Barth Syndrome-Related Cardiomyopathy is Associated with a Reduction in Myocardial Glucose Oxidation

2021 ◽  
Author(s):  
Amanda A. Greenwell ◽  
Keshav Gopal ◽  
Tariq Altamimi ◽  
Christina T. Saed ◽  
Faqi Wang ◽  
...  
Keyword(s):  
Heart Failure ◽  
Energy Metabolism ◽  
Glucose Oxidation ◽  
Genetic Disorder ◽  
Left Ventricular ◽  
Barth Syndrome ◽  
Acid Oxidation ◽  
Functional Impairments ◽  
Myocardial Energy Metabolism ◽  
Oxidation Rates

Heart failure presents as the leading cause of infant mortality in individuals with Barth syndrome (BTHS), a rare genetic disorder due to mutations in the tafazzin (TAZ) gene affecting mitochondrial structure and function. Investigations into the perturbed bioenergetics in the BTHS heart remain limited. Hence, our objective was to identify the potential alterations in myocardial energy metabolism and molecular underpinnings that may contribute to the early cardiomyopathy and heart failure development in BTHS. Cardiac function and myocardial energy metabolism were assessed via ultrasound echocardiography and isolated working heart perfusions, respectively, in a mouse model of BTHS (doxycycline-inducible Taz knockdown (TazKD) mice). In addition, we also performed mRNA/protein expression profiling for key regulators of energy metabolism in hearts from TazKD mice and their wild-type (WT) littermates. TazKD mice developed hypertrophic cardiomyopathy as evidenced by increased left ventricular anterior and posterior wall thickness, as well as increased cardiac myocyte cross sectional area, though no functional impairments were observed. Glucose oxidation rates were markedly reduced in isolated working hearts from TazKD mice compared to their WT littermates in the presence of insulin, which was associated with decreased pyruvate dehydrogenase activity. Conversely, myocardial fatty acid oxidation rates were elevated in TazKD mice, whereas no differences in glycolytic flux or ketone body oxidation rates were observed. Our findings demonstrate that myocardial glucose oxidation is impaired prior to the development of overt cardiac dysfunction in TazKD mice, and may thus represent a pharmacological target for mitigating the development of cardiomyopathy in BTHS.

Perturbations in myocardial energy metabolism in the ischemic heart

2020 ◽  
pp. 17-22
Keyword(s):  
Energy Metabolism ◽  
Oxidative Metabolism ◽  
Glucose Oxidation ◽  
Ischemic Heart ◽  
Acid Oxidation ◽  
Ischemia And Reperfusion ◽  
Metabolic Demand ◽  
Cardiac Efficiency ◽  
Myocardial Energy Metabolism ◽  
Oxidation Rates

As an organ that must continuously pump oxygenated blood throughout the body, the heart has an enormous metabolic demand, which is primarily met via oxidative metabolism of fatty acids and carbohydrates. Because of its high metabolic demand, during times of reduced oxygen supply such as ischemia, the heart becomes highly susceptible to injury, and if flow is not re-established, myocardial tissue is lost and can result in death (myocardial infarction). Of interest, both myocardial ischemia and reperfusion are associated with a number of perturbations in energy metabolism that contribute to the pathology of ischemic heart disease. This includes marked elevations in glycolysis to counteract the reduction in oxidative metabolism, whereas fatty acids predominate as the primary fuel source for residual oxidative metabolism. During the early stages of cardiac recovery after successful reperfusion of the ischemic heart, fatty acid oxidation rates also rapidly recover at the expense of low glucose oxidation rates. These metabolic perturbations increase myocardial acidosis due to glycolysis being uncoupled from glucose oxidation, which impairs cardiac efficiency. As such, therapeutic approaches to stimulate glucose oxidation or inhibit fatty acid oxidation have the potential to correct dysregulated myocardial energy metabolism during ischemia and reperfusion, which improves cardiac efficiency and may lead to improved clinical outcomes in people with ischemic heart disease. L

scholarly journals Acetylation and succinylation contribute to maturational alterations in energy metabolism in the newborn heart

2016 ◽  
Vol 311 (2) ◽  
pp. H347-H363 ◽  
Author(s):  
Arata Fukushima ◽  
Osama Abo Alrob ◽  
Liyan Zhang ◽  
Cory S. Wagg ◽  
Tariq Altamimi ◽  
...  
Keyword(s):  
Fatty Acid ◽  
Energy Metabolism ◽  
Fatty Acid Oxidation ◽  
Glucose Oxidation ◽  
Acid Oxidation ◽  
Amino Acid Synthesis ◽  
Oxidation Rates ◽  
Cardiac Energy Metabolism ◽  
Cardiac Energy ◽  
The Impact

Dramatic maturational changes in cardiac energy metabolism occur in the newborn period, with a shift from glycolysis to fatty acid oxidation. Acetylation and succinylation of lysyl residues are novel posttranslational modifications involved in the control of cardiac energy metabolism. We investigated the impact of changes in protein acetylation/succinylation on the maturational changes in energy metabolism of 1-, 7-, and 21-day-old rabbit hearts. Cardiac fatty acid β-oxidation rates increased in 21-day vs. 1- and 7-day-old hearts, whereas glycolysis and glucose oxidation rates decreased in 21-day-old hearts. The fatty acid oxidation enzymes, long-chain acyl-CoA dehydrogenase (LCAD) and β-hydroxyacyl-CoA dehydrogenase (β-HAD), were hyperacetylated with maturation, positively correlated with their activities and fatty acid β-oxidation rates. This alteration was associated with increased expression of the mitochondrial acetyltransferase, general control of amino acid synthesis 5 like 1 (GCN5L1), since silencing GCN5L1 mRNA in H9c2 cells significantly reduced acetylation and activity of LCAD and β-HAD. An increase in mitochondrial ATP production rates with maturation was associated with the decreased acetylation of peroxisome proliferator-activated receptor-γ coactivator-1α, a transcriptional regulator for mitochondrial biogenesis. In addition, hypoxia-inducible factor-1α, hexokinase, and phosphoglycerate mutase expression declined postbirth, whereas acetylation of these glycolytic enzymes increased. Phosphorylation rather than acetylation of pyruvate dehydrogenase (PDH) increased in 21-day-old hearts, accounting for the low glucose oxidation postbirth. A maturational increase was also observed in succinylation of PDH and LCAD. Collectively, our data are the first suggesting that acetylation and succinylation of the key metabolic enzymes in newborn hearts play a crucial role in cardiac energy metabolism with maturation. Listen to this article’s corresponding podcast at http://ajpheart.podbean.com/e/acetylation-control-of-energy-metabolism-in-newborn-hearts/ .

Abstract 328: ES1 Is A Novel Mitochondrial Protein Protecting The Heart Via Direct Regulation Of Mitochondrial Energy Metabolism

2014 ◽  
Vol 115 (suppl_1) ◽  
Author(s):  
Qinqiang Long ◽  
Huan Yang ◽  
Yiqun Zhou ◽  
Aibing Wang ◽  
Lan He ◽  
...  
Keyword(s):  
Heart Failure ◽  
Energy Metabolism ◽  
Cardiac Hypertrophy ◽  
Atp Synthase ◽  
Mitochondrial Protein ◽  
Left Ventricular ◽  
Mitochondrial Energy Metabolism ◽  
Myocardial Energy Metabolism ◽  
H9c2 Cardiomyocytes ◽  
Direct Regulation

Defects in the myocardial energy metabolism have been linked to pathological cardiac hypertrophy and congestive heart failure. However, the regulation of myocardial energy metabolism remains obscure. ATP synthase is an enzyme complex in the mitochondria and plays a central role in energy metabolism. In this study, we identified ES1, a mitochondrial protein with unknown function, as a key determinant of myocardial energy metabolism via controlling ATP synthase activities. We uncovered that ES1 interacts with both α and β subunit of ATP synthase, and its expression levels in H9C2 cardiomyocytes were directly correlated to ATP synthesis and inversely to ATP hydrolysis. Cellular energetic analysis revealed that ES1 levels in H9C2 cardiomyocytes were directly correlated with mitochondrial oxidative metabolism. ATP synthase activity assays revealed increased synthesis activities and decreased hydrolysis activities on cardiac mitochondria from a mouse line with Cre-LoxP mediated, tamoxifen inducible, cardiomyocyte-restricted ES1 overexpression (TM-ES1oe) compared with mice of tamoxifen-inducible Mer-Cre-Mer (TMCM). We induced ES1 overexpression in TM-ES1oe mice (3-month-old) 7 days after transverse aortic constriction(TAC) and compared with TMCM mice with identical treatment. Echocardiography assessment revealed a substantially improved Ejection fraction (EF%) and Fractional shortening (FS%) and diminished left ventricular hypertrophy in TM-ES1oe mice compared with TMCM mice. Sections of TM-ES1oe hearts stained with Masson’s Trichrome blue showed markedly decreased interstitial fibrosis compared with TMCM control. We have also generated an ES1 knockout line. ES1 knockout mice(3-month-old)showed cardiac dysfunction with decreased EF% and FS% under a basal condition. Transmission electron microscope examination revealed substantial loss of mitochondrial cristae structure on ES1 knockout hearts. These results indicate that ES1 protecting the heart by direct regulation of mitochondrial energy metabolism. ES1 may be directly involved in pathological development of cardiac hypertrophy and heart failure. We suggest that ES1 is a potential therapeutic target in treating cardiomyopathy and other heart diseases.

ANG II causes insulin resistance and induces cardiac metabolic switch and inefficiency: a critical role of PDK4

2013 ◽  
Vol 304 (8) ◽  
pp. H1103-H1113 ◽  
Author(s):  
Jun Mori ◽  
Osama Abo Alrob ◽  
Cory S. Wagg ◽  
Robert A. Harris ◽  
Gary D. Lopaschuk ◽  
...  
Keyword(s):  
Heart Failure ◽  
Insulin Resistance ◽  
Energy Metabolism ◽  
Pyruvate Dehydrogenase ◽  
Glucose Oxidation ◽  
Critical Role ◽  
Pyruvate Dehydrogenase Kinase ◽  
Ang Ii ◽  
Oxidation Rates

The renin-angiotensin system (RAS) may alter cardiac energy metabolism in heart failure. Angiotensin II (ANG II), the main effector of the RAS in heart failure, has emerged as an important regulator of cardiac hypertrophy and energy metabolism. We studied the metabolic perturbations and insulin response in an ANG II-induced hypertrophy model. Ex vivo heart perfusion showed that hearts from ANG II-treated mice had a lower response to insulin with significantly reduced rates of glucose oxidation in association with increased pyruvate dehydrogenase kinase 4 (PDK4) levels. Palmitate oxidation rates were significantly reduced in response to insulin in vehicle-treated hearts but remained unaltered in ANG II-treated hearts. Furthermore, phosphorylation of Akt was also less response to insulin in ANG II-treated wild-type (WT) mice, suggestive of insulin resistance. We evaluated the role of PDK4 in the ANG II-induced pathology and showed that deletion of PDK4 prevented ANG II-induced diastolic dysfunction and normalized glucose oxidation to basal levels. ANG II-induced reduction in the levels of the deacetylase, SIRT3, was associated with increased acetylation of pyruvate dehydrogenase (PDH) and a reduced PDH activity. In conclusion, our findings show that a combination of insulin resistance and decrease in PDH activity are involved in ANG II-induced reduction in glucose oxidation, resulting in cardiac inefficiency. ANG II reduces PDH activity via acetylation of PDH complex, as well as increased phosphorylation in response to increased PDK4 levels.

Energy metabolism in patients with diabetes and heart failure

2019 ◽  
pp. 32-36
Keyword(s):  
Heart Failure ◽  
Energy Metabolism ◽  
Oxidative Phosphorylation ◽  
Energy Demand ◽  
Glucose Oxidation ◽  
High Energy ◽  
Energy Deficit ◽  
Diabetic Patients ◽  
Mitochondrial Oxidative Phosphorylation ◽  
Myocardial Energy Metabolism

The heart has a very high energy demand, which is mostly met by mitochondrial oxidative phosphorylation and, to a lesser extent, by glycolysis. In heart failure, there are substantial alterations in myocardial energy metabolism that lead to an “energy-deficient” state. This includes a marked reduction in overall mitochondrial oxidative phosphorylation and an uncoupling between high glycolysis rates and low glucose oxidation, which together contributes to the energy deficit and deteriorates contractile dysfunction. Cardiac ketone oxidation is also increased in heart failure, although it has yet to be determined whether this is an adaptive or maladaptive alteration. Diabetes is a major risk factor for heart failure development. It induces alterations in myocardial energy metabolism and is often associated with ventricular dysfunction. Similar to heart failure, a major change in myocardial energy metabolism in diabetic patients is a reduction in glucose oxidation, which negatively influences cardiac function. In both heart failure and diabetes, a growing body of evidence suggests that targeting myocardial energy metabolism by optimizing cardiac energy substrate preference could be a potential therapeutic approach to improve patient outcomes.

scholarly journals Metabolic Profiling of Hearts Exposed to Sevoflurane and Propofol Reveals Distinct Regulation of Fatty Acid and Glucose Oxidation

2010 ◽  
Vol 113 (3) ◽  
pp. 541-551 ◽  
Author(s):  
Lianguo Wang ◽  
Kerry W. S. Ko ◽  
Eliana Lucchinetti ◽  
Liyan Zhang ◽  
Heinz Troxler ◽  
...  
Keyword(s):  
Fatty Acid ◽  
Energy Metabolism ◽  
Lipid Rafts ◽  
Metabolic Profiling ◽  
Glucose Oxidation ◽  
Molecular Mechanisms ◽  
Glucose Transporter ◽  
Left Ventricular ◽  
Glucose Transporter 4 ◽  
Oxidative Energy Metabolism

Background Myocardial energy metabolism is a strong predictor of postoperative cardiac function. This study profiled the metabolites and metabolic changes in the myocardium exposed to sevoflurane, propofol, and Intralipid and investigated the underlying molecular mechanisms. Methods Sevoflurane (2 vol%) and propofol (10 and 100 microM) in the formulation of 1% Diprivan (AstraZeneca Inc., Mississauga, ON, Canada) were compared for their effects on oxidative energy metabolism and contractility in the isolated working rat heart model. Intralipid served as a control. Substrate flux through the major pathways for adenosine triphosphate generation in the heart, that is, fatty acid and glucose oxidation, was measured using [H]palmitate and [C]glucose. Biochemical analyses of nucleotides, acyl-CoAs, ceramides, and 32 acylcarnitine species were used to profile individual metabolites. Lipid rafts were isolated and used for Western blotting of the plasma membrane transporters CD36 and glucose transporter 4. Results Metabolic profiling of the hearts exposed to sevoflurane and propofol revealed distinct regulation of fatty acid and glucose oxidation. Sevoflurane selectively decreased fatty acid oxidation, which was closely related to a marked reduction in left ventricular work. In contrast, propofol at 100 microM but not 10 microM increased glucose oxidation without affecting cardiac work. Sevoflurane decreased fatty acid transporter CD36 in lipid rafts/caveolae, whereas high propofol increased pyruvate dehydrogenase activity without affecting glucose transporter 4, providing mechanisms for the fuel shifts in energy metabolism. Propofol increased ceramide formation, and Intralipid increased hydroxy acylcarnitine species. Conclusions Anesthetics and their solvents elicit distinct metabolic profiles in the myocardium, which may have clinical implications for the already jeopardized diseased heart.

scholarly journals Metabolic Therapy in Heart Failure

2015 ◽  
Vol 1 (2) ◽  
pp. 112 ◽  
Author(s):  
Yury Lopatin ◽  
Keyword(s):  
Heart Failure ◽  
Fatty Acid ◽  
Glucose Oxidation ◽  
Acid Oxidation ◽  
Patients With Heart Failure ◽  
Cardiac Energy Metabolism ◽  
Conventional Medical Therapy ◽  
Cardiac Energy ◽  
Metabolic Impairments

Metabolic impairments play an important role in the development and progression of heart failure. The use of metabolic modulators, the number of which is steadily increasing, may be particularly effective in the treatment of heart failure. Recent evidence suggests that modulating cardiac energy metabolism by reducing fatty acid oxidation and/or increasing glucose oxidation represents a promising approach to the treatment of patients with heart failure. This review focuses on the role of metabolic modulators, in particular trimetazidine, as a potential additional medication to conventional medical therapy in heart failure.

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