SNTA1-deficient human cardiomyocytes are associated with increased structural components, calcium handling disorder, and shorter field potential duration

Background α-1-syntrophin (SNTA1), a protein encoded by SNTA1 , is highly expressed in human cardiomyocytes. Mutations in SNTA1 are associated with arrhythmia and cardiomyopathy. Previous research on SNTA1 has been based on nonhuman cardiomyocytes. Our study was designed to identify phenotype of SNTA1 -deficient using human cardiomyocytes. Methods SNTA1 was knocked out in H9 cell line using CRISPR-Cas9 system. H9SNTA1KO cells were then induced to differentiate into cardiomyocytes using small molecule inhibitors. The phenotypic discrepancies associated with SNTA1 -deficient cardiomyocytes were investigated. Results SNTA1 was truncated in PH1 domain by a stop codon (TGA) using CRISPR-Cas9 system. SNTA1 -deficient did not affect the pluripotency of H9SNTA1KO, and they retain their in vitro ability to differentiate into cardiomyocytes. However, H9SNTA1KO derived cardiomyocytes exhibited increased structural components, weak calcium transient intensity, low levels of calcium in sarcoplasmic reticulum, lower cardiac contractility, and shorter field potential duration. Early treatment of SNTA1 -deficient cardiomyocytes with ranolazine improved the calcium transient intensity and cardiac contractility. Conclusions SNTA1 -deficient cardiomyocytes can be used to research the etiology, pathogenesis, and potential therapies for myocardial diseases. The SNTA1- deficient cardiomyocyte model suggests that the maintenance of cardiac calcium homeostasis is a key target in the treatment of myocardial-related diseases.