Wild‐type troponin T gene overexpression in mice with troponin T mutant‐induced dilated cardiomyopathy partially rescued cardiac pathology

Abstract

Introduction and Aim Dilated cardiomyopathy (DCM) is characterized by cardiac dilation and pump failure. Cardiac transplant is the only curative treatment for DCM. We reported that cardiac troponin T (TNNT2) amino acid mutation (ΔK210) knock-in mice (DCM KI) have the similar phenotypes of human DCM. Previous reports demonstrated that excessive troponin complex in myofibrils resulted in the replacement of endogenous troponin complex and that overexpression of mutant TNNT2 in wild-type mice exhibits DCM phenotype. Therefore, we hypothesized that the overexpression of wild-type TNNT2 in DCM KI mice would rescue the DCM phenotype, which may contribute to inventing a curative therapy for DCM pathology. Methods and Results First, we generated human TNNT2 overexpression mice (hTNNT2 Tg: Tg) and confirmed that human TNNT2 was overexpressed in hTNNT2 Tg mice. We also confirmed that Tg mice exhibited no cardiac abnormality and that there was no difference in the tissue weight such as heart, liver and lung between WT mice and Tg mice. Then, we mated Tg mice with DCM KI mice to generate Tg/DCM KI mice. The life span of Tg/DCM KI mice was longer than that of DCM KI mice, although cardiac weight of Tg/DCM KI mice was comparable with that of DCM KI. Echocardiographic analysis showed that ejection fraction of Tg/DCM KI mice was slightly improved when compared to that of DCM KI mice, although there was no difference in wall thickness and internal dimension of the left ventricle. Conclusion The results suggest that overexpression of wild-type TNNT2 in DCM KI mice partially rescued the DCM pathology. However, in order to analyze why the improvement is not sufficient, we will conduct further experiments, such as measuring TNNT2 replacement ratio and confirming whether there is another cause of death.