SNTA1-deficient human cardiomyocytes demonstrate hypertrophic phenotype and calcium handling disorder

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 non-human cardiomyocytes. This study was designed to identify the
phenotype ofSNTA1-deficiency using human cardiomyocytes. Methods: SNTA1
was knocked out in the H9 embryonic stem cell line using the 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 at the 149th amino acid
position of PH1 domain by a stop codon (TGA) using the CRISPR-Cas9 system.
SNTA1-deficiency did not affect the pluripotency of H9SNTA1KO, and they
retain their in vitro ability to differentiate into cardiomyocytes.
However, H9SNTA1KO derived cardiomyocytes exhibited hypertrophic
phenotype, lower cardiac contractility, weak calcium transient intensity,
and lower level of calcium in the sarcoplasmic reticulum. Early treatment
of SNTA1-deficient cardiomyocytes with ranolazine improved the calcium
transient intensity and cardiac contractility. Conclusion: 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.