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

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. © 2012 Frock et al.