Prolonged QT interval and lipid alterations beyond β-oxidation in very long-chain acyl-CoA dehydrogenase null mouse hearts

Gélinas, Roselle; Thompson-Legault, Julie; Bouchard, Bertrand; Daneault, Caroline; Mansour, Asmaa; Gillis, Marc‐Antoine; Charron, Guy; Gavino, Victor C.; Labarthe, François; Rosiers, Christine Des

doi:10.1152/ajpheart.01275.2010

Cited by 48 publications

(48 citation statements)

References 66 publications

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“…The Langendorff experiment not only identified decreased systolic and diastolic function in the hearts of cVLCAD Ϫ/Ϫ mice but also confirmed significant reduction of ATP synthesis in these hearts. Contrary to our findings, a recent study of global VLCAD KO mice demonstrated the ability of VLCAD deficient hearts perfused ex vivo to maintain normal contractile performance and metabolic fluxes (20). Discrepancies in results between these two studies may have resulted from possible differences in adaptive metabolic remodeling in hearts of global-and cardiac-specific VLCAD KO models.…”

Section: Discussioncontrasting

confidence: 99%

“…39). This has been attributed to the capacity of LCAD to substitute for VLCAD in mice but not in humans (11,20). This substrate overlap between VLCAD and LCAD in mice may be compensating for VLCAD deficiency during the first months of life and preventing acute metabolic decompensation, unlike the situation in children with null VLCAD gene mutations.…”

Section: Discussionmentioning

confidence: 99%

“…Adult KO mice demonstrate cardiomyopathy with increased numbers of degenerative fibers, collagen deposition, and vacuolated myocytes as well as increased lipid accumulation in cardiomyocytes (16), abnormal cardiac electrophysiological changes including facilitated induction of polymorphic ventricular tachycardia, abnormal intracellular Ca 2ϩ homeostasis and dynamics in cardiomyocytes (45), and prolonged QT interval (20). Global VLCAD KO mice stressed by cold and/or fasting develop hypoglycemia, hypothermia, and severe bradycardia and become moribund within several hours (15).…”

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confidence: 99%

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Cardiac-specific VLCAD deficiency induces dilated cardiomyopathy and cold intolerance

Xiong

James

et al. 2014

American Journal of Physiology-Heart and Circulatory Physiology

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The very long-chain acyl-CoA dehydrogenase (VLCAD) enzyme catalyzes the first step of mitochondrial ␤-oxidation. Patients with VLCAD deficiency present with hypoketotic hypoglycemia and cardiomyopathy, which can be exacerbated by fasting and/or cold stress. Global VLCAD knockout mice recapitulate these phenotypes: mice develop cardiomyopathy, and cold exposure leads to rapid hypothermia and death. However, the contribution of different tissues to development of these phenotypes has not been studied. We generated cardiac-specific VLCAD-deficient (cVLCAD Ϫ/Ϫ ) mice by Cre-mediated ablation of the VLCAD in cardiomyocytes. By 6 mo of age, cVLCAD Ϫ/Ϫ mice demonstrated increased end-diastolic and endsystolic left ventricular dimensions and decreased fractional shortening. Surprisingly, selective VLCAD gene ablation in cardiomyocytes was sufficient to evoke severe cold intolerance in mice who rapidly developed severe hypothermia, bradycardia, and markedly depressed cardiac function in response to fasting and cold exposure (ϩ5°C). We conclude that cardiac-specific VLCAD deficiency is sufficient to induce cold intolerance and cardiomyopathy and is associated with reduced ATP production. These results provide strong evidence that fatty acid oxidation in myocardium is essential for maintaining normal cardiac function under these stress conditions. fatty acid oxidation; mitochondria; cardiac metabolism; cardiomyopathy; mouse; VLCAD; cold intolerance FATTY ACIDS ARE THE PREFERRED substrate for ATP production in the mammalian heart. Very long-chain acyl-CoA dehydrogenase (VLCAD) catalyzes the first step of mitochondrial ␤-oxidation, the dehydrogenation of acyl-CoAs with 14 to 20 carbon-chain fatty acids. Mutations in the VLCAD gene are the most common inherited long-chain fatty acid oxidation (FAO) disorder, with an incidence currently estimated to be between 1/42,500 and 1/120,000 (3,7,27, 46). Affected individuals demonstrate a variety of clinical symptoms including nonketotic hypoglycemia, heart and liver lipidosis, encephalopathy, skeletal myopathy, cardiomyopathy, arrhythmias, and sudden death (2,5,7,22,34). Because VLCAD is highly expressed in the liver, heart, lung, brown adipose tissue (BAT), and skeletal muscles, global VLCAD deficiency causes multiple organ dysfunction and diverse clinical symptoms. Three phenotypes have been described: 1) a severe childhood form with no residual enzyme activity, typically presenting with cardiomyopathy and resulting in high mortality (2, 29, 41); 2) a milder childhood form with hypoketotic hypoglycemia as the main feature (2, 3) and 3) an adult presentation with intermittent skeletal myopathy mainly triggered by fasting or exercise (2).Global VLCAD knockout (KO) mice recapitulate some features of human VLCAD deficiency. Adult KO mice demonstrate cardiomyopathy with increased numbers of degenerative fibers, collagen deposition, and vacuolated myocytes as well as increased lipid accumulation in cardiomyocytes (16), abnormal cardiac electrophysiological changes including facilitated i...

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Section: Discussioncontrasting

confidence: 99%

Section: Discussionmentioning

confidence: 99%

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confidence: 99%

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Cardiac-specific VLCAD deficiency induces dilated cardiomyopathy and cold intolerance

Xiong

James

et al. 2014

American Journal of Physiology-Heart and Circulatory Physiology

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“…Our previous work with various transgenic mouse models does, however, provide some evidence of differences among commonly used control mouse strains, particularly in the partitioning of exogenous long-chain fatty acids (LCFA) for oxidation and storage between hearts from 129S6/SvEvTac versus various C57Bl/6 or C57Bl/10 substrains (17,18,26,27,30). These results were all obtained in our validated experimental paradigm, namely, ex vivo perfusion in working mode, with concomitant evaluation of myocardial contractility and metabolic fluxes with 13 C-labeled substrates.…”

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confidence: 99%

Mouse strain differences in metabolic fluxes and function of ex vivo working hearts

Vaillant

Lauzier

Poirier

et al. 2014

American Journal of Physiology-Heart and Circulatory Physiology

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In mice, genetic background is known to influence various parameters, including cardiac function. Its impact on cardiac energy substrate metabolism-a factor known to be closely related to function and contributes to disease development-is, however, unclear. This was examined in this study. In commonly used control mouse substrains SJL/JCrNTac, 129S6/SvEvTac, C57Bl/6J, and C57Bl/6NCrl, we assessed the functional and metabolic phenotypes of 3-mo-old working mouse hearts perfused ex vivo with physiological concentrations of 13C-labeled carbohydrates (CHO) and a fatty acid (FA). Marked variations in various functional and metabolic flux parameters were observed among all mouse substrains, although the pattern observed differed for these parameters. For example, among all strains, C57Bl/6NCrl hearts had a greater cardiac output (+1.7-fold vs. SJL/JCrNTac and C57Bl/6J; P < 0.05), whereas at the metabolic level, 129S6/SvEvTac hearts stood out by displaying (vs. all 3 strains) a striking shift from exogenous FA (∼−3.5-fold) to CHO oxidation as well as increased glycolysis (+1.7-fold) and FA incorporation into triglycerides (+2-fold). Correlation analyses revealed, however, specific linkages between 1) glycolysis, FA oxidation, and pyruvate metabolism and 2) cardiac work, oxygen consumption with heart rate, respectively. This implies that any genetically determined factors affecting a given metabolic flux parameter may impact on the associated functional parameters. Our results emphasize the importance of selecting the appropriate control strain for cardiac metabolic studies using transgenic mice, a factor that has often been neglected. Understanding the molecular mechanisms underlying the diversity of strain-specific cardiac metabolic and functional profiles, particularly the 129S6/SvEvTac, may ultimately disclose new specific metabolic targets for interventions in heart disease.

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“…General evidence for the importance of mTAG in FA provision for oxidation and efficient cardiac metabolism is the huge (>20 fold) increase in mTAG seen in inborn errors [145,146] and mouse models [146,147] of defective mitochondrial -oxidation, especially as this is associated with cardiac dysfunction. Similar observations were noted for human subjects with neutral lipid storage disease [137].…”

Section: Myocardial Triacylglycerol-fatty Acid Oxidationmentioning

confidence: 99%

The role of triacylglycerol in cardiac energy provision

Evans

Hui‐Kang

2016

Biochimica et Biophysica Acta (BBA) - Molecular and Cell Biolog

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Triacylglycerols (TAG) constitute the main energy storage resource in mammals, by virtue of their high energy density. This in turn is a function of their highly reduced state and hydrophobicity.Limited water solubility, however, imposes specific requirements for delivery and uptake mechanisms on TAG-utilising tissues, including the heart, as well as intracellular disposition. TAGs constitute potentially the major energy supply for working myocardium, both through bloodborne provision and as intracellular TAG within lipid droplets, but also provide the heart with fatty acids (FA) which the myocardium cannot itself synthesise but are required for glycerolipid derivatives with (non-energetic) functions, including membrane phospholipids and lipid signalling molecules. Furthermore they serve to buffer potentially toxic amphipathic fatty acid derivatives.Intracellular handling and disposition of TAGs and their FA and glycerolipid derivatives similarly requires dedicated mechanisms in view of their hydrophobic character. Dysregulation of utilisation can result in inadequate energy provision, accumulation of TAG and/or esterified species, and these may be responsible for significant cardiac dysfunction in a variety of disease states. This review will focus on the role of TAG in myocardial energy provision, by providing FAs from exogenous and endogenous TAG sources for mitochondrial oxidation and ATP production, and how this can change in disease and impact on cardiac function. A C C E P T E D M A N U S C R I P T ACCEPTED MANUSCRIPT 3Key words:heart; triacylglycerol; very-low-density lipoprotein; VLDL; chylomicron; lipid droplet Highlights: Triacylglycerols are supplied to the myocardium within chylomicrons and VLDL  Heart assimilates triacylglycerol-rich lipoproteins by LPL and receptor-mediated routes  Exogenous triacylglycerol-derived fatty acids enter an intracellular lipid pool  Intracardiac triacylglycerol is an important source of fatty acids for oxidation  Dysregulation of triacylglycerol metabolism is associated with cardiac dysfunction

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Prolonged QT interval and lipid alterations beyond β-oxidation in very long-chain acyl-CoA dehydrogenase null mouse hearts

Cited by 48 publications

References 66 publications

Cardiac-specific VLCAD deficiency induces dilated cardiomyopathy and cold intolerance

Cardiac-specific VLCAD deficiency induces dilated cardiomyopathy and cold intolerance

Mouse strain differences in metabolic fluxes and function of ex vivo working hearts

The role of triacylglycerol in cardiac energy provision

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