Cardiomyocyte-Specific Expression of Lamin A Improves Cardiac Function in Lmna (−/−) Mice

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.