Construction of a Zebrafish Model of Cardiac Hypertrophy Caused by ATIC Gene Deletion and Preliminary Exploration of Aerobic Exercise Improvement

Hypertrophic cardiomyopathy (HCM) is a relatively common global cardiac disease, usually inherited, with complex phenotypes, genetic features, and a natural history. In this study, we constructed atic^-/- zebrafish using the CRISPR/Cas9 gene-editing system and found that atic^-/- zebrafish hearts exhibited HCM symptoms, and atic^-/- zebrafish hearts showed progressive enlargement, eccentric hypertrophy, cardiomyocyte enlargement, and collagen fiber deposition. Echocardiography results also showed that compared with atic^-/- zebrafish hearts, in wild-type zebrafish hearts, the ejection fraction was significantly reduced, shortening fraction was reduced, and ventricular wall thickness was significantly increased. Meanwhile, aerobic exercise intervention in atic^-/- zebrafish showed that aerobic exercise effectively improved the symptoms of HCM and improved cardiac function in atic^-/- zebrafish hearts. Transcriptome sequencing results showed that aerobic exercise improved the symptoms of HCM in atic^-/- zebrafish hearts involving the calcium signaling pathway, Apelin signaling pathway and ECM-receptor interaction. The q-PCR results of key differential genes involved in these pathways further confirmed that aerobic exercise could bring beneficial effects to atic^-/- zebrafish. In conclusion, this study found that the loss of ATIC can lead to hypertrophic cardiomyopathy in zebrafish, and aerobic exercise intervention can effectively improve the hypertrophic pathological characteristics of atic^-/- zebrafish hearts, providing new intervention targets and effective lifestyle interventions for HCM.