R-92L and R-92W Mutations in Cardiac Troponin T Lead to Distinct Energetic Phenotypes in Intact Mouse Hearts

He, Hui; Javadpour, Maryam M.; Latif, F.; Tardiff, Jil C.; Ingwall, Joanne S.

doi:10.1529/biophysj.107.107557

Cited by 53 publications

(66 citation statements)

References 23 publications

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“…Another study on energy utilization in TnT-FHC showed that transgenic hearts with R92W and R92L TnT mutations both showed greater ATP utilization during muscle contraction, with the R92W hearts showing more severe energetic abnormalities and greater contractile dysfunction than the R92L hearts (81). These hearts had higher intracellular ADP and P i levels, as well as lower ATP and phosphocreatine levels (81). It was shown in our study that the levels of creatinine were higher in I79N hearts than WT hearts.…”

Section: Proteins Involved In Metabolism-supporting

confidence: 56%

Delineation of Molecular Pathways Involved in Cardiomyopathies Caused by Troponin T Mutations

Gilda

Lai

Witzmann

et al. 2016

Molecular & Cellular Proteomics

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Familial hypertrophic cardiomyopathy (FHC) is associated with mild to severe cardiac problems and is the leading cause of sudden death in young people and athletes. Although the genetic basis for FHC is well-established, the molecular mechanisms that ultimately lead to cardiac dysfunction are not well understood. To obtain important insights into the molecular mechanism(s) involved in FHC, hearts from two FHC troponin T models (Ile79Asn [I79N] and Arg278Cys [R278C]) were investigated using labelfree proteomics and metabolomics. Mutations in troponin T are the third most common cause of FHC, and the I79N mutation is associated with a high risk of sudden cardiac death. Most FHC-causing mutations, including I79N, increase the Ca 2؉ sensitivity of the myofilament; however, the R278C mutation does not alter Ca 2؉ sensitivity and is associated with a better prognosis than most FHC mutations. Out of more than 1200 identified proteins, 53 and 76 proteins were differentially expressed in I79N and R278C hearts, respectively, when compared with wild-type hearts. Interestingly, more than 400 proteins were differentially expressed when the I79N and R278C hearts were directly compared. The three major pathways affected in I79N hearts relative to R278C and wild-type hearts were the ubiquitin-proteasome system, antioxidant systems, and energy production pathways. Further investigation of the proteasome system using Western blotting and activity assays showed that proteasome dysfunction occurs in I79N hearts. Metabolomic results corroborate the proteomic data and suggest the glycolytic, citric acid, and electron transport chain pathways are important pathways that are altered in I79N hearts relative to R278C or wild-type hearts. Our findings suggest that impaired energy production and protein degradation dysfunction are important mechanisms in FHCs associated with poor prognosis and that cardiac hypertrophy is not likely needed for a switch from fatty acid to glucose metabolism. Molecular & Cellular

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Section: Proteins Involved In Metabolism-supporting

confidence: 56%

Delineation of Molecular Pathways Involved in Cardiomyopathies Caused by Troponin T Mutations

Gilda

Lai

Witzmann

et al. 2016

Molecular & Cellular Proteomics

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“…Hearts were isolated and perfused in the Langendorff mode as described previously (23). The hearts were excised from 5-to 6-mo-old cVLCAD ϩ/ϩ (n ϭ 13) and cVLCAD…”

Section: Methodsmentioning

confidence: 99%

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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“…Measurement of heart function by MRI was performed on anesthetized mice using gated Flash-CINE sequences. Langendorff perfusion was performed as described previously (34).…”

Section: Figurementioning

confidence: 99%

Adult mouse epicardium modulates myocardial injury by secreting paracrine factors

Zhou¹,

Honor²,

He³

et al. 2011

J. Clin. Invest.

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463

659

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The epicardium makes essential cellular and paracrine contributions to the growth of the fetal myocardium and the formation of the coronary vasculature. However, whether the epicardium has similar roles postnatally in the normal and injured heart remains enigmatic. Here, we have investigated this question using genetic fate-mapping approaches in mice. In uninjured postnatal heart, epicardial cells were quiescent. Myocardial infarction increased epicardial cell proliferation and stimulated formation of epicardium-derived cells (EPDCs), which remained in a thickened layer on the surface of the heart. EPDCs did not adopt cardiomyocyte or coronary EC fates, but rather differentiated into mesenchymal cells expressing fibroblast and smooth muscle cell markers. In vitro and in vivo assays demonstrated that EPDCs secreted paracrine factors that strongly promoted angiogenesis. In a myocardial infarction model, EPDC-conditioned medium reduced infarct size and improved heart function. Our findings indicate that epicardium modulates the cardiac injury response by conditioning the subepicardial environment, potentially offering a new therapeutic strategy for cardiac protection.

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R-92L and R-92W Mutations in Cardiac Troponin T Lead to Distinct Energetic Phenotypes in Intact Mouse Hearts

Cited by 53 publications

References 23 publications

Delineation of Molecular Pathways Involved in Cardiomyopathies Caused by Troponin T Mutations

Delineation of Molecular Pathways Involved in Cardiomyopathies Caused by Troponin T Mutations

Cardiac-specific VLCAD deficiency induces dilated cardiomyopathy and cold intolerance

Adult mouse epicardium modulates myocardial injury by secreting paracrine factors

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