Construction of Zebra Model of Cardiac Hypertrophy Caused by ATIC Gene Deletion and Preliminary Exploration of Aerobic Exercise's Improvement

Hypertrophic cardiomyopathy (HCM) is a relatively common global cardiac disease, usually inherited, with complex phenotypes, genetic features, and natural history. In this study, we constructed atic-/-zebrafish by CRISPR/Cas9 gene editing system and found that atic-/-zebrafish heart had HCM symptoms, and atic-/-zebrafish heart showed progressive enlargement, eccentric hypertrophy, cardiomyocyte enlargement and collagen fiber deposition. Echocardiography results also showed that compared with atic-/-zebrafish heart, 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 heart involving Calcium signaling pathway, Apelin signaling pathway and ECM-receptor interaction. 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 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.