Abstract 047: Transgenic troponin T in Zebrafish recapitulates a Unique type of Cardiomyopathy

Background: Cardiomyopathy-like phenotype has been recently reported in adult zebrafish stressed by either anemia or doxorubicin. However, it still remains unclear whether gene-based manipulation in this emerging animal model can faithfully recapitulate cardiomyopathy phenotypes in mammals. Here, we aim to address this question by generating the first transgenic model for cardiomyopathy in zebrafish. Results: We generated a panel of three transgenic fish lines, including Tg(cmlc2:Tnnt2) that overexpress wild type Tnnt2 in the whole heart, Tg(cmlc2:Tnnt2c) that drive a C-terminal amino acid truncated Tnnt2 (Tnnt2C) in the whole heart, and Tg(vmhc:Tnnt2c) that drives Tnnt2c expression only in the ventricle. Upon overexpression of the Tnnt2C, but not the full-length control, in the heart caused reduced ventricular size but enlarged atrium. A same morphological phenotype was noted in Tg(vmhc:Tnnt2c). At the cellular level, we found significantly reduced size of cardiomyocyte and increased cell proliferation. The morphological remodeling is accompanied by hallmarks of cardiomyopathy including reduced cardiac function and myofibril disarray. Conclusion: Transgenic overexpression of Tnnt2C in zebrafish faithfully recapitulates unique cardiomyopathy phenotypes noted in both human patients harboring the similar mutation and mice transgenic models, underscoring zebrafish as a conserved vertebrate model for cardiomyopathy. Our study further suggested that the dysfunction of Tnnt2C in ventricle is primarily responsible for cardiac phenotypes, while the enlarged atrium is a consequence of a defective ventricle.