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

Journal of Molecular and Cellular Cardiology
Jennifer DavisJoseph M Metzger

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 Ca(2+)-activated tension assays yet prolonged relaxation and Ca(2+) decay. In comparison RCM cTnI mutants in the helix-4/C-terminal region demonstrated a) hyper-sensitivity to Ca(2+) under loaded conditions, b) slowed myocyte mechanical relaxation and Ca(2+) transient decay, c) frequency-dependent Ca(2+)-independent diastolic tone, d) heightened myofilament incorporation and ...Continue Reading

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Jul 10, 2010·Journal of Biomedicine & Biotechnology·Michelle S ParvatiyarJames D Potter
Sep 12, 2014·Basic Research in Cardiology·Alexandra EderThomas Eschenhagen
Jul 12, 2012·Journal of Geriatric Cardiology : JGC·Pierre-Yves Jean-CharlesXu-Pei Huang
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Jan 13, 2021·International Journal of Molecular Sciences·Diana CimiottiKornelia Jaquet
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Apr 12, 2018·Biophysical Journal·Anthony D VetterJoseph M Metzger
Jul 18, 2014·Circulation. Cardiovascular Genetics·Adam S HelmsSharlene M Day

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