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    Phenotyping an adult zebrafish lamp2 cardiomyopathy model identifies mTOR inhibition as a candidate therapy

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    Final Accepted Manuscript
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    Author
    Dvornikov, Alexey V
    Wang, Mingmin
    Yang, Jingchun
    Zhu, Ping
    Le, Tai
    Lin, Xueying
    Cao, Hung
    Xu, Xiaolei
    Affiliation
    Univ Arizona, Dept Cellular & Mol Med
    Issue Date
    2019-08-01
    Keywords
    Cardiac contractility
    Cardiomyopathy
    Danon disease
    Disease modeling
    Hypertrophic remodeling
    Single myofibril
    Zebrafish
    mTOR
    
    Metadata
    Show full item record
    Publisher
    ELSEVIER SCI LTD
    Citation
    Dvornikov, 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.
    Journal
    JOURNAL OF MOLECULAR AND CELLULAR CARDIOLOGY
    Rights
    © 2019 Elsevier Ltd. All rights reserved.
    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
    Adult 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.
    Note
    12 month embargo; published online: 20 June 2019
    ISSN
    0022-2828
    PubMed ID
    31228518
    DOI
    10.1016/j.yjmcc.2019.06.013
    Version
    Final accepted manuscript
    Sponsors
    NIH [R01HL107304, HL81753, HL111437]; Mayo Foundation
    ae974a485f413a2113503eed53cd6c53
    10.1016/j.yjmcc.2019.06.013
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