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Dis Model Mech. 2019 Oct 1;12(10). pii: dmm040154. doi: 10.1242/dmm.040154.

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

Ding Y1,2, Dvornikov AV3,2, Ma X3,2,4,5, Zhang H3,2,6, Wang Y3,2,7, Lowerison M8, Packard RR9, Wang L10, Chen J11, Zhang Y10, Hsiai T9, Lin X3,2, Xu X1,2,4,5.

Author information

1
Department of Biochemistry and Molecular Biology, Mayo Clinic, Rochester, MN 55905, USA Xu.Xiaolei@mayo.edu Ding.Yonghe@mayo.edu.
2
Department of Cardiovascular Medicine, Mayo Clinic, Rochester, MN 55905, USA.
3
Department of Biochemistry and Molecular Biology, Mayo Clinic, Rochester, MN 55905, USA.
4
Center for Clinical and Translational Science, Mayo Clinic, Rochester, MN 55905, USA.
5
Mayo Graduate School of Biomedical Sciences, Mayo Clinic, Rochester, MN 55905, USA.
6
Clinical Center for Gene Diagnosis and Therapy, the Second Xiangya Hospital of Central South University, Changsha, China 410011.
7
Institute of Life Science, Beijing University of Chinese Medicine, Beijing, China 100029.
8
Department of Urology, Mayo Clinic, Rochester, MN 55905, USA.
9
School of Medicine, University of California Los Angeles, Los Angeles, CA 90073, USA.
10
Department of Epidemiology and Public Health, University of Maryland School of Medicine, Baltimore, MD 21201, USA.
11
Division of Biomedical Statistics and Informatics, Mayo Clinic, Rochester, MN 55905, USA.

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.

KEYWORDS:

BCL2-associated athanogene 3; Danio rerio; Dilated cardiomyopathy; mTOR

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