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Mechanisms of TTNtv-Related Dilated Cardiomyopathy: Insights from Zebrafish Models
Celine F Santiago1,2, Inken G Huttner1,2, Diane Fatkin1,2,3
1Molecular Cardiology and Biophysics Division, Victor Chang Cardiac Research Institute, Darlinghurst, NSW 2010, Australia.
Insights
Truncating variants in the TTN gene cause dilated cardiomyopathy (DCM). A new zebrafish model carrying a human TTN variant spontaneously develops DCM, offering insights into disease mechanisms and potential therapies.
Area of Science:
- Cardiovascular Research
- Genetics
- Zebrafish Models
Background:
- Dilated cardiomyopathy (DCM) is a prevalent heart muscle disorder with high morbidity and mortality.
- Truncating variants in the TTN gene (TTNtv) are the leading genetic cause of DCM, but underlying mechanisms remain unclear.
- Rodent models have limitations for studying TTNtv-related DCM.
Purpose of the Study:
- To investigate the utility of zebrafish as a model for TTNtv-related DCM.
- To develop and characterize a zebrafish model carrying a human TTN variant.
- To explore potential therapeutic strategies for DCM.
Main Methods:
- Generation of genetically modified zebrafish with a human A-band TTNtv.
- Longitudinal assessment of cardiac function and structure in adult zebrafish.
- Utilizing advanced imaging techniques for heart function analysis.
Main Results:
- Zebrafish carrying the human TTNtv spontaneously developed DCM with age.
- The model recapitulates key features of human DCM.
- Demonstrated the feasibility of using zebrafish for DCM research.
Conclusions:
- Zebrafish serve as a powerful and relevant model for studying TTNtv-related DCM.
- This model facilitates the investigation of genetic and environmental factors influencing DCM.
- The zebrafish model is a valuable platform for preclinical drug screening and therapeutic development.
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.
