Zebrafish dspb-/- mutant as a model for non-dilated left ventricular cardiomyopathy: exploring cardiac dysfunction and exercise modulation.

Truncating variants in the DSP gene are associated with non-dilated left ventricular cardiomyopathy (ND-LVC), characterized by impaired ventricular function without dilation. The influence of physical activity in disease onset, severity, and progression in DSP variant carriers remains unclear. This study aimed to generate a zebrafish model carrying a human DSP truncating variant to characterize homozygous dspb-/- mutants in terms of cardiac function, structure, and gene expression. The impact of moderate and endurance exercise was additionally evaluated. Clinical data from human carriers were also analysed to assess the relationship between physical activity, age at diagnosis, disease severity and arrhythmic events. A CRISPR/Cas9-generated dspb-/- zebrafish model (p.T449fs*) was used to characterize structural, functional, and molecular phenotypes. Moderate exercise training protocols were applied to assess their effect on cardiac function, endurance capacity, and survival. Physically active human carriers were diagnosed at a younger age but did not show increased disease severity or events rates. Zebrafish mutants exhibited baseline systolic dysfunction, sarcomeric disorganization, and signaling pathway dysregulation. Importantly, moderate exercise partially restored cardiac function and improved endurance without increasing mortality. These findings indicate that exercise may serve as a phenotypic modifier in DSP-related ND-LVC, enhancing functional outcomes without accelerating disease progression. The dspb-/- zebrafish model provides a robust translational platform to investigate the interactions between lifestyle factors and the pathogenesis of inherited desmosomal cardiomyopathies.