Abstract
RationaleThe E2F pathway plays a critical role in cardiac growth and development, yet its role in cardiac metabolism remains to be defined. Metabolic changes play important roles in human heart failure and studies imply the ketogenic enzyme β-hydroxybutyrate dehydrogenase I (BDH1) is a potential biomarker.ObjectiveTo define the role of the E2F pathway in cardiac metabolism and dilated cardiomyopathy (DCM) with a focus on BDH1.Methods and ResultsWe previously developed transgenic (Tg) mice expressing the transcriptional repressor, E2F6, to interfere with the E2F/Rb pathway in post-natal myocardium. These Tg mice present with an E2F6 dose dependent DCM and deregulated connexin-43 (CX-43) levels in myocardium. Using the Seahorse platform, a 22% decrease in glycolysis was noted in neonatal cardiomyocytes isolated from E2F6-Tg hearts. This was associated with a 39% reduction in the glucose transporter GLUT4 and 50% less activation of the regulator of glucose metabolism AKT2. The specific reduction of cyclin B1 (70%) in Tg myocardium implicates its importance in supporting glycolysis in the postnatal heart. No changes in cyclin D expression (known to regulate mitochondrial activity) were noted and lipid metabolism remained unchanged in neonatal cardiomyocytes from Tg hearts. However, E2F6 induced a 40-fold increase of the Bdh1 transcript and 890% increase in its protein levels in hearts from Tg pups implying a potential impact on ketolysis. By contrast, BDH1 expression is not activated until adulthood in normal myocardium. Neonatal cardiomyocytes from Wt hearts incubated with the ketone β-hydroxybutyrate (β-OHB) showed a 100% increase in CX-43 protein levels, implying a role for ketone signaling in gap junction biology. Neonatal cardiomyocyte cultures from Tg hearts exhibited enhanced levels of BDH1 and CX-43 and were not responsive to β-OHB.ConclusionsThe data reveal a novel role for the E2F pathway in regulating glycolysis in the developing myocardium through a mechanism involving cyclin B1. We reveal BDH1 expression as an early biomarker of heart failure and its potential impact, through ketone signaling, on CX-43 levels in E2F6-induced DCM.
Highlights
The failing heart shows transcriptional and metabolic remodeling which may have detrimental effects on cardiac function[1,2]
The data reveal a novel role for the E2F pathway in regulating glycolysis in the developing myocardium through a mechanism involving cyclin B1
We reveal BDH1 expression as an early biomarker of heart failure and its potential impact, through ketone signaling, on CX-43 levels in E2F6-induced dilated cardiomyopathy (DCM)
Summary
The failing heart shows transcriptional and metabolic remodeling which may have detrimental effects on cardiac function[1,2]. Given the extensive energy requirements of the heart, and its limited ATP reserve, understanding the mechanisms which regulate cardiac metabolism is critical to the understanding of heart function and failure [3,4]. In the normal adult heart, fatty acid oxidation accounts for up to 90% of the ATP production while glycolysis supplies the remainder [5]. The heart shows a remarkable capacity to adapt to substrate utilization under stress. A reduction of fatty acid oxidation and changes in glycolysis are observed [5,6]. It was recently demonstrated that there is an increase in ketone metabolism and the ketogenic enzyme, β-hydroxybutyrate dehydrogenase 1 (BDH1), in human and mouse heart failure [7,8,9,10]
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