Lethal cardiomyopathy in juvenile mice caused by tropomodulin overexpression

Mark A. Sussman, Natalie Cambon, Timothy Hewett, Raisa Klevitsky, Hanna Osinska, Sara Welch

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Loss of myofibril organization is a common feature of chronic dilated and progressive cardiomyopathy. To study how the heart attempts to compensate for loss of myofibrils, we have created transgenic mice which undergo a progressive loss of myofibrillar structure after birth. Degeneration of myofibrils was induced by overexpression of tropomodulin, a component of the thin filament complex thought to function in determination and/or maintenance of sarcomeric actin filament length. The tropomodulin cDNA was placed under control of the α-myosin heavy chain gene promoter in order to create transgenic mice which overexpress tropomodulin specifically in the myocardium. Selective breeding has produced a line of mice which succumb to cardiomyopathy between 14 to 18 days after birth. Expression of the transgene was confirmed by northern and western blot analyses. Hearts of these mice are enlarged and dilated with histologic evidence of failure such as loss of contractile material and myofibril disarray. Fluorescence 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. Primary features of ultrastructural analysis included contracted sarcomeric bands, mitochondrial proliferation, and abnormal endothelial cells in the coronary vasculature. Contractile function in these hearts was severely compromised as determined by Langendorff heart preparations, and transgenic hearts were unable to function in working heart preparations. These transgenic mice will be useful for greater understanding of how thin filament-based myofibril degeneration affects cardiac structure and function.

Original languageEnglish (US)
JournalFASEB Journal
Issue number3
StatePublished - 1997
Externally publishedYes

ASJC Scopus subject areas

  • Agricultural and Biological Sciences (miscellaneous)
  • Biochemistry, Genetics and Molecular Biology(all)
  • Biochemistry
  • Cell Biology


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