The heart is a highly metabolic organ that uses multiple energy sources to meet its demand for ATP production. Diurnal feeding-fasting cycles result in substrate availability fluctuations which, together with increased energetic demand during the active period, impose a need for rhythmic cardiac metabolism. The nuclear receptors REV-ERBα and β are essential repressive components of the molecular circadian clock and major regulators of metabolism. To investigate their role in the heart, here we generated mice with cardiomyocyte (CM)-specific deletion of both Rev-erb s, which died prematurely due to dilated cardiomyopathy. Loss of Rev-erbs markedly downregulated fatty acid oxidation genes prior to overt pathology, which was mediated by induction of the transcriptional repressor E4BP4, a direct target of cardiac REV-ERBs. E4BP4 directly controls circadian expression of Nampt and its biosynthetic product NAD + via distal cis -regulatory elements. Thus, REV-ERB-mediated E4BP4 repression is required for Nampt expression and NAD + production by the salvage pathway. Together, these results highlight the indispensable role of circadian REV-ERBs in cardiac gene expression, metabolic homeostasis and function.

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Evidence suggests that mitochondrial network integrity is impaired in cardiomyocytes from failing hearts. While oxidative stress has been implicated in heart failure (HF)-associated mitochondrial remodeling, the effect of mitochondrial-targeted antioxidants, such as mitoquinone (MitoQ), on the mitochondrial network in a model of HF (e.g., pressure overload) has not been demonstrated. Furthermore, the mechanism of this regulation is not completely understood with an emerging role for posttranscriptional regulation via long noncoding RNAs (lncRNAs). We hypothesized that MitoQ preserves mitochondrial fusion proteins (i.e., mitofusin), likely through redox-sensitive lncRNAs, leading to improved mitochondrial network integrity in failing hearts. To test this hypothesis, 8-wk-old C57BL/6J mice were subjected to ascending aortic constriction (AAC), which caused substantial left ventricular (LV) chamber remodeling and remarkable contractile dysfunction in 1 wk. Transmission electron microscopy and immunostaining revealed defective intermitochondrial and mitochondrial-sarcoplasmic reticulum ultrastructure in AAC mice compared with sham-operated animals, which was accompanied by elevated oxidative stress and suppressed mitofusin (i.e., Mfn1 and Mfn2) expression. MitoQ (1.36 mg·day−1·mouse−1, 7 consecutive days) significantly ameliorated LV dysfunction, attenuated Mfn2 downregulation, improved interorganellar contact, and increased metabolism-related gene expression. Moreover, our data revealed that MitoQ alleviated the dysregulation of an Mfn2-associated lncRNA (i.e., Plscr4). In summary, the present study supports a unique mechanism by which MitoQ improves myocardial intermitochondrial and mitochondrial-sarcoplasmic reticulum (SR) ultrastructural remodeling in HF by maintaining Mfn2 expression via regulation by an lncRNA. These findings underscore the important role of lncRNAs in the pathogenesis of HF and the potential of targeting them for effective HF treatment. NEW & NOTEWORTHY We have shown that MitoQ improves cardiac mitochondrial network integrity and mitochondrial-SR alignment in a pressure-overload mouse heart-failure model. This may be occurring partly through preventing the dysregulation of a redox-sensitive lncRNA-microRNA pair (i.e., Plscr4-miR-214) that results in an increase in mitofusin-2 expression.

An intrinsic property of the heart is an ability to rapidly and coordinately adjust flux through metabolic pathways in response to physiologic stimuli (termed metabolic flexibility). Cardiac metabolism also fluctuates across the 24‐hours day, in association with diurnal sleep‐wake and fasting‐feeding cycles. Although loss of metabolic flexibility has been proposed to play a causal role in the pathogenesis of cardiac disease, it is currently unknown whether day‐night variations in cardiac metabolism are altered during disease states. Here, we tested the hypothesis that diet‐induced obesity disrupts cardiac “diurnal metabolic flexibility”, which is normalized by time‐of‐day‐restricted feeding. Chronic high fat feeding (20‐wk)‐induced obesity in mice, abolished diurnal rhythms in whole body metabolic flexibility, and increased markers of adverse cardiac remodeling (hypertrophy, fibrosis, and steatosis). RNAseq analysis revealed that 24‐hours rhythms in the cardiac transcriptome were dramatically altered during obesity; only 22% of rhythmic transcripts in control hearts were unaffected by obesity. However, day‐night differences in cardiac substrate oxidation were essentially identical in control and high fat fed mice. In contrast, day‐night differences in both cardiac triglyceride synthesis and lipidome were abolished during obesity. Next, a subset of obese mice (induced by 18‐wks ad libitum high fat feeding) were allowed access to the high fat diet only during the 12‐hours dark (active) phase, for a 2‐wk period. Dark phase restricted feeding partially restored whole body metabolic flexibility, as well as day‐night differences in cardiac triglyceride synthesis and lipidome. Moreover, this intervention partially reversed adverse cardiac remodeling in obese mice. Collectively, these studies reveal diurnal metabolic inflexibility of the heart during obesity specifically for nonoxidative lipid metabolism (but not for substrate oxidation), and that restricting food intake to the active period partially reverses obesity‐induced cardiac lipid metabolism abnormalities and adverse remodeling of the heart.

Methionine restriction (MR) has been studied extensively over the last 25 years for its role in altering metabolic hallmarks of disease. Animals subjected to MR, display changes in metabolic flexibility demonstrated by increases in energy expenditure, glucose tolerance, and lifespan. These changes have been well characterized in a number of model systems and significant progress has been made in understanding how hepatic fibroblast growth factor 21 links MR to several components of its metabolic phenotype. Despite these advances, a complete understanding of mechanisms engaged by dietary MR remains elusive. In this review, we offer a brief history of MR and its known mechanisms associated with stress, metabolism, and lifespan extension. We consider the role of epigenetics in the response of animals to MR and propose a novel epigenetic pathway involving the regulation of microRNAs during MR.