The role of cardiac troponin T quantity and function in cardiac development and dilated cardiomyopathy

Ferhaan Ahmad; Sanjay K Banerjee; Michele L Lage; Xueyin N Huang; Stephen H Smith; Samir Saba; Jennifer Rager; David A Conner; Andrzej M Janczewski; Kimimasa Tobita; Joseph P Tinney; Ivan P Moskowitz; Antonio R Perez-Atayde; Bradley B Keller; Michael A Mathier; Sanjeev G Shroff; Christine E Seidman; J G Seidman

doi:10.1371/journal.pone.0002642

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The role of cardiac troponin T quantity and function in cardiac development and dilated cardiomyopathy

Journal article

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Peer reviewed

The role of cardiac troponin T quantity and function in cardiac development and dilated cardiomyopathy

Ferhaan Ahmad, Sanjay K Banerjee, Michele L Lage, Xueyin N Huang, Stephen H Smith, Samir Saba, Jennifer Rager, David A Conner, Andrzej M Janczewski, Kimimasa Tobita, …

PloS one, Vol.3(7), pp.e2642-e2642

07/09/2008

DOI: 10.1371/journal.pone.0002642

PMCID: PMC2441440

PMID: 18612386

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Abstract

Hypertrophic (HCM) and dilated (DCM) cardiomyopathies result from sarcomeric protein mutations, including cardiac troponin T (cTnT, TNNT2). We determined whether TNNT2 mutations cause cardiomyopathies by altering cTnT function or quantity; whether the severity of DCM is related to the ratio of mutant to wildtype cTnT; whether Ca(2+) desensitization occurs in DCM; and whether absence of cTnT impairs early embryonic cardiogenesis. We ablated Tnnt2 to produce heterozygous Tnnt2(+/-) mice, and crossbreeding produced homozygous null Tnnt2(-/-) embryos. We also generated transgenic mice overexpressing wildtype (TG(WT)) or DCM mutant (TG(K210Delta)) Tnnt2. Crossbreeding produced mice lacking one allele of Tnnt2, but carrying wildtype (Tnnt2(+/-)/TG(WT)) or mutant (Tnnt2(+/-)/TG(K210Delta)) transgenes. Tnnt2(+/-) mice relative to wildtype had significantly reduced transcript (0.82+/-0.06[SD] vs. 1.00+/-0.12 arbitrary units; p = 0.025), but not protein (1.01+/-0.20 vs. 1.00+/-0.13 arbitrary units; p = 0.44). Tnnt2(+/-) mice had normal hearts (histology, mass, left ventricular end diastolic diameter [LVEDD], fractional shortening [FS]). Moreover, whereas Tnnt2(+/-)/TG(K210Delta) mice had severe DCM, TG(K210Delta) mice had only mild DCM (FS 18+/-4 vs. 29+/-7%; p<0.01). The difference in severity of DCM may be attributable to a greater ratio of mutant to wildtype Tnnt2 transcript in Tnnt2(+/-)/TG(K210Delta) relative to TG(K210Delta) mice (2.42+/-0.08, p = 0.03). Tnnt2(+/-)/TG(K210Delta) muscle showed Ca(2+) desensitization (pCa(50) = 5.34+/-0.08 vs. 5.58+/-0.03 at sarcomere length 1.9 microm, p<0.01), but no difference in maximum force generation. Day 9.5 Tnnt2(-/-) embryos had normally looped hearts, but thin ventricular walls, large pericardial effusions, noncontractile hearts, and severely disorganized sarcomeres. Absence of one Tnnt2 allele leads to a mild deficit in transcript but not protein, leading to a normal cardiac phenotype. DCM results from abnormal function of a mutant protein, which is associated with myocyte Ca(2+) desensitization. The severity of DCM depends on the ratio of mutant to wildtype Tnnt2 transcript. cTnT is essential for sarcomere formation, but normal embryonic heart looping occurs without contractile activity.

Phenotype

Cardiomyopathy, Dilated - genetics

Troponin T - genetics

Echocardiography

Cardiomyopathy, Hypertrophic - metabolism

Heart - embryology

Mice, Transgenic

Cardiomyopathy, Dilated - metabolism

Embryo, Mammalian - metabolism

Mice, Knockout

Troponin T - physiology

Troponin T - metabolism

Animals

Myocardium - metabolism

Mice

Details

Title: Subtitle: The role of cardiac troponin T quantity and function in cardiac development and dilated cardiomyopathy
Creators: Ferhaan Ahmad - Cardiovascular Institute, Department of Medicine, University of Pittsburgh, Pittsburgh, Pennsylvania, United States of America. ahmadf@upmc.edu
Sanjay K Banerjee
Michele L Lage
Xueyin N Huang
Stephen H Smith
Samir Saba
Jennifer Rager
David A Conner
Andrzej M Janczewski
Kimimasa Tobita
Joseph P Tinney
Ivan P Moskowitz
Antonio R Perez-Atayde
Bradley B Keller
Michael A Mathier
Sanjeev G Shroff
Christine E Seidman
J G Seidman
Resource Type: Journal article
Publication Details: PloS one, Vol.3(7), pp.e2642-e2642
DOI: 10.1371/journal.pone.0002642
PMID: 18612386
PMCID: PMC2441440
NLM abbreviation: PLoS One
ISSN: 1932-6203
eISSN: 1932-6203
Publisher: Public Library of Science; United States
Grant note: Howard Hughes Medical Institute
Language: English
Date published: 07/09/2008
Academic Unit: Radiology; Molecular Physiology and Biophysics; Cardiovascular Medicine; Fraternal Order of Eagles Diabetes Research Center; Internal Medicine
Record Identifier: 9984025670102771

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