Allele and species dependent contractile defects by restrictive and hypertrophic cardiomyopathy-linked troponin I mutants

Jennifer Davis, Haitao Wen, Terri Edwards, Joseph M. Metzger

Research output: Contribution to journalArticle

30 Scopus citations

Abstract

Restrictive cardiomyopathy (RCM) is a debilitating disease characterized by impaired ventricular filling, reduced ventricular volumes, and severe diastolic dysfunction. Hypertrophic cardiomyopathy (HCM) is characterized by ventricular hypertrophy and heightened risk of premature sudden cardiac death. These cardiomyopathies can result from mutations in the same gene that encodes for cardiac troponin I (cTnI). Acute genetic engineering of adult rat cardiac myocytes was used to ascertain whether primary physiologic outcomes could distinguish between RCM and HCM alleles at the cellular level. Co-transduction of cardiac myocytes with wild-type (WT) cTnI and RCM/HCM linked mutants in cTnI's inhibitory region (IR) demonstrated that WT cTnI preferentially incorporated into the sarcomere over IR mutants. The cTnI IR mutants exhibited minor effects in single myocyte Ca2+-activated tension assays yet prolonged relaxation and Ca2+ decay. In comparison RCM cTnI mutants in the helix-4/C-terminal region demonstrated a) hyper-sensitivity to Ca2+ under loaded conditions, b) slowed myocyte mechanical relaxation and Ca2+ transient decay, c) frequency-dependent Ca2+-independent diastolic tone, d) heightened myofilament incorporation and e) irreversible cellular contractile defects with acute diltiazem administration. For species comparison, a subset of cTnI mutants were tested in isolated adult rabbit cardiac myocytes. Here, RCM and HCM mutant cTnIs exerted similar effects of slowed myocyte relaxation and Ca2+ transient decay but did not show variable phenotypes by cTnI region. This study highlights cellular contractile defects by cardiomyopathy mutant cTnIs that are allele and species dependent. The species dependent results in particular raise important issues toward elucidating a unifying mechanistic pathway underlying the inherited cardiomyopathies.

Original languageEnglish (US)
Pages (from-to)891-904
Number of pages14
JournalJournal of Molecular and Cellular Cardiology
Volume44
Issue number5
DOIs
Publication statusPublished - May 1 2008

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Keywords

  • Cardiac troponin I
  • Contraction
  • Inherited cardiomyopathy
  • Myocyte

ASJC Scopus subject areas

  • Molecular Biology
  • Cardiology and Cardiovascular Medicine

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