Cardiomyocyte-Specific Expression of Lamin A Improves Cardiac Function in Lmna.sup.-/- Mice

• Published in: PloS one 2012-08, Vol.7 (8), p.e42918
• Main Authors: Frock, Richard L, Chen, Steven C, Da, Dao-Fu, Frett, Ellie, Lau, Carmen, Brown, Christina, Pak, Diana N, Wang, Yuexia, Muchir, Antoine, Worman, Howard J, Santana, Luis F, Ladiges, Warren C, Rabinovitch, Peter S, Kennedy, Brian K
• Format: Article
• Language: English
• Subjects: Comparative analysis; Heart
• ISSN: 1932-6203; 1932-6203
• DOI: 10.1371/journal.pone.0042918

Lmna.sup.-/- 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.sup.-/- mice. We observed increased total desmin protein levels and disorganization of the cytoplasmic desmin network in ~20% of Lmna.sup.-/- ventricular myocytes, rescued in a cell-autonomous manner in Lmna.sup.-/- mice expressing a cardiac-specific lamin A transgene (Lmna.sup.-/- ; Tg). Lmna.sup.-/- ; Tg mice displayed significantly increased contractility and preservation of myocardial performance compared to Lmna.sup.-/- mice. Lmna.sup.-/- ; Tg mice attenuated ERK1/2 phosphorylation relative to Lmna.sup.-/- mice, potentially underlying the improved localization of connexin43 to the intercalated disc. Electrocardiographic recordings from Lmna.sup.-/- mice revealed arrhythmic events and increased frequency of PR interval prolongation, which is partially rescued in Lmna.sup.-/- ; Tg mice. These findings support our observation that Lmna.sup.-/- ; Tg mice have a 12% median extension in lifespan compared to Lmna.sup.-/- mice. While significant, Lmna.sup.-/- ; Tg mice only have modest improvement in cardiac function and survival likely stemming from the observation that only 40% of Lmna.sup.-/- ; Tg cardiomyocytes have detectable lamin A expression. Cardiomyocyte-specific restoration of lamin A in Lmna.sup.-/- mice improves heart-specific pathology and extends lifespan, demonstrating that the cardiac pathology of Lmna.sup.-/- 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.