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

摘要

Mia S, Kane MS, Latimer MN, Reitz CJ, Sonkar R, Benavides GA, Smith SR, Frank SJ, Martino TA, Zhang J, Darley-Usmar VM, Young ME. Differential effects of REV-ERBa/p agonism on cardiac gene expression, metabolism, and contractile function in a mouse model of circadian disruption. Am J Physiol Heart Circ Physiol 318: H1487-H1508, 2020. First published May 1, 2020; doi:10.1152/ajp-heart.00709.2019.—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 transcrip-tional 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 mito-chondrial 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~-1.day~-1 for 8 days). SR-9009 administration was sufficient to normalize cardiac gly-cogen 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. NEW NOTEWORTHY 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). 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 highlight decreased REV-ERBα/β as a mediator of glycogen synthesis, cardiomyocyte size, interstitial fibrosis, and contractile function abnormalities observed in CBK hearts.