Myofibril degeneration caused by tropomodulin overexpression leads to dilated cardiomyopathy in juvenile mice

Mark A. Sussman, Sara Welch, Natalie Cambon, Raisa Klevitsky, Timothy E. Hewett, Robert Price, Sandra A. Witt, Thomas R. Kimball

Research output: Contribution to journalArticlepeer-review

130 Scopus citations

Abstract

Loss of myofibril organization is a common feature of chronic dilated and progressive cardiomyopathy. To study how the heart compensates for myofibril degeneration, transgenic mice were created that undergo progressive loss of myofibrils after birth. Myofibril degeneration was induced by overexpression of tropomodulin, a component of the thin filament complex which determines and maintains sarcomeric actin filament length. The tropomodulin cDNA was placed under control of the α-myosin heavy chain gene promoter to overexpress tropomodulin specifically in the myocardium. Offspring with the most severe phenotype showed cardiomyopathic changes between 2 and 4 wk after birth. Hearts from these mice present characteristics consistent with dilated cardiomyopathy and a failed hypertrophic response. Histological analysis showed widespread loss of myofibril organization. Confocal microscopy of isolated cardiomyocytes revealed intense tropomodulin immunoreactivity in transgenic mice together with abnormal coincidence of tropomodulin and α-actinin reactivity at Z discs. Contractile function was compromised severely as determined by echocardiographic analyses and isolated Langendorff heart preparations. This novel experimentally induced cardiomyopathy will be useful for understanding dilated cardiomyopathy and the effect of thin filament-based myofibril degeneration upon cardiac structure and function.

Original languageEnglish (US)
Pages (from-to)51-61
Number of pages11
JournalJournal of Clinical Investigation
Volume101
Issue number1
DOIs
StatePublished - Jan 1 1998

Keywords

  • Cardiomyopathy
  • Myocardial diseases
  • Myocardium
  • Myofibrils
  • Ventricular dysfunction

ASJC Scopus subject areas

  • Medicine(all)

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