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dc.contributor.authorDvornikov, Alexey V
dc.contributor.authorWang, Mingmin
dc.contributor.authorYang, Jingchun
dc.contributor.authorZhu, Ping
dc.contributor.authorLe, Tai
dc.contributor.authorLin, Xueying
dc.contributor.authorCao, Hung
dc.contributor.authorXu, Xiaolei
dc.date.accessioned2019-09-06T23:04:50Z
dc.date.available2019-09-06T23:04:50Z
dc.date.issued2019-08-01
dc.identifier.citationDvornikov, A. V., Wang, M., Yang, J., Zhu, P., Le, T., Lin, X., ... & Xu, X. (2019). Phenotyping an adult zebrafish lamp2 cardiomyopathy model identifies mTOR inhibition as a candidate therapy. Journal of molecular and cellular cardiology.en_US
dc.identifier.issn0022-2828
dc.identifier.pmid31228518
dc.identifier.doi10.1016/j.yjmcc.2019.06.013
dc.identifier.urihttp://hdl.handle.net/10150/634136
dc.description.abstractAdult zebrafish is an emerging vertebrate model for studying genetic basis of cardiomyopathies; but whether the simple fish heart can model essential features of hypertrophic cardiomyopathy (HCM) remained unknown. Here, we report a comprehensive phenotyping of a lamp2 knockout (KO) mutant. LAMP2 encodes a lysosomal protein and is a causative gene of Danon disease that is characterized by HCM and massive autophagic vacuoles accumulation in the tissues. There is no effective therapy yet to treat this most lethal cardiomyopathy in the young. First, we did find the autophagic vacuoles accumulation in cardiac tissues from lamp2 KO. Next, through employing a set of emerging phenotyping tools, we revealed heart failure phenotypes in the lamp2 KO mutants, including decreased ventricular ejection fraction, reduced physical exercise capacity, blunted beta-adrenergic contractile response, and enlarged atrium. We also noted changes of the following indices suggesting cardiac hypertrophic remodeling in lamp2 KO: a rounded heart shape, increased end-systolic ventricular volume and density of ventricular myocardium, elevated actomyosin activation kinetics together with increased maximal isometric tension at the level of cardiac myofibrils. Lastly, we assessed the function of lysosomal-localized mTOR on the lamp2-associated Danon disease. We found that haploinsufficiency of mtor was able to normalize some characteristics of the lamp2 KO, including ejection fraction, beta-adrenergic response, and the actomyosin activation kinetics. In summary, we demonstrate the feasibility of modeling the inherited HCM in the adult zebrafish, which can be used to develop potential therapies.en_US
dc.description.sponsorshipNIH [R01HL107304, HL81753, HL111437]; Mayo Foundationen_US
dc.language.isoenen_US
dc.publisherELSEVIER SCI LTDen_US
dc.rights© 2019 Elsevier Ltd. All rights reserved.en_US
dc.subjectCardiac contractilityen_US
dc.subjectCardiomyopathyen_US
dc.subjectDanon diseaseen_US
dc.subjectDisease modelingen_US
dc.subjectHypertrophic remodelingen_US
dc.subjectSingle myofibrilen_US
dc.subjectZebrafishen_US
dc.subjectmTORen_US
dc.titlePhenotyping an adult zebrafish lamp2 cardiomyopathy model identifies mTOR inhibition as a candidate therapyen_US
dc.typeArticleen_US
dc.contributor.departmentUniv Arizona, Dept Cellular & Mol Meden_US
dc.identifier.journalJOURNAL OF MOLECULAR AND CELLULAR CARDIOLOGYen_US
dc.description.note12 month embargo; published online: 20 June 2019en_US
dc.description.collectioninformationThis item from the UA Faculty Publications collection is made available by the University of Arizona with support from the University of Arizona Libraries. If you have questions, please contact us at repository@u.library.arizona.edu.en_US
dc.eprint.versionFinal accepted manuscripten_US
dc.source.journaltitleJournal of molecular and cellular cardiology


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