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Published on: June 7, 2018
A novel DSP zebrafish model reveals training- and drug-induced modulation of arrhythmogenic cardiomyopathy phenotypes
Rudy Celeghin1, Giovanni Risato1,2, Giorgia Beffagna3
1Department of Cardiac-Thoracic-Vascular Sciences and Public Health, University of Padova, Padova, 35128, Italy.
Insights
A new Desmoplakin (Dsp) knock-out zebrafish model mimics arrhythmogenic cardiomyopathy (AC) in humans. This model shows cardiac defects and pathway dysregulation, offering a platform for testing environmental factors and drugs.
Area of Science:
- Cardiovascular Genetics
- Inherited Cardiac Diseases
- Zebrafish Models
Background:
- Arrhythmogenic cardiomyopathy (AC) is a genetic disorder affecting the heart muscle, leading to arrhythmias and sudden death.
- Mutations in desmosomal proteins, such as Desmoplakin (Dsp), are implicated in approximately 40% of AC cases.
- Existing models often lack the complexity to fully recapitulate AC's multifaceted pathology and therapeutic responses.
Purpose of the Study:
- To develop and characterize the first stable Desmoplakin (Dsp) knock-out (KO) zebrafish line for modeling arrhythmogenic cardiomyopathy (AC).
- To investigate the impact of environmental factors, specifically physical exercise, on AC progression in vivo.
- To screen for potential therapeutic interventions targeting key signaling pathways in AC.
Main Methods:
- Generation and characterization of a stable Dsp knock-out (KO) zebrafish line.
- Histological and Transmission Electron Microscopy (TEM) analysis of cardiac morphology and desmosome structure.
- Assessment of cardiac function, signaling pathway activity (Wnt/β-catenin, Hippo/YAP-TAZ, TGF-β), and response to physical training and pharmacological treatment (SB216763).
Main Results:
- Dsp KO zebrafish exhibited larval cardiac abnormalities (edema, bradycardia) and adult heart defects (thinning myocardium, adipocyte infiltration, desmosome disorganization).
- Intensive physical training exacerbated the cardiac phenotype, accelerating disease progression.
- Dysregulation of Wnt/β-catenin, Hippo/YAP-TAZ, and TGF-β signaling pathways was observed; Wnt/β-catenin agonist treatment rescued cardiac defects and stabilized heart rhythm.
Conclusions:
- The Dsp KO zebrafish line effectively recapitulates key features of human arrhythmogenic cardiomyopathy, including structural and signaling abnormalities.
- This model serves as a valuable platform for in vivo studies of environmental influences like exercise on AC.
- The findings highlight the potential of targeting the Wnt/β-catenin pathway for therapeutic intervention in AC.
Abstract:
Arrhythmogenic cardiomyopathy (AC) is an inherited disorder characterized by progressive loss of the ventricular myocardium causing life-threatening ventricular arrhythmias, syncope and sudden cardiac death in young and athletes. About 40% of AC cases carry one or more mutations in genes encoding for desmosomal proteins, including Desmoplakin (Dsp). We present here the first stable Dsp knock-out (KO) zebrafish line able to model cardiac alterations and cell signalling dysregulation, characteristic of the AC disease, on which environmental factors and candidate drugs can be tested. Our stable Dsp knock-out (KO) zebrafish line was characterized by cardiac alterations, oedema and bradycardia at larval stages. Histological analysis of mutated adult hearts showed reduced contractile structures and abnormal shape of the ventricle, with thinning of the myocardial layer, vessels dilation and presence of adipocytes within the myocardium. Moreover, TEM analysis revealed "pale", disorganized and delocalized desmosomes. Intensive physical training protocol caused a global worsening of the cardiac phenotype, accelerating the progression of the disease. Of note, we detected a decrease of Wnt/β-catenin signalling, recently associated with AC pathogenesis, as well as Hippo/YAP-TAZ and TGF-β pathway dysregulation. Pharmacological treatment of mutated larvae with SB216763, a Wnt/β-catenin agonist, rescued pathway expression and cardiac abnormalities, stabilizing the heart rhythm. Overall, our Dsp KO zebrafish line recapitulates many AC features observed in human patients, pointing at zebrafish as a suitable system for in vivo analysis of environmental modulators, such as the physical exercise, and the screening of pathway-targeted drugs, especially related to the Wnt/β-catenin signalling cascade.
