashok D.; Durumutla, Hima Bindu; Sargent, Michelle A.; Peek, Clara Bien; Bass, Joseph; Molkentin, Jeffery D; Quattrocelli, Mattia

doi:10.1016/j.molmet.2022.101528

Cited by 4 publications

(13 citation statements)

References 66 publications

(99 reference statements)

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“…In prior published work, we reported that circadian time-of-intake gated the cardioprotective effects of the glucocorticoid prednisone in infarcted murine hearts [11]. Through subsequent analysis of the RNA-seq datasets obtained from uninjured (sham-operated) myocardial tissues from that study (GSE186875), we found that compared to vehicle control ZT0 intermittent prednisone (once-weekly i.p.…”

Section: Resultsmentioning

confidence: 87%

“…Recent studies unveil two temporal dimensions within GC pharmacology: circadian time-of-intake and chronic frequency-of-intake. Light-phase dosing of prednisone demonstrated benefits, contrasting with deleterious effects observed with dark-phase dosing [14]. Intermittent once-weekly prednisone dosing showed promise in reversing dysmetabolic effects [15].…”

Section: Introductionmentioning

confidence: 99%

“…GC intermittence appears applicable and potentially effective in humans, as suggested by pilot clinical data of exercise tolerance obtained from adult dystrophic patients [10]. Notably for the context of heart failure, a once-weekly 1mg/kg prednisone treatment partially rescued cardiac function and bioenergetics after myocardial infarction in mice [11]. Moreover, the Krüppel-like factor 15 (KLF15) is a glucocorticoid-responsive GR target and co-factor [12].…”

Section: Introductionmentioning

confidence: 99%

“…Furthermore, we recently reported that circadian time of intake determines the cardioprotective GC action in normal and infarcted hearts. Specifically, a single prednisone pulse induced pro-energetic effects in the myocardium when dosed in the light-phase (ZT0, lights-on) but not in the dark-phase (ZT12, lights-off) [11]. However, the molecular mediators of GC chrono-pharmacology remain unidentified.…”

Section: Introductionmentioning

confidence: 99%

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Light-phase prednisone promotes glucose oxidation in heart through novel transactivation targets of cardiomyocyte-specific GR and KLF15

Soussi,

Durumutla,

Latimer

et al. 2023

Preprint

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Circadian time of intake determines the cardioprotective outcome of glucocorticoids in normal and infarcted hearts. The cardiomyocyte-specific glucocorticoid receptor (GR) is genetically required to preserve normal heart function in the long-term. The GR co-factor KLF15 is a pleiotropic regulator of cardiac metabolism. However, the cardiomyocyte-autonomous metabolic targets of the GR-KLF15 concerted epigenetic action remain undefined. Here we report that circadian time of intake determines the activation of a transcriptional and functional glucose oxidation program in heart by the glucocorticoid prednisone with comparable magnitude between sexes. We overlayed transcriptomics, epigenomics and cardiomyocyte-specific inducible ablation of either GR or KLF15. Downstream of a light-phase prednisone stimulation in mice, we found that both factors are non-redundantly required in heart to transactivate the adiponectin receptor expression (Adipor1)and promote insulin-stimulated glucose uptake, as well as transactivate the mitochondrial pyruvate complex expression(Mpc1/2)and promote pyruvate oxidation. We then challenged this time-specific drug effect in obese diabeticdb/dbmice, where the heart shows insulin resistance and defective glucose oxidation. Opposite to dark-phase dosing, light-phase prednisone rescued glucose oxidation indb/dbcardiomyocytes and diastolic function indb/dbhearts towards control-like levels with sex-independent magnitude of effect. In summary, our study identifies novel cardiomyocyte-autonomous metabolic targets of the GR-KLF15 concerted program mediating the time-specific cardioprotective effects of glucocorticoids on cardiomyocyte glucose utilization.

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Section: Resultsmentioning

confidence: 87%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Light-phase prednisone promotes glucose oxidation in heart through novel transactivation targets of cardiomyocyte-specific GR and KLF15

Soussi,

Durumutla,

Latimer

et al. 2023

Preprint

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“…Our serendipitous identification of GR binding site enrichment in ZT12 open chromatin profiles for ion channels is significant for 2 reasons: not only does it highlight an unappreciated noncanonical clock TF mechanism that exerts significant regulatory control over day-night variation in the electrical activity of the heart but also presents the cardiac GR as a potential nodal regulator capable of transducing exogenous systemic signals to changes in the cardiac electrophysiological substrate in preparation for transition to activity in the awake period. Glucocorticoid release is clock-controlled, 83 and GR is regarded as a conduit between the suprachiasmatic master clock and the circadian clocks in peripheral tissues, supported by evidence that synthetic steroids can transiently modify mRNA expression of core circadian clock genes (Per1, Per2, Dbp, Clock, and Bmal1), [44][45][46] as well as GR function being modulated by the clock TFs CRY1/2 84 and CLOCK. 85 However, in this study, the GR block with RU486 did not impact rhythmic Bmal1 expression patterns (Figure 5D), and, in cardioGRKO hearts, key clock genes continued to show expected day-night rhythms, albeit with dampened amplitude in the case of Per and Clock genes (Figure 7D-7F).…”

Section: Discussionmentioning

confidence: 99%

Cardiac GR Mediates the Diurnal Rhythm in Ventricular Arrhythmia Susceptibility

Tikhomirov,

Oakley,

Anderson

et al. 2024

Circulation Research

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RATIONALE: Ventricular arrhythmias (VAs) demonstrate a prominent day-night rhythm, commonly presenting in the early morning. Transcriptional rhythms in cardiac ion channels accompany this phenomenon, but their role in the morning vulnerability to VAs and the underlying mechanisms are not understood. OBJECTIVE: The objectives are to investigate the recruitment of transcription factors to time-of-day differentially accessible chromatin that underpins day-night ion channel rhythms and to assess the significance of this for the heart’s day-night rhythm in VA susceptibility. METHODS AND RESULTS: Assay for transposase-accessible chromatin with sequencing performed in mouse ventricular myocyte nuclei at the beginning of the inactive (zeitgeber time, time of lights on, start of sleep period) and active (time of lights off, start of awake period [ZT12]) periods revealed differentially accessible chromatin sites annotating to rhythmically transcribed ion channels and transcription factor binding motifs in these regions. Notably, motif enrichment for the glucocorticoid receptor (GR; transcriptional effector of corticosteroid signaling) binding site in open chromatin profiles at ZT12 was observed, in line with the well-recognized ZT12 peak in circulating corticosteroids. Molecular, electrophysiological, and in silico biophysically detailed modeling approaches demonstrated GR-mediated transcriptional control of ion channels (including Scn5a underlying the cardiac Na + current, Kcnh2 underlying the rapid delayed rectifier K + current, and Gja1 responsible for electrical coupling) and their contribution to the day-night rhythm in the vulnerability to VA. Strikingly, both pharmacological block of GR and cardiomyocyte-specific genetic knockout of GR blunted or abolished ion channel expression rhythms and abolished the ZT12 susceptibility to pacing-induced VA in isolated hearts. CONCLUSIONS: Our study registers a day-night rhythm in chromatin accessibility that accompanies diurnal cycles in ventricular myocytes. Our approaches directly implicate the cardiac GR in the myocyte excitability rhythm and mechanistically link the ZT12 surge in glucocorticoids to intrinsic VA propensity at this time.

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