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In Vivo Analysis of Troponin C Knock-In (A8V) Mice

Title: In Vivo Analysis of Troponin C Knock-In (A8V) Mice: Evidence that TNNC1 Is a Hypertrophic Cardiomyopathy Susceptibility Gene.
Name(s): Martins, Adriano S, author
Parvatiyar, Michelle S, author
Feng, Han-Zhong, author
Bos, J Martijn, author
Gonzalez-Martinez, David, author
Vukmirovic, Milica, author
Turna, Rajdeep S, author
Sanchez-Gonzalez, Marcos A, author
Badger, Crystal-Dawn, author
Zorio, Diego A R, author
Singh, Rakesh K, author
Wang, Yingcai, author
Jin, J-P, author
Ackerman, Michael J, author
Pinto, Jose R, author
Type of Resource: text
Genre: Journal Article
Date Issued: 2015-10-01
Physical Form: computer
online resource
Extent: 1 online resource
Language(s): English
Abstract/Description: Mutations in thin-filament proteins have been linked to hypertrophic cardiomyopathy, but it has never been demonstrated that variants identified in the TNNC1 (gene encoding troponin C) can evoke cardiac remodeling in vivo. The goal of this study was to determine whether TNNC1 can be categorized as an hypertrophic cardiomyopathy susceptibility gene, such that a mouse model can recapitulate the clinical presentation of the proband. The TNNC1-A8V proband diagnosed with severe obstructive hypertrophic cardiomyopathy at 34 years of age exhibited mild-to-moderate thickening in left and right ventricular walls, decreased left ventricular dimensions, left atrial enlargement, and hyperdynamic left ventricular systolic function. Genetically engineered knock-in (KI) mice containing the A8V mutation (heterozygote=KI-TnC-A8V(+/-); homozygote=KI-TnC-A8V(+/+)) were characterized by echocardiography and pressure-volume studies. Three-month-old KI-TnC-A8V(+/+) mice displayed decreased ventricular dimensions, mild diastolic dysfunction, and enhanced systolic function, whereas KI-TnC-A8V(+/-) mice displayed cardiac restriction at 14 months of age. KI hearts exhibited atrial enlargement, papillary muscle hypertrophy, and fibrosis. Liquid chromatography-mass spectroscopy was used to determine incorporation of mutant cardiac troponin C (≈ 21%) into the KI-TnC-A8V(+/-) cardiac myofilament. Reduced diastolic sarcomeric length, increased shortening, and prolonged Ca(2+) and contractile transients were recorded in intact KI-TnC-A8V(+/-) and KI-TnC-A8V(+/+) cardiomyocytes. Ca(2+) sensitivity of contraction in skinned fibers increased with mutant gene dose: KI-TnC-A8V(+/+)>KI-TnC-A8V(+/-)>wild-type, whereas KI-TnC-A8V(+/+) relaxed more slowly on flash photolysis of diazo-2. The TNNC1-A8V mutant increases the Ca(2+)-binding affinity of the thin filament and elicits changes in Ca(2+) homeostasis and cellular remodeling, which leads to diastolic dysfunction. These in vivo alterations further implicate the role of TNNC1 mutations in the development of cardiomyopathy.
Identifier: FSU_pmch_26304555 (IID), 10.1161/CIRCGENETICS.114.000957 (DOI), PMC4618104 (PMCID), 26304555 (RID), 26304555 (EID)
Keywords: Ca handling, TNNC1, Calcium sensitization, Cardiomyopathy, Hypertrophic cardiomyopathy, Knock-in mouse model, Mouse, Myofilament protein, Troponin, Troponin C
Grant Number: HL103840, R01 HL098945, HL098945, K99 HL103840, R00 HL103840
Publication Note: This NIH-funded author manuscript originally appeared in PubMed Central at
Subject(s): Adult
Cardiomyopathy, Hypertrophic/diagnostic imaging
Cardiomyopathy, Hypertrophic/genetics
Gene Knock-In Techniques
Genetic Predisposition to Disease
Myocardial Contraction
Myocytes, Cardiac/metabolism
Organ Size
Troponin C/genetics
Persistent Link to This Record:
Owner Institution: FSU
Is Part Of: Circulation. Cardiovascular genetics.
Issue: iss. 5, vol. 8

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Martins, A. S., Parvatiyar, M. S., Feng, H. -Z., Bos, J. M., Gonzalez-Martinez, D., Vukmirovic, M., … Pinto, J. R. (2015). In Vivo Analysis of Troponin C Knock-In (A8V) Mice: Evidence that TNNC1 Is a Hypertrophic Cardiomyopathy Susceptibility Gene. Circulation. Cardiovascular Genetics. Retrieved from