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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\u2013\/\u2013 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\u2013\/\u2013 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\u2013\/\u2013 zebrafish model provides a robust translational platform to investigate the interactions between lifestyle factors and the pathogenesis of inherited desmosomal cardiomyopathies.<\/jats:p>","DOI":"10.1186\/s43556-026-00476-7","type":"journal-article","created":{"date-parts":[[2026,6,15]],"date-time":"2026-06-15T05:57:15Z","timestamp":1781503035000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Zebrafish dspb-\/- mutant as a model for non-dilated left ventricular cardiomyopathy: exploring cardiac dysfunction and exercise modulation"],"prefix":"10.1186","volume":"7","author":[{"ORCID":"https:\/\/orcid.org\/0009-0007-3423-930X","authenticated-orcid":false,"given":"Serena","family":"Munteanu","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0000-3413-809X","authenticated-orcid":false,"given":"Jes\u00fas","family":"Wagih G\u00f3mez","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0008-6053-3251","authenticated-orcid":false,"given":"\u00c1ngel","family":"J\u00fadez Serrano","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7824-2814","authenticated-orcid":false,"given":"Daniel","family":"Saura Esp\u00edn","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3546-4350","authenticated-orcid":false,"given":"Juan Jos\u00e9","family":"Santos Mateo","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0003-7069-786X","authenticated-orcid":false,"given":"Mar\u00eda Elisa","family":"Nicol\u00e1s Rocamora","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7296-3445","authenticated-orcid":false,"given":"Cristina","family":"Gil Ortu\u00f1o","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2266-5949","authenticated-orcid":false,"given":"\u00c1ngel","family":"Bernab\u00e9 Garc\u00eda","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5818-1754","authenticated-orcid":false,"given":"Juan Ramon","family":"Gimeno-Blanes","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2021-9822","authenticated-orcid":false,"given":"Mar\u00eda Luisa","family":"Cayuela Fuentes","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1352-1748","authenticated-orcid":false,"given":"Mar\u00eda","family":"Sabater Molina","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2026,6,15]]},"reference":[{"issue":"37","key":"476_CR1","doi-asserted-by":"publisher","first-page":"3503","DOI":"10.1093\/eurheartj\/ehad194","volume":"44","author":"E Arbelo","year":"2023","unstructured":"Arbelo E, Protonotarios A, Gimeno JR, Arbustini E, Barriales-Villa R, Basso C, et al. 2023 ESC guidelines for the management of cardiomyopathies. 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The study protocol was reviewed and approved by the Ethics Committee of the Virgen de la Arrixaca University Hospital (reference number 2023\u20131-12-HCUVA). Written informed consent was obtained from all participants prior to inclusion in the study.Animal handling and experimentation followed the protocols and guidelines established by the European Union Directive 2010\/63\/EU and the Spanish RD 53\/2013. These protocols were approved by the Animal Experimentation Ethics Committee (CEEA) of the Virgen de la Arrixaca University Hospital-IMIB (approval number N\u00ba A13211204, REGA ES300303340098).","order":2,"name":"Ethics","group":{"name":"EthicsHeading","label":"Ethics approval and consent to participate"}},{"value":"Not applicable. No identifiable human data are included in this manuscript.","order":3,"name":"Ethics","group":{"name":"EthicsHeading","label":"Consent for publication"}},{"value":"The authors declare that they have no competing interests.","order":4,"name":"Ethics","group":{"name":"EthicsHeading","label":"Competing interests"}}],"article-number":"90"}}