PMID- 31492659 OWN - NLM STAT- MEDLINE DCOM- 20200526 LR - 20240421 IS - 1754-8411 (Electronic) IS - 1754-8403 (Print) IS - 1754-8403 (Linking) VI - 12 IP - 10 DP - 2019 Oct 1 TI - Haploinsufficiency of mechanistic target of rapamycin ameliorates bag3 cardiomyopathy in adult zebrafish. LID - 10.1242/dmm.040154 [doi] LID - dmm040154 AB - 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 (bag3(e2/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 bag3(e2/e2) mutant hearts. Further genetic studies showed that mtor(xu015/+) , an mTOR haploinsufficiency mutant, repaired abnormal proteostasis, improved cardiac function and rescued the survival of the bag3(e2/e2) mutant. This study established the bag3(e2/e2) mutant as a DCM model in adult zebrafish and suggested mtor as a candidate therapeutic target gene for BAG3 cardiomyopathy. CI - (c) 2019. Published by The Company of Biologists Ltd. FAU - Ding, Yonghe AU - Ding Y AUID- ORCID: 0000-0002-4531-1721 AD - Department of Biochemistry and Molecular Biology, Mayo Clinic, Rochester, MN 55905, USA Xu.Xiaolei@mayo.edu Ding.Yonghe@mayo.edu. AD - Department of Cardiovascular Medicine, Mayo Clinic, Rochester, MN 55905, USA. FAU - Dvornikov, Alexey V AU - Dvornikov AV AUID- ORCID: 0000-0003-1514-4747 AD - Department of Biochemistry and Molecular Biology, Mayo Clinic, Rochester, MN 55905, USA. AD - Department of Cardiovascular Medicine, Mayo Clinic, Rochester, MN 55905, USA. FAU - Ma, Xiao AU - Ma X AD - Department of Biochemistry and Molecular Biology, Mayo Clinic, Rochester, MN 55905, USA. AD - Department of Cardiovascular Medicine, Mayo Clinic, Rochester, MN 55905, USA. AD - Center for Clinical and Translational Science, Mayo Clinic, Rochester, MN 55905, USA. AD - Mayo Graduate School of Biomedical Sciences, Mayo Clinic, Rochester, MN 55905, USA. FAU - Zhang, Hong AU - Zhang H AD - Department of Biochemistry and Molecular Biology, Mayo Clinic, Rochester, MN 55905, USA. AD - Department of Cardiovascular Medicine, Mayo Clinic, Rochester, MN 55905, USA. AD - Clinical Center for Gene Diagnosis and Therapy, the Second Xiangya Hospital of Central South University, Changsha, China 410011. FAU - Wang, Yong AU - Wang Y AD - Department of Biochemistry and Molecular Biology, Mayo Clinic, Rochester, MN 55905, USA. AD - Department of Cardiovascular Medicine, Mayo Clinic, Rochester, MN 55905, USA. AD - Institute of Life Science, Beijing University of Chinese Medicine, Beijing, China 100029. FAU - Lowerison, Matthew AU - Lowerison M AD - Department of Urology, Mayo Clinic, Rochester, MN 55905, USA. FAU - Packard, Rene R AU - Packard RR AD - School of Medicine, University of California Los Angeles, Los Angeles, CA 90073, USA. FAU - Wang, Lei AU - Wang L AD - Department of Epidemiology and Public Health, University of Maryland School of Medicine, Baltimore, MD 21201, USA. FAU - Chen, Jun AU - Chen J AD - Division of Biomedical Statistics and Informatics, Mayo Clinic, Rochester, MN 55905, USA. FAU - Zhang, Yuji AU - Zhang Y AD - Department of Epidemiology and Public Health, University of Maryland School of Medicine, Baltimore, MD 21201, USA. FAU - Hsiai, Tzung AU - Hsiai T AD - School of Medicine, University of California Los Angeles, Los Angeles, CA 90073, USA. FAU - Lin, Xueying AU - Lin X AUID- ORCID: 0000-0002-4928-3422 AD - Department of Biochemistry and Molecular Biology, Mayo Clinic, Rochester, MN 55905, USA. AD - Department of Cardiovascular Medicine, Mayo Clinic, Rochester, MN 55905, USA. FAU - Xu, Xiaolei AU - Xu X AUID- ORCID: 0000-0002-4928-3422 AD - Department of Biochemistry and Molecular Biology, Mayo Clinic, Rochester, MN 55905, USA Xu.Xiaolei@mayo.edu Ding.Yonghe@mayo.edu. AD - Department of Cardiovascular Medicine, Mayo Clinic, Rochester, MN 55905, USA. AD - Center for Clinical and Translational Science, Mayo Clinic, Rochester, MN 55905, USA. AD - Mayo Graduate School of Biomedical Sciences, Mayo Clinic, Rochester, MN 55905, USA. LA - eng GR - R01 HL081753/HL/NHLBI NIH HHS/United States GR - R01 HL118650/HL/NHLBI NIH HHS/United States GR - R01 HL107304/HL/NHLBI NIH HHS/United States GR - R01 HL111437/HL/NHLBI NIH HHS/United States GR - R01 GM063904/GM/NIGMS NIH HHS/United States GR - R56 GM063904/GM/NIGMS NIH HHS/United States PT - Journal Article PT - Research Support, N.I.H., Extramural PT - Research Support, Non-U.S. Gov't DEP - 20191001 PL - England TA - Dis Model Mech JT - Disease models & mechanisms JID - 101483332 RN - 0 (Adaptor Proteins, Signal Transducing) RN - 0 (Apoptosis Regulatory Proteins) RN - 0 (BAG3 protein, zebrafish) RN - 0 (Zebrafish Proteins) RN - EC 2.7.11.1 (TOR Serine-Threonine Kinases) RN - EC 2.7.11.1 (mTOR protein, zebrafish) RN - EC 3.1.- (Transcription Activator-Like Effector Nucleases) SB - IM MH - Adaptor Proteins, Signal Transducing/genetics/*metabolism MH - Amino Acid Sequence MH - Animals MH - Apoptosis Regulatory Proteins/genetics/*metabolism MH - Base Sequence MH - Cardiomyopathies/*genetics/pathology MH - Gene Expression Profiling MH - Haploinsufficiency/*genetics MH - Mutation/genetics MH - Myocardium/metabolism/pathology MH - Phenotype MH - Signal Transduction MH - TOR Serine-Threonine Kinases/*metabolism MH - Transcription Activator-Like Effector Nucleases MH - Zebrafish/*genetics MH - Zebrafish Proteins/genetics/*metabolism PMC - PMC6826022 OTO - NOTNLM OT - BCL2-associated athanogene 3 OT - Danio rerio OT - Dilated cardiomyopathy OT - mTOR COIS- Competing interestsThe authors declare no competing or financial interests. EDAT- 2019/09/08 06:00 MHDA- 2020/05/27 06:00 PMCR- 2019/10/01 CRDT- 2019/09/08 06:00 PHST- 2019/04/16 00:00 [received] PHST- 2019/08/28 00:00 [accepted] PHST- 2019/09/08 06:00 [pubmed] PHST- 2020/05/27 06:00 [medline] PHST- 2019/09/08 06:00 [entrez] PHST- 2019/10/01 00:00 [pmc-release] AID - dmm.040154 [pii] AID - DMM040154 [pii] AID - 10.1242/dmm.040154 [doi] PST - epublish SO - Dis Model Mech. 2019 Oct 1;12(10):dmm040154. doi: 10.1242/dmm.040154.