Abstract
Dilated cardiomyopathy (DCM) is a common heart muscle disorder characterized by ventricular dilation and contractile dysfunction that is associated with significant morbidity and mortality. New insights into disease mechanisms and strategies for treatment and prevention are urgently needed. Truncating variants in the TTN gene, which encodes the giant sarcomeric protein titin (TTNtv), are the most common genetic cause of DCM, but exactly how TTNtv promote cardiomyocyte dysfunction is not known. Although rodent models have been widely used to investigate titin biology, they have had limited utility for TTNtv-related DCM. In recent years, zebrafish (Danio rerio) have emerged as a powerful alternative model system for studying titin function in the healthy and diseased heart. Optically transparent embryonic zebrafish models have demonstrated key roles of titin in sarcomere assembly and cardiac development. The increasing availability of sophisticated imaging tools for assessment of heart function in adult zebrafish has revolutionized the field and opened new opportunities for modelling human genetic disorders. Genetically modified zebrafish that carry a human A-band TTNtv have now been generated and shown to spontaneously develop DCM with age. This zebrafish model will be a valuable resource for elucidating the phenotype modifying effects of genetic and environmental factors, and for exploring new drug therapies.
Highlights
This review summarizes the contribution that zebrafish models have made to our current understanding of titin’s role in the heart and how they might be used to elucidate mechanisms of
This is partially regulated at the transcriptional level by the master splicing regulator RNA binding motif 20 (RBM20), as a previous study performed in RBM20 knockout rats found that the loss of RBM20 is associated with the exclusive expression of longer N2BA isoforms [31]
Using IHC on whole-mount embryonic skeletal muscle, Myhre et al found that homozygous hel mutants appeared to express a truncated titin protein that was incorporated into rudimentary sarcomere structures
Summary
Publisher’s Note: MDPI stays neutral with regard to jurisdictional claims in published maps and institutional affiliations. Knowing how, when, and if, TTNtv will affect heart function in individual carriers are important questions for the clinical management of patients and their families. Further studies are required to elucidate the effects of TTNtv alone, as well as the potential interactions of TTNtv with other genetic and/or environmental risk factors. Such studies are difficult to perform in human patients given the enormous challenges in accurately controlling for differences in genetic background, co-morbidities and lifestyle factors. Summarizes the contribution that zebrafish models have made to our current understanding of titin’s role in the heart and how they might be used to elucidate mechanisms of TTNtv-related DCM
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