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

PLoS One. 2012;7(8):e42918. doi: 10.1371/journal.pone.0042918. Epub 2012 Aug 15.

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.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Animals
  • Cytoplasm / metabolism
  • Desmin / metabolism
  • Electrocardiography / methods
  • Heart Ventricles / cytology
  • Lamin Type A / genetics*
  • Lamin Type A / physiology*
  • Mice
  • Mice, Transgenic
  • Mitogen-Activated Protein Kinase 1 / metabolism
  • Mitogen-Activated Protein Kinase 3 / metabolism
  • Models, Genetic
  • Muscle Cells / metabolism
  • Myocytes, Cardiac / cytology*
  • Phenotype
  • Transgenes

Substances

  • Desmin
  • Lamin Type A
  • Mapk1 protein, mouse
  • Mitogen-Activated Protein Kinase 1
  • Mitogen-Activated Protein Kinase 3