Cardiac and Skeletal Muscle Defects in a Mouse Model of Human Barth Syndrome

Acehan, Devrim; Vaz, Frédéric M.; Houtkooper, Riekelt H.; James, Jeanne; Moore, Vicky; Tokunaga, Chonan; Kulik, Willem; Wansapura, Janaka; Toth, Matthew J.; Strauss, Arnold W.; Khuchua, Zaza

doi:10.1074/jbc.m110.171439

Cited by 220 publications

(360 citation statements)

References 49 publications

(53 reference statements)

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“…[19][20][21] This system offers two primary advantages: (1) the knockdown can be rescued at an arbitrary time point and (2) this system presumably models pharmacological inhibition more closely than genetic mutagenesis. This is particularly relevant, because previous studies established LSD1 as a potential drug target for cancer treatment.…”

Section: Discussionmentioning

confidence: 99%

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Lysine-specific demethylase 1 restricts hematopoietic progenitor proliferation and is essential for terminal differentiation

Sprüssel¹,

Schulte²,

et al. 2012

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Section: Discussionmentioning

confidence: 99%

“…This technical approach is capable of facilitating in vivo doxycyline-dependent loss-of-function. [19][20][21] Here, we used this newly established model to investigate the impact of LSD1-kd on adult hematopoiesis.…”

Section: Introductionmentioning

confidence: 99%

Lysine-specific demethylase 1 restricts hematopoietic progenitor proliferation and is essential for terminal differentiation

Sprüssel¹,

Schulte²,

et al. 2012

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“…Two-dimensional and M-mode transthoracic echocardiography was performed as previously described using a Vevo 2100 MicroImaging system (VisualSonics) equipped with a 40-MHz high-frequency transducer (82). The imaging platform was warmed to prevent hypothermia and sickling in SCA mice.…”

Section: Methodsmentioning

confidence: 99%

Sickle cell anemia mice develop a unique cardiomyopathy with restrictive physiology

Bakeer

James

Roy

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

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Cardiopulmonary complications are the leading cause of mortality in sickle cell anemia (SCA). Elevated tricuspid regurgitant jet velocity, pulmonary hypertension, diastolic, and autonomic dysfunction have all been described, but a unifying pathophysiology and mechanism explaining the poor prognosis and propensity to sudden death has been elusive. Herein, SCA mice underwent a longitudinal comprehensive cardiac analysis, combining state-of-the-art cardiac imaging with electrocardiography, histopathology, and molecular analysis to determine the basis of cardiac dysfunction. We show that in SCA mice, anemia-induced hyperdynamic physiology was gradually superimposed with restrictive physiology, characterized by progressive left atrial enlargement and diastolic dysfunction with preserved systolic function. This phenomenon was absent in WT mice with experimentally induced chronic anemia of similar degree and duration. Restrictive physiology was associated with microscopic cardiomyocyte loss and secondary fibrosis detectable as increased extracellular volume by cardiac-MRI. Ultrastructural mitochondrial changes were consistent with severe chronic hypoxia/ischemia and sarcomere diastolic-length was shortened. Transcriptome analysis revealed up-regulation of genes involving angiogenesis, extracellular-matrix, circadian-rhythm, oxidative stress, and hypoxia, whereas ion-channel transport and cardiac conduction were down-regulated. Indeed, progressive corrected QT prolongation, arrhythmias, and ischemic changes were noted in SCA mice before sudden death. Sudden cardiac death is common in humans with restrictive cardiomyopathies and long QT syndromes. Our findings may thus provide a unifying cardiac pathophysiology that explains the reported cardiac abnormalities and sudden death seen in humans with SCA.sickle cell anemia | cardiomyopathy | restrictive physiology | arrhythmias | sudden death S ickle cell anemia (SCA) results from a point mutation in the β-globin gene and affects millions world-wide. It is characterized by production of the mutant hemoglobin S (HbS), which polymerizes upon deoxygenation and distorts the shape of RBCs, increasing their propensity to hemolysis and microvascular occlusion. Recurrent cycles of HbS polymerization result in a host of acute and chronic complications, including vaso-occlusive pain crisis, chronic hemolytic anemia, and organ damage. SCA-associated mortality rates have improved because of early diagnosis with universal newborn screening, immunization, and penicillin prophylaxis, which has changed the natural history of SCA (1, 2) and the impact of SCA on organ pathologies is now becoming evident.Despite improved early survival, nearly one-third of young adults with SCA die suddenly (3-9). The sickle myocardium has been presumed to be relatively resistant to the effects of sickling (10), and studies/autopsies show little evidence of atherosclerosis or coronary disease (11)(12)(13)(14). Mildly increased systolic pulmonary arterial pressure (PAP) estimated by tricuspid regurgitant jet vel...

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“…by guest, on May 9, 2018 www.jlr.org Downloaded from ( 32 ), we also determined whether changes in the content and composition of CL and the CL intermediate MLCL might explain differences in Ad-Ctrl and Ad-Acot2 liver. This seemed important to test also because, although oleoyl-CoA (18:1-CoA) and linoleoyl-CoA (18:2-CoA) are not the major substrates of Acot2, Acot2 overexpression more than doubled the mitochondrial thioesterase activity for these substrates (see Fig.…”

Section: Studies In Mice: Hepatic Acot2 Overexpression Increases Hepamentioning

confidence: 99%

“…Mice were by guest, on May 9, 2018 www.jlr.org Downloaded from .html http://www.jlr.org/content/suppl/2014/08/11/jlr.M046961.DC1 Supplemental Material can be found at:…”

Section: Indirect Calorimetry Food Intake and Spontaneous Activity mentioning

confidence: 99%

Acyl-CoA thioesterase-2 facilitates mitochondrial fatty acid oxidation in the liver

Moffat

Bhatia

Nguyen

et al. 2014

Journal of Lipid Research

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This article is available online at http://www.jlr.org Pathophysiological mechanisms that underlie metabolic dysfunction such as insulin resistance and nonalcoholic fatty liver disease are complex. A role for mitochondrial FA oxidation (FAO) as a driver of dysfunction has been postulated ( 1-3 ), yet the mechanistic link between cellular metabolic dysfunction and mitochondrial FAO remains poorly defi ned ( 2 ). Insight would be gained by a better understanding of FAO. In particular, the modulation of ␤ -oxidation substrates and intermediates by mechanisms within the mitochondria is poorly understood, but is of interest in the context of evidence suggesting that longchain fatty acyl-CoA esters can inhibit FAO ( 4-6 ).Acyl-CoA thioesterases (Acots) in mitochondria, by virtue of their major substrates (long-chain fatty acyl-CoAs) and hydrolase activity which generates FA anion and free CoASH, have the potential to modulate the levels of FAO substrates and intermediates, and consequently to modulate FAO. The Acots are classifi ed as type I or II based on catalytic domain structure, and localize to the cytosol, peroxisomes, and mitochondria. The mitochondrial Acots are Acot2 (mitochondrial matrix) ( 7 ), Acot9 (matrix) ( 8 ), Acot15/Them5 (matrix) ( 9 ), Acot11/Them1 (outside the matrix) ( 10 ), and Acot13/Them2 (outside the matrix) ( 11 ). All are type II thioesterases except for Acot2. The only matrix-localized Acot for which a functional role has been delineated is Acot15. Its germline deletion in mice Abstract Acyl-CoA thioesterase (Acot)2 localizes to the mitochondrial matrix and hydrolyses long-chain fatty acyl-CoA into free FA and CoASH. Acot2 is expressed in highly oxidative tissues and is poised to modulate mitochondrial FA oxidation (FAO), yet its biological role is unknown. Using a model of adenoviral Acot2 overexpression in mouse liver (Ad-Acot2), we show that Acot2 increases the utilization of FA substrate during the daytime in ad libitum-fed mice, but the nighttime switch to carbohydrate oxidation is similar to control mice. In further support of elevated FAO in Acot2 liver, daytime serum ketones were higher in Ad-Acot2 mice, and overnight fasting led to minimal hepatic steatosis as compared with control mice. In liver mitochondria from AdAcot2 mice, phosphorylating O 2 consumption was higher with lipid substrate, but not with nonlipid substrate. This increase depended on whether FA could be activated on the outer mitochondrial membrane, suggesting that the FA released by Acot2 could be effl uxed from mitochondria then taken back up again for oxidation. This circuit would prevent the build-up of inhibitory long-chain fatty acyl-CoA esters. Altogether, our fi ndings indicate that Acot2 can enhance FAO, possibly by mitigating the accumulation of FAO intermediates within the mitochondrial matrix. -Moffat, C., L. Bhatia, T. Nguyen, P. Lynch, M. Wang, D. Wang, O. R. Ilkayeva, X. Han, M. D. Hirschey, S. M. Claypool, and E. L. Seifert. Acyl-CoA thioesterase-2 facilitates mitochondrial fatty acid oxidation in t...

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Cardiac and Skeletal Muscle Defects in a Mouse Model of Human Barth Syndrome

Cited by 220 publications

References 49 publications

Lysine-specific demethylase 1 restricts hematopoietic progenitor proliferation and is essential for terminal differentiation

Lysine-specific demethylase 1 restricts hematopoietic progenitor proliferation and is essential for terminal differentiation

Sickle cell anemia mice develop a unique cardiomyopathy with restrictive physiology

Acyl-CoA thioesterase-2 facilitates mitochondrial fatty acid oxidation in the liver

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