Differential effects of REV-ERBα/β agonism on cardiac gene expression, metabolism, and contractile function in a mouse model of circadian disruption

May 2, 2020American journal of physiology. Heart and circulatory physiology

REV-ERBα/β activators differently affect heart gene activity, metabolism, and pumping in mice with disrupted daily rhythms

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Abstract

Administration of the selective REV-ERBα/β agonist SR-9009 normalized several cardiac parameters in cardiomyocyte-specific BMAL1-knockout mice.

CBK mice displayed a dysfunctional circadian clock, characterized by reduced REV-ERBα/β expression and associated cardiac abnormalities.
Decreased REV-ERBα/β activity may contribute to distinct phenotypical alterations in CBK hearts.
SR-9009 treatment improved cardiac glycogen synthesis rates and contractility in CBK hearts.
Cardiomyocyte size and interstitial fibrosis were also normalized following SR-9009 administration.
No significant effects were observed on mitochondrial complex activities or substrate oxidation in treated CBK hearts.

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Cell-autonomous circadian clocks have emerged as temporal orchestrators of numerous biological processes. For example, the cardiomyocyte circadian clock modulates transcription, translation, posttranslational modifications, ion homeostasis, signaling cascades, metabolism, and contractility of the heart over the course of the day. Circadian clocks are composed of more than 10 interconnected transcriptional modulators, all of which have the potential to influence the cardiac transcriptome (and ultimately cardiac processes). These transcriptional modulators include BMAL1 and REV-ERBα/β; BMAL1 induces REV-ERBα/β, which in turn feeds back to inhibit BMAL1. Previous studies indicate that cardiomyocyte-specific BMAL1-knockout (CBK) mice exhibit a dysfunctional circadian clock (including decreased REV-ERBα/β expression) in the heart associated with abnormalities in cardiac mitochondrial function, metabolism, signaling, and contractile function. Here, we hypothesized that decreased REV-ERBα/β activity is responsible for distinct phenotypical alterations observed in CBK hearts. To test this hypothesis, CBK (and littermate control) mice were administered with the selective REV-ERBα/β agonist SR-9009 (100 mg·kg·dayfor 8 days). SR-9009 administration was sufficient to normalize cardiac glycogen synthesis rates, cardiomyocyte size, interstitial fibrosis, and contractility in CBK hearts (without influencing mitochondrial complex activities, nor normalizing substrate oxidation and Akt/mTOR/GSK3β signaling). Collectively, these observations highlight a role for REV-ERBα/β as a mediator of a subset of circadian clock-controlled processes in the heart. -1 -1

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Differential effects of REV-ERBα/β agonism on cardiac gene expression, metabolism, and contractile function in a mouse model of circadian disruption

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