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dc.contributor.authorDing, Yonghe
dc.contributor.authorDvornikov, Alexey V
dc.contributor.authorMa, Xiao
dc.contributor.authorZhang, Hong
dc.contributor.authorWang, Yong
dc.contributor.authorLowerison, Matthew
dc.contributor.authorPackard, Rene R
dc.contributor.authorWang, Lei
dc.contributor.authorChen, Jun
dc.contributor.authorZhang, Yuji
dc.contributor.authorHsiai, Tzung
dc.contributor.authorLin, Xueying
dc.contributor.authorXu, Xiaolei
dc.date.accessioned2019-12-06T02:08:46Z
dc.date.available2019-12-06T02:08:46Z
dc.date.issued2019-10-01
dc.identifier.citationDing, Y., Dvornikov, A. V., Ma, X., Zhang, H., Wang, Y., Lowerison, M., ... & Hsiai, T. (2019). Haploinsufficiency of mechanistic target of rapamycin ameliorates bag3 cardiomyopathy in adult zebrafish. Disease models & mechanisms, 12(10), dmm040154.en_US
dc.identifier.issn1754-8403
dc.identifier.pmid31492659
dc.identifier.doi10.1242/dmm.040154
dc.identifier.urihttp://hdl.handle.net/10150/636286
dc.description.abstractThe adult zebrafish is an emerging vertebrate model for studying human cardiomyopathies; however, whether the simple zebrafish heart can model different subtypes of cardiomyopathies, such as dilated cardiomyopathy (DCM), remains elusive. Here, we generated and characterized an inherited DCM model in adult zebrafish and used this model to search for therapeutic strategies. We employed transcription activator-like effector nuclease (TALEN) genome editing technology to generate frame-shift mutants for the zebrafish ortholog of human BCL2-associated athanogene 3 (BAG3), an established DCM-causative gene. As in mammals, the zebrafish bag3 homozygous mutant (bag3e2/e2 ) exhibited aberrant proteostasis, as indicated by impaired autophagy flux and elevated ubiquitinated protein aggregation. Through comprehensive phenotyping analysis of the mutant, we identified phenotypic traits that resembled DCM phenotypes in mammals, including cardiac chamber enlargement, reduced ejection fraction characterized by increased end-systolic volume/body weight (ESV/BW), and reduced contractile myofibril activation kinetics. Nonbiased transcriptome analysis identified the hyperactivation of the mechanistic target of rapamycin (mTOR) signaling in bag3e2/e2 mutant hearts. Further genetic studies showed that mtorxu015/+ , an mTOR haploinsufficiency mutant, repaired abnormal proteostasis, improved cardiac function and rescued the survival of the bag3e2/e2 mutant. This study established the bag3e2/e2 mutant as a DCM model in adult zebrafish and suggested mtor as a candidate therapeutic target gene for BAG3 cardiomyopathy.en_US
dc.description.sponsorshipAmerican Heart Association [14SDG18160021]; Mayo Clinic; United States Department of Health & Human Services National Institutes of Health (NIH) - USA [HL81753, HL107304, HL111437, GM63904]; Mayo Foundation for Medical Education and Researchen_US
dc.language.isoenen_US
dc.publisherCOMPANY BIOLOGISTS LTDen_US
dc.rightsCopyright © 2019. Published by The Company of Biologists Ltd. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (https://creativecommons.org/licenses/by/4.0).en_US
dc.rights.urihttps://creativecommons.org/licenses/by/4.0/
dc.subjectBCL2-associated athanogene 3en_US
dc.subjectDanio rerioen_US
dc.subjectDilated cardiomyopathyen_US
dc.subjectmTORen_US
dc.titleHaploinsufficiency of mechanistic target of rapamycin ameliorates bag3 cardiomyopathy in adult zebrafishen_US
dc.typeArticleen_US
dc.contributor.departmentUniv Arizona, Dept Cellular & Mol Meden_US
dc.identifier.journalDISEASE MODELS & MECHANISMSen_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 published versionen_US
dc.source.journaltitleDisease models & mechanisms
refterms.dateFOA2019-12-06T02:08:47Z


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Copyright © 2019. Published by The Company of Biologists Ltd. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (https://creativecommons.org/licenses/by/4.0).
Except where otherwise noted, this item's license is described as Copyright © 2019. Published by The Company of Biologists Ltd. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (https://creativecommons.org/licenses/by/4.0).