| First Author | Dieseldorff Jones KM | Year | 2019 |
| Journal | Arch Biochem Biophys | Volume | 661 |
| Pages | 125-131 | PubMed ID | 30445044 |
| Mgi Jnum | J:269084 | Mgi Id | MGI:6272925 |
| Doi | 10.1016/j.abb.2018.11.006 | Citation | Dieseldorff Jones KM, et al. (2019) Pathogenic troponin T mutants with opposing effects on myofilament Ca(2+) sensitivity attenuate cardiomyopathy phenotypes in mice. Arch Biochem Biophys 661:125-131 |
| abstractText | Mutations in cardiac troponin T (TnT) associated with hypertrophic cardiomyopathy generally lead to an increase in the Ca(2+) sensitivity of contraction and susceptibility to arrhythmias. In contrast, TnT mutations linked to dilated cardiomyopathy decrease the Ca(2+) sensitivity of contraction. Here we tested the hypothesis that two TnT disease mutations with opposite effects on myofilament Ca(2+) sensitivity can attenuate each other's phenotype. We crossed transgenic mice expressing the HCM TnT-I79N mutation (I79N) with a DCM knock-in mouse model carrying the heterozygous TnT-R141W mutation (HET). The results of the Ca(2+) sensitivity in skinned cardiac muscle preparations ranked from highest to lowest were as follow: I79N>I79N/HET>NTg>HET. Echocardiographic measurements revealed an improvement in hemodynamic parameters in I79N/HET compared to I79N and normalization of left ventricular dimensions and volumes compared to both I79N and HET. Ex vivo testing showed that the I79N/HET mouse hearts had reduced arrhythmia susceptibility compared to I79N mice. These results suggest that two disease mutations in TnT that have opposite effects on the myofilament Ca(2+) sensitivity can paradoxically ameliorate each other's disease phenotype. Normalizing myofilament Ca(2+) sensitivity may be a promising new treatment approach for a variety of diseases. |
