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

Ahmad, F and Banerjee, SK and Lage, ML and Huang, XN and Smith, SH and Saba, S and Rager, J and Conner, DA and Janczewski, AM and Tobita, K and Tinney, JP and Moskowitz, IP and Perez-Atayde, AR and Keller, BB and Mathier, MA and Shroff, SG and Seidman, CE and Seidman, JG (2008) The role of cardiac troponin T quantity and function in cardiac development and dilated cardiomyopathy. PLoS ONE, 3 (7).

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Abstract

Background: Hypertrophic (HCM) and dilated (DCM) cardiomyopathies results 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 desensitization occurs in DCM; and whether absence of cTnT impairs early embryonic cardiogenesis. Methods and Findings: We ablated Tnnt2 to produce heterozygous Tnnt2 mice, and crossbreeding produced homozygous null Tnnt2 embryos. We also generated transgenic mice overexpressing wildtype (TG ) or DCM mutant (TG ) Tnnt2. Crossbreeding produced mice lacking one allele of Tnnt2, but carrying wildtype (Tnnt2 /TG ) or mutant (Tnnt2 /TG ) 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 mice had severe DCM, TG 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 relative to TG mice (2.42±0.08, p = 0.03). Tnnt2 /TG muscle showed Ca desensitization (pCa = 5.34 ± 0.08 vs. 5.58 ± 0.03 at sarcomere length 1.9 μm. 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. Conclusions: 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 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. © 2008 Ahmad et al. 2+ +/ -/- WT K210Δ +/- WT +/- K210Δ +/- +/- +/- K210Δ K210Δ + - K210Δ K210Δ +/- K210Δ 2+ -/- 2+ 50


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Item Type: Article
Status: Published
Creators/Authors:
CreatorsEmailPitt UsernameORCID
Ahmad, F
Banerjee, SK
Lage, ML
Huang, XN
Smith, SHshs46@pitt.eduSHS46
Saba, Ssfs3@pitt.eduSFS3
Rager, J
Conner, DA
Janczewski, AM
Tobita, Kkit3@pitt.eduKIT3
Tinney, JP
Moskowitz, IP
Perez-Atayde, AR
Keller, BB
Mathier, MAmam44@pitt.eduMAM44
Shroff, SGsshroff@pitt.eduSSHROFF
Seidman, CE
Seidman, JG
Contributors:
ContributionContributors NameEmailPitt UsernameORCID
EditorSchwartz, ArnoldUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Date: 9 July 2008
Date Type: Publication
Journal or Publication Title: PLoS ONE
Volume: 3
Number: 7
DOI or Unique Handle: 10.1371/journal.pone.0002642
Schools and Programs: Graduate School of Public Health > Human Genetics
Swanson School of Engineering > Bioengineering
Refereed: Yes
PubMed ID: 18612386
Date Deposited: 18 Jul 2012 20:26
Last Modified: 30 Mar 2021 14:55
URI: http://d-scholarship.pitt.edu/id/eprint/12981

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