Haploinsufficiency of mechanistic target of rapamycin ameliorates cardiomyopathy in adult zebrafish
Dvornikov, Alexey V
Packard, Rene R
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PublisherCompany of Biologists
CitationDing, Y., Dvornikov, A. V., Ma, X., Zhang, H., Wang, Y., Lowerison, M., ... & Hsiai, T. (2019). Haploinsufficiency of mechanistic target of rapamycin ameliorates bag3 cardiomyopathy in adult zebrafish. Disease models & mechanisms, 12(10), dmm040154.
JournalDisease Models & Mechanisms
Rights© 2019. Published by The Company of Biologists Ltd. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (https://creativecommons.org/licenses/by/4.0), which permits unrestricted use, distribution and reproduction in any medium provided that the original work is properly attributed.
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AbstractThe 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.
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SponsorsThis work was supported in part by the Scientist Development Grant from the American Heart Association (14SDG18160021) to Y.D., the Ted and Loretta Rogers Cardiovascular Career Development Award Honoring Hugh C. Smith (from the Mayo Clinic) to Y.D., the National Institutes of Health (HL81753, HL107304, HL111437 and GM63904) to X.X., and the Mayo Foundation for Medical Education and Research to X.X.