Cardiomyocyte-specific expression of lamin A improves cardiac function in Lmna-/- mice

Richard L. Frock, Steven C. Chen, Dao Fu Da, Ellie Frett, Carmen Lau, Christina Brown, Diana N. Pak, Yuexia Wang, Antoine Muchir, Howard J. Worman, Luis Fernando Santana, Warren C. Ladiges, Peter S. Rabinovitch, Brian K. Kennedy

Research output: Contribution to journalArticle

20 Scopus citations

Abstract

Lmna-/- mice display multiple tissue defects and die by 6-8 weeks of age reportedly from dilated cardiomyopathy with associated conduction defects. We sought to determine whether restoration of lamin A in cardiomyocytes improves cardiac function and extends the survival of Lmna-/- mice. We observed increased total desmin protein levels and disorganization of the cytoplasmic desmin network in ~20% of Lmna-/- ventricular myocytes, rescued in a cell-autonomous manner in Lmna-/- mice expressing a cardiac-specific lamin A transgene (Lmna-/-; Tg). Lmna-/-; Tg mice displayed significantly increased contractility and preservation of myocardial performance compared to Lmna-/- mice. Lmna-/-; Tg mice attenuated ERK1/2 phosphorylation relative to Lmna-/- mice, potentially underlying the improved localization of connexin43 to the intercalated disc. Electrocardiographic recordings from Lmna-/- mice revealed arrhythmic events and increased frequency of PR interval prolongation, which is partially rescued in Lmna-/-; Tg mice. These findings support our observation that Lmna-/-; Tg mice have a 12% median extension in lifespan compared to Lmna-/- mice. While significant, Lmna-/-; Tg mice only have modest improvement in cardiac function and survival likely stemming from the observation that only 40% of Lmna-/-; Tg cardiomyocytes have detectable lamin A expression. Cardiomyocyte-specific restoration of lamin A in Lmna-/- mice improves heart-specific pathology and extends lifespan, demonstrating that the cardiac pathology of Lmna-/- mice limits survival. The expression of lamin A is sufficient to rescue certain cellular defects associated with loss of A-type lamins in cardiomyocytes in a cell-autonomous fashion.

Original languageEnglish (US)
Article numbere42918
JournalPLoS One
Volume7
Issue number8
DOIs
StatePublished - Aug 15 2012
Externally publishedYes

ASJC Scopus subject areas

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

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    Frock, R. L., Chen, S. C., Da, D. F., Frett, E., Lau, C., Brown, C., Pak, D. N., Wang, Y., Muchir, A., Worman, H. J., Santana, L. F., Ladiges, W. C., Rabinovitch, P. S., & Kennedy, B. K. (2012). Cardiomyocyte-specific expression of lamin A improves cardiac function in Lmna-/- mice. PLoS One, 7(8), [e42918]. https://doi.org/10.1371/journal.pone.0042918