title: cTnT1, a cardiac troponin T isoform, decreases myofilament tension and affects the left ventricular pressure waveform.
abstract: 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, hcTnT(1), 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 hcTnT(1) expression. The pCa at half-maximal force development, Hill coefficient, and rate of redevelopment of force did not change significantly with hcTnT(1) expression. In vivo maximum rates of rise and fall of left ventricular pressure decreased, and the half-time of isovolumic relaxation increased, with hcTnT(1) expression. Substituting total cTnT charge for hcTnT(1) 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 hcTnT(1) expression levels present during human development and in human heart disease can affect in vivo ventricular function.
authors.affiliation: Department of Pediatrics, Duke University, Durham, NC, USA.
authors.forename: Rashid
authors.initials: R
authors.lastname: Nassar
authors.forename: Nadia N
authors.initials: NN
authors.lastname: Malouf
authors.forename: Lan
authors.initials: L
authors.lastname: Mao
authors.forename: Howard A
authors.initials: HA
authors.lastname: Rockman
authors.forename: Annette E
authors.initials: AE
authors.lastname: Oakeley
authors.forename: James R
authors.initials: JR
authors.lastname: Frye
authors.forename: J René
authors.initials: JR
authors.lastname: Herlong
authors.forename: Stephen P
authors.initials: SP
authors.lastname: Sanders
authors.forename: Page A W
authors.initials: PA
authors.lastname: Anderson
mesh_terms: D008841:Actin Cytoskeleton / Q000502:physiology; D000595:Amino Acid Sequence; D000818:Animals; D004452:Echocardiography; D005260:Female; D015870:Gene Expression; D006321:Heart / Q000502:physiology*; D006801:Humans; D007536:Isomerism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D008969:Molecular Sequence Data; D009200:Myocardial Contraction / Q000502:physiology; D014335:Tropomyosin / Q000235:genetics / Q000378:metabolism; D014336:Troponin / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism*; D016277:Ventricular Function, Left / Q000502:physiology*; D017725:Ventricular Pressure / Q000502:physiology*
chemical_list: D014335:Tropomyosin; D014336:Troponin