Key result
In a novel Dsp knock-out zebrafish model of arrhythmogenic cardiomyopathy, treatment with the Wnt/β-catenin agonist SB216763 rescued cardiac abnormalities and more than doubled the survival rate during physical training.
Why the study?
Arrhythmogenic cardiomyopathy is an inherited disorder linked to desmosomal protein mutations such as Desmoplakin, requiring models to test environmental factors and candidate drugs.
Does Wnt/β-catenin modulation or physical training alter the arrhythmogenic cardiomyopathy phenotype in a Dsp knock-out zebrafish model?
Does Wnt/β-catenin modulation or physical training alter the arrhythmogenic cardiomyopathy phenotype in a Dsp knock-out zebrafish model?
A novel Dsp knock-out zebrafish model successfully recapitulates arrhythmogenic cardiomyopathy features, demonstrating that physical exercise exacerbates the phenotype while Wnt/β-catenin activation rescues it.
Should not yet alter exercise counseling or prompt Wnt agonists in DSP-AC; extends transient models and leaves human translation open.
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.
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Celeghin et al. (2023) studied Arrhythmogenic cardiomyopathy. SB216763 (Wnt/β-catenin agonist) vs. Untreated mutants was evaluated on Survival rate and cardiac abnormalities after physical training. In a novel Dsp knock-out zebrafish model of arrhythmogenic cardiomyopathy, treatment with the Wnt/β-catenin agonist SB216763 rescued cardiac abnormalities and more than doubled the survival rate during physical training.
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