{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,26]],"date-time":"2026-09-26T05:09:04Z","timestamp":1790399344394,"version":"4.1.0"},"reference-count":57,"publisher":"The Company of Biologists","issue":"10","license":[{"start":{"date-parts":[[2021,2,8]],"date-time":"2021-02-08T00:00:00Z","timestamp":1612742400000},"content-version":"vor","delay-in-days":496,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0"}],"funder":[{"DOI":"10.13039\/100000968","name":"American Heart Association","doi-asserted-by":"publisher","award":["14SDG18160021"],"award-info":[{"award-number":["14SDG18160021"]}],"id":[{"id":"10.13039\/100000968","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000871","name":"Mayo Clinic","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100000871","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"publisher","award":["HL81753"],"award-info":[{"award-number":["HL81753"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"publisher","award":["HL107304"],"award-info":[{"award-number":["HL107304"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"publisher","award":["HL111437"],"award-info":[{"award-number":["HL111437"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"publisher","award":["GM63904"],"award-info":[{"award-number":["GM63904"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100007048","name":"Mayo Foundation for Medical Education and Research","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100007048","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2019,10,1]]},"abstract":"<jats:title>ABSTRACT<\/jats:title>\n               <jats:p>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.<\/jats:p>","DOI":"10.1242\/dmm.040154","type":"journal-article","created":{"date-parts":[[2019,9,6]],"date-time":"2019-09-06T13:05:12Z","timestamp":1567775112000},"source":"Crossref","is-referenced-by-count":26,"title":["Haploinsufficiency of mechanistic target of rapamycin ameliorates <i>bag3<\/i> cardiomyopathy in adult zebrafish"],"prefix":"10.1242","volume":"12","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-4531-1721","authenticated-orcid":false,"given":"Yonghe","family":"Ding","sequence":"first","affiliation":[{"name":"Mayo Clinic 1 Department of Biochemistry and Molecular Biology , , Rochester, MN 55905 , USA"},{"name":"Mayo Clinic 2 Department of Cardiovascular Medicine , , Rochester, MN 55905 , USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1514-4747","authenticated-orcid":false,"given":"Alexey V.","family":"Dvornikov","sequence":"additional","affiliation":[{"name":"Mayo Clinic 1 Department of Biochemistry and Molecular Biology , , Rochester, MN 55905 , USA"},{"name":"Mayo Clinic 2 Department of Cardiovascular Medicine , , Rochester, MN 55905 , USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xiao","family":"Ma","sequence":"additional","affiliation":[{"name":"Mayo Clinic 1 Department of Biochemistry and Molecular Biology , , Rochester, MN 55905 , USA"},{"name":"Mayo Clinic 2 Department of Cardiovascular Medicine , , Rochester, MN 55905 , USA"},{"name":"Center for Clinical and Translational Science, Mayo Clinic 3 , Rochester, MN 55905 , USA"},{"name":"Mayo Graduate School of Biomedical Sciences, Mayo Clinic 4 , Rochester, MN 55905 , USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hong","family":"Zhang","sequence":"additional","affiliation":[{"name":"Mayo Clinic 1 Department of Biochemistry and Molecular Biology , , Rochester, MN 55905 , USA"},{"name":"Mayo Clinic 2 Department of Cardiovascular Medicine , , Rochester, MN 55905 , USA"},{"name":"Clinical Center for Gene Diagnosis and Therapy, the Second Xiangya Hospital of Central South University 5 , Changsha , China 410011"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yong","family":"Wang","sequence":"additional","affiliation":[{"name":"Mayo Clinic 1 Department of Biochemistry and Molecular Biology , , Rochester, MN 55905 , USA"},{"name":"Mayo Clinic 2 Department of Cardiovascular Medicine , , Rochester, MN 55905 , USA"},{"name":"Institute of Life Science, Beijing University of Chinese Medicine 6 , Beijing , China 100029"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Matthew","family":"Lowerison","sequence":"additional","affiliation":[{"name":"Mayo Clinic 7 Department of Urology , , Rochester, MN 55905 , USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rene R.","family":"Packard","sequence":"additional","affiliation":[{"name":"School of Medicine, University of California Los Angeles 8 , Los Angeles, CA 90073 , USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lei","family":"Wang","sequence":"additional","affiliation":[{"name":"University of Maryland School of Medicine 9 Department of Epidemiology and Public Health , , Baltimore, MD 21201 , USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jun","family":"Chen","sequence":"additional","affiliation":[{"name":"Mayo Clinic 10 Division of Biomedical Statistics and Informatics , , Rochester, MN 55905 , USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yuji","family":"Zhang","sequence":"additional","affiliation":[{"name":"University of Maryland School of Medicine 9 Department of Epidemiology and Public Health , , Baltimore, MD 21201 , USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tzung","family":"Hsiai","sequence":"additional","affiliation":[{"name":"School of Medicine, University of California Los Angeles 8 , Los Angeles, CA 90073 , USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4928-3422","authenticated-orcid":false,"given":"Xueying","family":"Lin","sequence":"additional","affiliation":[{"name":"Mayo Clinic 1 Department of Biochemistry and Molecular Biology , , Rochester, MN 55905 , USA"},{"name":"Mayo Clinic 2 Department of Cardiovascular Medicine , , Rochester, MN 55905 , USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4928-3422","authenticated-orcid":false,"given":"Xiaolei","family":"Xu","sequence":"additional","affiliation":[{"name":"Mayo Clinic 1 Department of Biochemistry and Molecular Biology , , Rochester, MN 55905 , USA"},{"name":"Mayo Clinic 2 Department of Cardiovascular Medicine , , Rochester, MN 55905 , USA"},{"name":"Center for Clinical and Translational Science, Mayo Clinic 3 , Rochester, MN 55905 , USA"},{"name":"Mayo Graduate School of Biomedical Sciences, Mayo Clinic 4 , Rochester, MN 55905 , USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"237","published-online":{"date-parts":[[2019,10,1]]},"reference":[{"key":"2024061302153389200_DMM040154C1","doi-asserted-by":"publisher","first-page":"1481","DOI":"10.1002\/humu.21603","article-title":"Dilated cardiomyopathy-associated BAG3 mutations impair Z-disc assembly and enhance sensitivity to apoptosis in 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Cardiol."},{"key":"2024061302153389200_DMM040154C4","doi-asserted-by":"publisher","first-page":"2782","DOI":"10.1016\/j.bpj.2012.04.049","article-title":"Cell-intrinsic functional effects of the alpha-cardiac myosin Arg-403-Gln mutation in familial hypertrophic cardiomyopathy","volume":"102","author":"Chuan","year":"2012","journal-title":"Biophys. J."},{"key":"2024061302153389200_DMM040154C5","doi-asserted-by":"publisher","first-page":"H284","DOI":"10.1152\/ajpheart.00128.2007","article-title":"Hypertrophic and dilated cardiomyopathy mutations differentially affect the molecular force generation of mouse alpha-cardiac myosin in the laser trap assay","volume":"293","author":"Debold","year":"2007","journal-title":"Am. J. Physiol. Heart Circ. 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