Myocardial Rev-erb-mediated diurnal metabolic rhythm( Part1/3)
Ontology highlight
ABSTRACT:
ORGANISM(S): Mouse Mus Musculus
TISSUE(S): Heart
SUBMITTER: 
Shiyang Song
PROVIDER: ST001915 | MetabolomicsWorkbench | Fri Sep 10 00:00:00 BST 2021
REPOSITORIES: MetabolomicsWorkbench
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Project description:Agonists and antagonists of nuclear receptor Rev-erbα/β, key components of the circadian clock, can benefit the heart. Here, we show that mice with cardiomyocyte-specific knockout (KO) of Rev-erbα/β display progressive cardiac dilation and lethal heart failure. Inducible ablation of Rev-erbα/β in adult hearts causes similar phenotypes. Impaired fatty acid oxidation in the KO myocardium, particularly in the light cycle, precedes contractile dysfunctions with a reciprocal overreliance on carbohydrate utilization, particularly in the dark cycle. These findings delineate temporal coordination between clock-mediated anticipation and nutrient-induced response in myocardial metabolism.
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Project description:Ongoing cardiomyocyte injury is a major mechanism in the progression of heart failure, particularly in dystrophic hearts. Due to the poor regenerative capacity of the adult heart, cardiomyocyte death results in the permanent loss of functional myocardium. Understanding the factors contributing to myocyte injury is essential for the development of effective heart failure therapies. As a model of persistent cardiac injury, we examined mice lacking β-sarcoglycan (β-SG), a key component of the dystrophin glycoprotein complex (DGC). The loss of the sarcoglycan complex markedly compromises sarcolemmal integrity in this β-SG-/- model. Our studies aim to characterize the mechanisms underlying dramatic sex differences in susceptibility to cardiac injury in β-SG-/- mice. Male β-SG-/- hearts display significantly greater myocardial injury and death following isoproterenol-induced cardiac stress than female β-SG-/- hearts. This protection of females was independent of ovarian hormones. Male β-SG-/- hearts displayed increased susceptibility to exogenous oxidative stress and were significantly protected by angiotensin II type 1 receptor (AT1R) antagonism. Increasing general antioxidative defenses or increasing the levels of S-nitrosylation both provided protection to the hearts of β-SG-/- male mice. Here we demonstrate that increased susceptibility to oxidative damage leads to an AT1R-mediated amplification of workload-induced myocardial injury in male β-SG-/- mice. Improving oxidative defenses, specifically by increasing S-nitrosylation, provided protection to the male β-SG-/- heart from workload-induced injury. These studies describe a unique susceptibility of the male heart to injury and may contribute to the sex differences in other forms of cardiac injury.
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Project description:Circadian clocks are cell autonomous, transcriptionally-based, molecular mechanisms that confer the selective advantage of anticipation, enabling cells/organs to respond to environmental factors in a temporally appropriate manner. Critical to circadian clock function are two transcription factors, CLOCK and BMAL1. Previous studies in our laboratory have highlighted roles for CLOCK in cardiac physiology/pathophysiology. Here, we describe transcriptional, metabolic, and functional consequences of cardiomyocyte-specific Bmal1 knockout (CBK). Microarray analysis revealed 2037 differentially expressed genes in CBK hearts, many of which were previously identified in cardiomyocyte-specific Clock mutant (CCM) hearts. Subsequent analysis showed that Beta-hydroxybutyrate dehydrogenase 1 mRNA, protein, and enzymatic activity are markedly depressed in both CBK and CCM hearts, as is myocardial Beta-hydroxybutyrate oxidation, revealing a novel role for the circadian clock in ketone body utilization. A number of genes encoding for collagen isoforms were identified as oscillating in a time-of-day-dependent manner in wild-type, but not CBK, hearts, including col3a1, col4a1, and col4a2. Chronic induction of collagen isoform genes in CBK hearts was associated with severe age-dependent depression of cardiac function. Development of cardiomyopathy in CBK mice was associated with early mortality; all CBK mice die by one year of age. These studies highlight novel critical functions for BMAL1 in the heart, including regulation of ketone body metabolism and the extracellular matrix. RNA from whole hearts collected every 3 hours for 24 hours from wildtype and CBK mice was isolated and analyzed using MouseRef-8_V2 BeadChips (Illumina, Inc.). The 24-hour data were examined for rhythmicity using cosinor analysis and differences in rhythmicity between genotype groups were further examined for differences in the model fitting parameters.
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Project description:CCBE1 is a secreted extracellular matrix protein expressed by epicardial cells but its role during epicardial development was still unknown.Using a Ccbe1 knockout (KO) mouse model, we observed that loss of CCBE1 leads to congenital heart defects including thinner and hyper-trabeculated ventricular myocardium. In addition, Ccbe1 mutant hearts displayed reduced proliferation of cardiomyocyte and epicardial cells. RNA-seq data of CCBE1 KO and WT murine hearts indicated deregulation of genes associated with development and morphogenesis including the epithelial-to-mesenchymal transition.
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