Abstract
Circadian rhythms are generated by cell autonomous circadian clocks that perform a ubiquitous cellular time-keeping function and cell type-specific functions important for normal physiology. Studies show inducing the deletion of the core circadian clock transcription factor Bmal1 in adult mouse cardiomyocytes disrupts cardiac circadian clock function, cardiac ion channel expression, slows heart rate, and prolongs the QT-interval at slow heart rates. This study determined how inducing the deletion of Bmal1 in adult cardiomyocytes impacted the in vivo electrophysiological phenotype of a knock-in mouse model for the arrhythmogenic long QT syndrome (Scn5a+/ΔKPQ). Electrocardiographic telemetry showed inducing the deletion of Bmal1 in the cardiomyocytes of mice with or without the ΔKPQ-Scn5a mutation increased the QT-interval at RR-intervals that were ≥130 ms. Inducing the deletion of Bmal1 in the cardiomyocytes of mice with or without the ΔKPQ-Scn5a mutation also increased the day/night rhythm-adjusted mean in the RR-interval, but it did not change the period, phase or amplitude. Compared to mice without the ΔKPQ-Scn5a mutation, mice with the ΔKPQ-Scn5a mutation had reduced heart rate variability (HRV) during the peak of the day/night rhythm in the RR-interval. Inducing the deletion of Bmal1 in cardiomyocytes did not affect HRV in mice without the ΔKPQ-Scn5a mutation, but it did increase HRV in mice with the ΔKPQ-Scn5a mutation. The data demonstrate that deleting Bmal1 in cardiomyocytes exacerbates QT- and RR-interval prolongation in mice with the ΔKPQ-Scn5a mutation.
Highlights
Circadian rhythms alter physiology in anticipation of predictable changes in the daily environment
Studies using transgenic mouse models that allow for the selective deletion of Bmal1 in adult cardiomyocytes show the cardiomyocyte circadian clock mechanism contributes to heart rate, ventricular repolarization and the functional expression of several cardiac ion channels (Schroder et al, 2013, 2015; Delisle et al, 2020)
Studies suggest that Bmal1 directly and indirectly contributes to the transcription of cardiac ion channel genes Scn5a, Kcnh2, Hcn4, and Kchip2 (Jeyaraj et al, 2012; Schroder et al, 2013, 2015; D’Souza et al, 2020)
Summary
Circadian rhythms alter physiology in anticipation of predictable changes in the daily environment They are generated by cell autonomous circadian clocks in most of the cells in the body (Reppert and Weaver, 2002; Hastings et al, 2018; Michel and Meijer, 2020). Circadian clocks are formed by transcription-translation feedback loops that drive rhythmic changes in clock gene and protein expression with a periodicity of ∼24 h (Hastings et al, 2018; Michel and Meijer, 2020). Studies using transgenic mouse models that allow for the selective deletion of Bmal in adult cardiomyocytes show the cardiomyocyte circadian clock mechanism contributes to heart rate, ventricular repolarization and the functional expression of several cardiac ion channels (Schroder et al, 2013, 2015; Delisle et al, 2020). We determined how inducing the deletion of Bmal in adult cardiomyocytes impacted cardiac electrophysiology in a genetic mouse model of long QT syndrome (LQTS)
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