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This Article Full Text Full Text (PDF) All Versions of this Article: 288/3/H1147    most recent 00140.2004v1 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 Citing Articles Citing Articles via HighWire Citing Articles via Web of Science (2) Citing Articles via Google Scholar Google Scholar Articles by Nassar, R. Articles by Anderson, P. A. W. Search for Related Content PubMed PubMed Citation Articles by Nassar, R. Articles by Anderson, P. A. W.

cTnT₁, a cardiac troponin T isoform, decreases myofilament tension and affects the left ventricular pressure waveform

¹Department of Pediatrics and ²Department of Medicine, Duke University, Durham; and ³Department of Pathology, University of North Carolina, Chapel Hill, North Carolina

Submitted 10 February 2004 ; accepted in final form 25 October 2004

Four isoforms of cardiac troponin T (cTnT), a protein essential for calcium-dependent myocardial force development, are expressed in the human; they differ in charge and length. Their expression is regulated developmentally and is affected by disease states. Human cTnT (hcTnT) isoform effects have been examined in reconstituted myofilaments. In this study, we evaluated the modulatory effects of overexpressing one cTnT isoform on in vitro and in vivo myocardial function. A hcTnT isoform, hcTnT₁, expressed during development and in heart disease but not in the normal adult heart, was expressed in transgenic (TG) mice (1–30% of total cTnT). Maximal active tension measured in skinned myocardium decreased as a function of relative hcTnT₁ expression. The pCa at half-maximal force development, Hill coefficient, and rate of redevelopment of force did not change significantly with hcTnT₁ expression. In vivo maximum rates of rise and fall of left ventricular pressure decreased, and the half-time of isovolumic relaxation increased, with hcTnT₁ expression. Substituting total cTnT charge for hcTnT₁ expression resulted in similar conclusions. Morphometric analysis and electron microscopy revealed no differences between wild-type (non-TG) and TG myocardium. No differences in isoform expression of tropomyosin, myosin heavy chain, essential and regulatory myosin light chains (MLC), TnI, or in posttranslational modifications of mouse cTnT, cTnI, or regulatory MLC were observed. These results support the hypothesis that cTnT isoform amino-terminal differences affect myofilament function and suggest that hcTnT₁ expression levels present during human development and in human heart disease can affect in vivo ventricular function.

thin filaments; transgenic mice; ventricular function; myocardium

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