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This Article Full Text Full Text (PDF) Supplemental Tables All Versions of this Article: 297/2/H614    most recent 01143.2008v1 Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in Web of Science Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Google Scholar Articles by Guinto, P. J. Articles by Tardiff, J. C. PubMed PubMed Citation Articles by Guinto, P. J. Articles by Tardiff, J. C.

Temporal and mutation-specific alterations in Ca²⁺ homeostasis differentially determine the progression of cTnT-related cardiomyopathies in murine models

¹Department of Physiology and Biophysics, Albert Einstein College of Medicine, and ²Department of Internal Medicine, Division of Adult Cardiology, Albert Einstein College of Medicine, Bronx, New York

Submitted 29 October 2008 ; accepted in final form 2 June 2009

Naturally occurring mutations in cardiac troponin T (cTnT) result in a clinical subset of familial hypertrophic cardiomyopathy. To determine the mechanistic links between thin-filament mutations and cardiovascular phenotypes, we have generated and characterized several transgenic mouse models carrying cTnT mutations. We address two central questions regarding the previously observed changes in myocellular mechanics and Ca²⁺ homeostasis: 1) are they characteristic of all severe cTnT mutations, and 2) are they primary (early) or secondary (late) components of the myocellular response? Adult left ventricular myocytes were isolated from 2- and 6-mo-old transgenic mice carrying missense mutations at residue 92, flanking the TNT1 NH₂-terminal tail domain. Results from R92L and R92W myocytes showed mutation-specific alterations in contraction and relaxation indexes at 2 mo with improvements by 6 mo. Alterations in Ca²⁺ kinetics remained consistent with mechanical data in which R92L and R92W exhibited severe diastolic impairments at the early time point that improved with increasing age. A normal regulation of Ca²⁺ kinetics in the context of an altered baseline cTnI phosphorylation suggested a pathogenic mechanism at the myofilament level taking precedence for R92L. The quantitation of Ca²⁺-handling proteins in R92W mice revealed a synergistic compensatory mechanism involving an increased Ser16 and Thr17 phosphorylation of phospholamban, contributing to the temporal onset of improved cellular mechanics and Ca²⁺ homeostasis. Therefore, independent cTnT mutations in the TNT1 domain result in primary mutation-specific effects and a differential temporal onset of altered myocellular mechanics, Ca²⁺ kinetics, and Ca²⁺ homeostasis, complex mechanisms which may contribute to the clinical variability in cTnT-related familial hypertrophic cardiomyopathy mutations.

familial hypertrophic cardiomyopathy; cardiac troponin T; contractility; calcium handling