Mouse model of desmin-related cardiomyopathy

Xuejun Wang, Hanna Osinska, Gerald W. Dorn, Michelle Nieman, John N. Lorenz, A. Martin Gerdes, Sandra Witt, Thomas Kimball, James Gulick, Jeffrey Robbins

Research output: Contribution to journalArticle

163 Scopus citations

Abstract

Background - The consequence of upregulation of desmin in the heart is unknown. Mutations in desmin have been linked to desmin-related myopathy (DRM), which is characterized by abnormal intrasarcoplasmic accumulation of desmin, but direct causative evidence that a desmin mutation leads to aberrant intrasarcoplasmic desmin accumulation, aggregation, and cardiomyopathy is lacking. Methods and Results - Multiple transgenic mouse lines that expressed either murine wild-type desmin or a 7-amino acid deletion (R173 through E179) desmin (D7-des) mutation linked to DRM were made. The distribution of desmin protein was unchanged, and no overt phenotype was detected in the wild-type desmin transgenic mice. In contrast, the D7-des mouse heart showed aberrant intrasarcoplasmic and electron-dense granular filamentous aggregates that were desmin-positive and characteristic of human DRM. The desmin filament network was significantly disrupted, and myofibril alignment was visibly compromised. Although systolic function at the whole-organ level was substantially conserved in the young adult animals, the ability of the heart to respond to β-agonist stimulation, as measured in the intact animal, was significantly blunted. Conclusions - Upregulation of desmin protein at moderate levels is not detrimental. However, the D7-des mutation is dominant negative, and expression of the mutant protein leads to the appearance of aggregates that are characteristic of and diagnostic for human desmin-related cardiomyopathy.

Original languageEnglish (US)
Pages (from-to)2402-2407
Number of pages6
JournalCirculation
Volume103
Issue number19
DOIs
StatePublished - May 15 2001

Keywords

  • Cardiomyopathy
  • Heart diseases
  • Molecular biology
  • Pathology
  • Physiology

ASJC Scopus subject areas

  • Cardiology and Cardiovascular Medicine
  • Physiology (medical)

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    Wang, X., Osinska, H., Dorn, G. W., Nieman, M., Lorenz, J. N., Gerdes, A. M., Witt, S., Kimball, T., Gulick, J., & Robbins, J. (2001). Mouse model of desmin-related cardiomyopathy. Circulation, 103(19), 2402-2407. https://doi.org/10.1161/01.CIR.103.19.2402