Santiago Celine F, Huttner Inken G, Fatkin Diane
Molecular Cardiology and Biophysics Division, Victor Chang Cardiac Research Institute, Darlinghurst, NSW 2010, Australia.
St. Vincent's Clinical School, Faculty of Medicine, UNSW Sydney, Kensington, NSW 2052, Australia.
J Cardiovasc Dev Dis. 2021 Jan 25;8(2):10. doi: 10.3390/jcdd8020010.
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 gene, which encodes the giant sarcomeric protein titin (tv), are the most common genetic cause of DCM, but exactly how tv promote cardiomyocyte dysfunction is not known. Although rodent models have been widely used to investigate titin biology, they have had limited utility for tv-related DCM. In recent years, zebrafish () 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 tv 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.
扩张型心肌病（DCM）是一种常见的心肌疾病，其特征为心室扩张和收缩功能障碍，与显著的发病率和死亡率相关。迫切需要对疾病机制以及治疗和预防策略有新的认识。编码巨大肌节蛋白肌联蛋白（tv）的基因中的截短变异是DCM最常见的遗传原因，但tv究竟如何促进心肌细胞功能障碍尚不清楚。尽管啮齿动物模型已被广泛用于研究肌联蛋白生物学，但它们在与tv相关的DCM研究中的效用有限。近年来，斑马鱼已成为研究健康和患病心脏中肌联蛋白功能的强大替代模型系统。光学透明的斑马鱼胚胎模型已证明肌联蛋白在肌节组装和心脏发育中的关键作用。用于评估成年斑马鱼心脏功能的先进成像工具的日益普及彻底改变了该领域，并为模拟人类遗传疾病带来了新机会。现已培育出携带人类A带tv的转基因斑马鱼，并显示其会随着年龄增长自发发展为DCM。这种斑马鱼模型将成为阐明遗传和环境因素对表型的修饰作用以及探索新药物疗法的宝贵资源。
