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    Haploinsufficiency of mechanistic target of rapamycin ameliorates bag3 cardiomyopathy in adult zebrafish

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    Author
    Ding, Yonghe
    Dvornikov, Alexey V
    Ma, Xiao
    Zhang, Hong
    Wang, Yong
    Lowerison, Matthew
    Packard, Rene R
    Wang, Lei
    Chen, Jun
    Zhang, Yuji
    Hsiai, Tzung
    Lin, Xueying
    Xu, Xiaolei
    Show allShow less
    Affiliation
    Univ Arizona, Dept Cellular & Mol Med
    Issue Date
    2019-10-01
    Keywords
    BCL2-associated athanogene 3
    Danio rerio
    Dilated cardiomyopathy
    mTOR
    
    Metadata
    Show full item record
    Publisher
    COMPANY BIOLOGISTS LTD
    Citation
    Ding, 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.
    Journal
    DISEASE MODELS & MECHANISMS
    Rights
    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), which permits unrestricted use, distribution and reproduction in any medium provided that the original work is properly attributed.
    Collection Information
    This 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.
    Abstract
    The 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.
    ISSN
    1754-8403
    PubMed ID
    31492659
    DOI
    10.1242/dmm.040154
    Version
    Final published version
    Sponsors
    American 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 Research
    ae974a485f413a2113503eed53cd6c53
    10.1242/dmm.040154
    Scopus Count
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