Lethal mitochondrial cardiomyopathy in a hypomorphic
            <i>Med30</i>
            mouse mutant is ameliorated by ketogenic diet

Krebs, Philippe; Fan, Weiwei; Chen, Yen Hui; Tobita, Kimimasa; Downes, Michael; Wood, Malcolm R.; Sun, Lei; Li, Xiaohong; Xia, Yu; Ding, Ning; Spaeth, Jason M.; Moresco, Eva Marie Y.; Boyer, Thomas G.; Lo, Cecilia W.; Yen, J. J.; Evans, Ronald M.; Beutler, Bruce

doi:10.1073/pnas.1117835108

Cited by 59 publications

(59 citation statements)

References 41 publications

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“…In two studies using ex vivo perfusion approaches in rat hearts, maintenance on low-carbohydrate diets before ischemia-reperfusion protocols gave conflicting results with regard to infarct size and hemodynamic performance (6,221). Prospective cardioprotective effects of a low-carbohydrate diet may be attributable to an increase in the number of myocardial mitochondria or transcriptional upregulation of key mediators of oxidative phosphorylation (6,112). Cardioprotective effects have been observed using in vivo ischemia-reperfusion approaches in rats subjected to starvation-induced ketosis, initiated through prolonged fasting, and also via intravenous injection of DL-␤OHB immediately before ischemic injury, which conferred a significant decrease in both infarct size and myocardial cell death (191,244).…”

Section: Ketone Bodies and Myocardial Diseasementioning

confidence: 97%

“…Additionally, limited studies raise the possibility that humans with NAFLD could benefit from low-carbohydrate diet therapy (32,58). An experimental ketogenic diet has been used to mitigate a mitochondrial cardiomyopathy in mice (112). The full scope of cardiovascular diseases responsive to nutritional and/or pharmacological manipulation of ketone body metabolism and the associated metabolic mechanisms remain underexplored.…”

Section: Diagnostic and Therapeutic Targets Of Ketone Body Metabolismmentioning

confidence: 98%

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Ketone body metabolism and cardiovascular disease

Cotter

Schugar

Crawford

2013

American Journal of Physiology-Heart and Circulatory Physiology

373

304

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Ketone bodies are metabolized through evolutionarily conserved pathways that support bioenergetic homeostasis, particularly in brain, heart, and skeletal muscle when carbohydrates are in short supply. The metabolism of ketone bodies interfaces with the tricarboxylic acid cycle, β-oxidation of fatty acids, de novo lipogenesis, sterol biosynthesis, glucose metabolism, the mitochondrial electron transport chain, hormonal signaling, intracellular signal transduction pathways, and the microbiome. Here we review the mechanisms through which ketone bodies are metabolized and how their signals are transmitted. We focus on the roles this metabolic pathway may play in cardiovascular disease states, the bioenergetic benefits of myocardial ketone body oxidation, and prospective interactions among ketone body metabolism, obesity, metabolic syndrome, and atherosclerosis. Ketone body metabolism is noninvasively quantifiable in humans and is responsive to nutritional interventions. Therefore, further investigation of this pathway in disease models and in humans may ultimately yield tailored diagnostic strategies and therapies for specific pathological states.

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Section: Ketone Bodies and Myocardial Diseasementioning

confidence: 97%

Section: Diagnostic and Therapeutic Targets Of Ketone Body Metabolismmentioning

confidence: 98%

Ketone body metabolism and cardiovascular disease

Cotter

Schugar

Crawford

2013

American Journal of Physiology-Heart and Circulatory Physiology

373

304

View full text Add to dashboard Cite

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“…As Mediator function is closely associated with energy utilization and homeostasis (22,24,(39)(40)(41), it is not entirely unexpected that overexpression of Cdk8 results in a large enrichment of downregulated mitochondrial-based metabolic genes and pathways (Figures 6 and 7). In fact, we see considerable overlap between the RNA-seq results presented here (885 of 1,160 genes expressed >1.5-fold, r 2 = 0.61) and those from cardiac deletion of the core Mediator subunit Med1 (Med1cKO) that we recently reported (24).…”

Section: Discussionmentioning

confidence: 99%

Ectopic expression of Cdk8 induces eccentric hypertrophy and heart failure

et al. 2017

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“…Mice with missense mutations in Med30 develop DCM after weaning. Early lethality in these mice was linked to a decline in mitochondrial function, likely due to decreased expression of genes involved in oxidative phosphorylation in the heart (46). We recently demonstrated that cardiac MED13 regulates metabolic gene expression in the heart.…”

Section: Egr1mentioning

confidence: 99%

MED12 regulates a transcriptional network of calcium-handling genes in the heart

Baskin¹,

Makarewich²,

DeLeon³

et al. 2017

JCI Insight

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IntroductionHeart failure is the leading cause of death in the Western world (1). Defective calcium (Ca 2+ ) cycling, such as decreased Ca 2+ uptake in the sarcoplasmic reticulum (SR) or SR calcium leak occurs in failing hearts (2, 3), and genetic mutations in calcium-handling genes cause arrhythmias and dilated cardiomyopathy (DCM) (4). Altered expression of calcium-handling genes perturbs contractility (5-9), but relatively little is known about how the expression of these genes is coordinated in the heart.Mediator is a multiprotein complex of about 30 subunits that form the core and kinase submodules (10, 11). The kinase submodule, containing MED12, MED13, CDK8, and Cyclin C (12), can repress transcription through allosteric inhibition of RNA Pol II binding to the core submodule (13) but can also activate transcription by promoting Pol II recruitment to target genes via specific transcription factors (14). We previously demonstrated that cardiac MED13 regulates systemic energy homeostasis through signaling to extracardiac tissues (15,16), but the roles of the other kinase components in the heart have not been investigated.MED12, a component of the Mediator kinase submodule, is encoded on the X chromosome, and missense mutations are associated with a variety of X-linked disorders (17)(18)(19). Developmental signaling pathways and transcription factors converge on MED12, which acts as a transcriptional hub required to coordinate development (20)(21)(22)(23). Deletion of Med12 in Drosophila decreases expression of sonic hedgehog target genes and leads to defects in eye development (20), and mutations in Med12 in zebrafish disrupt SOX-mediated transcription during endoderm development (22). MED12 is also required for neuron development through its regulation of TBX2B in zebrafish (23). Med12 hypomorphic mutant mice die in utero due to various developmental defects (24, 25), but the function of MED12 in the heart has not yet been investigated.The Mediator complex regulates gene transcription by linking basal transcriptional machinery with DNA-bound transcription factors. The activity of the Mediator complex is mainly controlled by a kinase submodule that is composed of 4 proteins, including MED12. Although ubiquitously expressed, Mediator subunits can differentially regulate gene expression in a tissue-specific manner. Here, we report that MED12 is required for normal cardiac function, such that mice with conditional cardiac-specific deletion of MED12 display progressive dilated cardiomyopathy. Loss of MED12 perturbs expression of calcium-handling genes in the heart, consequently altering calcium cycling in cardiomyocytes and disrupting cardiac electrical activity. We identified transcription factors that regulate expression of calcium-handling genes that are downregulated in the heart in the absence of MED12, and we found that MED12 localizes to transcription factor consensus sequences within calcium-handling genes. We showed that MED12 interacts with one such transcription factor, MEF2, in cardiomyocytes an...

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Lethal mitochondrial cardiomyopathy in a hypomorphic Med30 mouse mutant is ameliorated by ketogenic diet

Cited by 59 publications

References 41 publications

Ketone body metabolism and cardiovascular disease

Ketone body metabolism and cardiovascular disease

Ectopic expression of Cdk8 induces eccentric hypertrophy and heart failure

MED12 regulates a transcriptional network of calcium-handling genes in the heart

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