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

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    Author
    Ding, Y.
    Dvornikov, A.V.
    Wang, Y.
    Date
    2019
    Journal
    Disease models & mechanisms
    Publisher
    The Company of Biologists
    Type
    Article
    
    Metadata
    Show full item record
    See at
    https://doi.org/10.1242/dmm.040154
    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.
    Keyword
    BCL2-associated athanogene 3
    Danio rerio
    Dilated cardiomyopathy
    mTOR
    Identifier to cite or link to this item
    https://www.scopus.com/inward/record.uri?eid=2-s2.0-85072993325&doi=10.1242%2fdmm.040154&partnerID=40&md5=45c5c1f2b86753a5d7455a907fb959e9; http://hdl.handle.net/10713/11161
    ae974a485f413a2113503eed53cd6c53
    10.1242/dmm.040154
    Scopus Count
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    UMB Open Access Articles 2019

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