A familial hypertrophic cardiomyopathy α-tropomyosin mutation causes severe cardiac hypertrophy and death in mice

Rethinasamy Prabhakar, Greg P. Boivin, Ingrid L. Grupp, Brian Hoit, Grace Arteaga, R. John Solaro, David F. Wieczorek

Research output: Contribution to journalArticle

94 Scopus citations

Abstract

Tropomyosin, an essential component of the sarcomere, regulates muscle contraction through Ca2+-mediated activation. Familial hypertrophic cardiomyopathy (FHC) is caused by mutations in numerous cardiac sarcomeric proteins, including myosin heavy and light chains, actin, troponin T and I, myosin binding protein C, and α-tropomyosin. This study developed transgenic mouse lines that encode an FHC mutation in α-tropomyosin: this mutation is an amino acid substitution at codon 180 (Glu180Gly) which occurs in a troponin T binding region. Non-transgenic and control mice expressing wildtype α-tropomyosin demonstrate no morphological or physiological changes. Expression of exogenous mutant tropomyosin leads to a concomitant decrease in endogenous α-tropomyosin without altering the expression of other contractile proteins. Histological analysis shows that initial pathological changes, which include ventricular concentric hypertrophy, fibrosis and atrial enlargement, are detected within 1 month. The disease-associated changes progressively increase and result in death between 4 and 5 months. Physiological analyses of the FHC mice using echocardiography, work-performing heart analyses, and force measurements of cardiac myofibers, demonstrate dramatic functional differences in diastolic performance and increased sensitivity to calcium. This report demonstrates that mutations in α-tropomyosin can be severely disruptive of sarcomeric function, which consequently triggers a dramatic hypertrophic response that culminates in lethality.

Original languageEnglish (US)
Pages (from-to)1815-1828
Number of pages14
JournalJournal of Molecular and Cellular Cardiology
Volume33
Issue number10
DOIs
StatePublished - Jan 1 2001

Keywords

  • Cardiac hypertrophy
  • Familial hypertrophic cardiomyopathy
  • Sarcomeric function
  • Transgenic mice
  • Tropomyosin

ASJC Scopus subject areas

  • Molecular Biology
  • Cardiology and Cardiovascular Medicine

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    Prabhakar, R., Boivin, G. P., Grupp, I. L., Hoit, B., Arteaga, G., Solaro, R. J., & Wieczorek, D. F. (2001). A familial hypertrophic cardiomyopathy α-tropomyosin mutation causes severe cardiac hypertrophy and death in mice. Journal of Molecular and Cellular Cardiology, 33(10), 1815-1828. https://doi.org/10.1006/jmcc.2001.1445