An α-cardiac myosin heavy chain gene mutation impairs contraction and relaxation function of cardiac myocytes

Song Jung Kim, Kenji Iizuka, Ralph A. Kelly, Yong Jian Geng, Sanford P. Bishop, Guiping Yang, Amelia Kudej, Bradley K. McConnell, Christine E. Seidman, Jonathan G. Seidman, Stephen F. Vatner

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59 Scopus citations

Abstract

Left Ventricular (LV) myocytes were isolated from 15-wk-old male mice bearing the Arg403 → Gin α-cardiac myosin heavy chain missense mutation (α-MHC(403/+)), a model of familial hypertrophic cardiomyopathy. LV myocytes were classified morphologically: type I, rod shaped with parallel myofibrils; type II, irregularly shaped, shorter and wider than wild-type (WT) control cells, with parallel myofibrils; and type III, irregularly shaped with disoriented myofibrils. Compared with WT myocytes, α-MHC(403/+) myocytes had fewer type I cells (WT = 74 ± 3%, α-MHC(403/+) = 41 + 4%, P < 0.01) and more type III cells (WT= 12 ± 3%, α-MHC(403/+) = 49 ± 7%, P < 0.01). In situ histology also demonstrated marked myofibrillar disarray in the α- MHC(403/+) hearts. With the use of video edge detection, myocytes were paced at 1 Hz (37°C) to determine the effects of the mutation on myocyte function: End-diastolic length was reduced in mutant myocytes, but fractional shortening (% contraction) and sarcomere length were not. Velocity of contraction (-dL/dt(max)) was depressed in mutant cells, but more in type II and III cells (-31%) than in type I cells (-18%). Velocity of relaxation (+dL/dt) was also depressed more in type II and III cells (-38%) than in type I cells (-16%). Using fura 2 dye with intracellular Ca2+ transients, we demonstrated that in α-MHC(403/+) myocytes, the amplitude of the Ca2+ signal during contraction was unchanged but that the time required for decay of the signal to decrease 70% from its maximum was delayed significantly (WT = 159 ± 8 ms; α-MHC(403/+) 217 ± 14 ms, P < 0.01). Sarco(endo)plasmic reticulum Ca2+-ATPase mRNA levels in α-MHC(403/+) and WT mice were similar. These data indicate that the altered cardiac dysfunction of α- MHC(403/+) myocytes is directly due to defective myocyte function rather than to secondary changes in global cardiac function and/or loading conditions.

Original languageEnglish (US)
Pages (from-to)H1780-H1787
JournalAmerican Journal of Physiology - Heart and Circulatory Physiology
Volume276
Issue number5 45-5
DOIs
StatePublished - May 1999
Externally publishedYes

All Science Journal Classification (ASJC) codes

  • Physiology
  • Cardiology and Cardiovascular Medicine
  • Physiology (medical)

Keywords

  • Calcium
  • Transgenic mice

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