Modeling Inherited Cardiomyopathies in Adult Zebrafish for Precision Medicine.

Yonghe Ding,Xiaolei Xu,Haisong Bu

doi:10.3389/fphys.2020.599244

Abstract

Cardiomyopathies are a highly heterogeneous group of heart muscle disorders. More than 100 causative genes have been linked to various cardiomyopathies, which explain about half of familial cardiomyopathy cases. More than a dozen candidate therapeutic signaling pathways have been identified; however, precision medicine is not being used to treat the various types of cardiomyopathy because knowledge is lacking for how to tailor treatment plans for different genetic causes. Adult zebrafish (Danio rerio) have a higher throughout than rodents and are an emerging vertebrate model for studying cardiomyopathy. Herein, we review progress in the past decade that has proven the feasibility of this simple vertebrate for modeling inherited cardiomyopathies of distinct etiology, identifying effective therapeutic strategies for a particular type of cardiomyopathy, and discovering new cardiomyopathy genes or new therapeutic strategies via a forward genetic approach. On the basis of this progress, we discuss future research that would benefit from integrating this emerging model, including discovery of remaining causative genes and development of genotype-based therapies. Studies using this efficient vertebrate model are anticipated to significantly accelerate the implementation of precision medicine for inherited cardiomyopathies.

Highlights

Cardiomyopathy refers to a group of heterogeneous heart muscle disorders that cause cardiac dysfunction
Described were increased maximal isometric tension and accelerated actomyosin activation kinetics at the single-myofibril level, suggesting myofibrillar “hypercontractility.” Because many of these phenotypes are characteristic features of hypertrophic cardiomyopathy (HCM) in human patients and mammalian models, this study provided a starting point to define HCM-like phenotypic traits in adult zebrafish
We detected decreased maximal isometric tension and reduced activation of myofibril kinetics at the single-myofibril level, suggesting “hypocontractility.” Because many phenotypic traits are characteristic features of dilated cardiomyopathy (DCM) in human patients and mammalian models, this study provides a starting point to define DCM-like phenotypic traits in adult zebrafish models

Summary

INTRODUCTION

Cardiomyopathy refers to a group of heterogeneous heart muscle disorders that cause cardiac dysfunction. Because a zebrafish heart is only sized about 1–2 mm in diameter, novel phenotyping toolkits, such as high-frequency echocardiography, the Langendorff ex vivo system, ECG, and single-myofibril contractility analysis, have been developed to define progression of cardiac remodeling in zebrafish (Dvornikov et al, 2014; Lin et al, 2015; Koth et al, 2017; Merrifield et al, 2017; Wang et al, 2017; Stoyek et al, 2018; Zhang et al, 2018; Wakamatsu et al, 2019; Yan et al, 2020) We did not include the RCM group because no adult zebrafish model for a human RCM gene has been reported yet

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CONCLUSION