Journal article
Pathogenic troponin T mutants with opposing effects on myofilament Ca2+ sensitivity attenuate cardiomyopathy phenotypes in mice
Archives of biochemistry and biophysics, Vol.661, pp.125-131
01/2019
DOI: 10.1016/j.abb.2018.11.006
PMCID: PMC6347385
PMID: 30445044
Abstract
Mutations in cardiac troponin T (TnT) associated with hypertrophic cardiomyopathy generally lead to an increase in the Ca2+ sensitivity of contraction and susceptibility to arrhythmias. In contrast, TnT mutations linked to dilated cardiomyopathy decrease the Ca2+ sensitivity of contraction. Here we tested the hypothesis that two TnT disease mutations with opposite effects on myofilament Ca2+ 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 Ca2+ 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 Ca2+ sensitivity can paradoxically ameliorate each other's disease phenotype. Normalizing myofilament Ca2+ sensitivity may be a promising new treatment approach for a variety of diseases.
Details
- Title: Subtitle
- Pathogenic troponin T mutants with opposing effects on myofilament Ca2+ sensitivity attenuate cardiomyopathy phenotypes in mice
- Creators
- Karissa M. Dieseldorff Jones - Biomedical Sciences, Florida State University, Tallahassee, FL, USAYeojung Koh - Florida State UniversityRebecca S. Weller - Vanderbilt UniversityRajdeep S. Turna - Florida State UniversityFerhaan Ahmad - University of IowaSabine Huke - University of Alabama at BirminghamBjörn C. Knollmann - Vanderbilt UniversityJose Renato Pinto - Florida State UniversityHyun Seok Hwang - Florida State University
- Resource Type
- Journal article
- Publication Details
- Archives of biochemistry and biophysics, Vol.661, pp.125-131
- Publisher
- Elsevier Inc
- DOI
- 10.1016/j.abb.2018.11.006
- PMID
- 30445044
- PMCID
- PMC6347385
- ISSN
- 0003-9861
- eISSN
- 1096-0384
- Grant note
- name: HSH, award: 12SDG12050597; name: JRP, award: RO1HL128683; name: BCK, award: R01HL071670; name: KMDJ, award: F31HL137408; name: SH, award: RO1HL128563
- Language
- English
- Date published
- 01/2019
- Academic Unit
- Radiology; Molecular Physiology and Biophysics; Cardiovascular Medicine; Fraternal Order of Eagles Diabetes Research Center; Internal Medicine
- Record Identifier
- 9984297604602771
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