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.
Department of Biochemistry, University of Washington, Seattle, Washington, United States of America.
Richard L
RL
Frock
Steven C
SC
Chen
Dao-Fu
DF
Da
Ellie
E
Frett
Carmen
C
Lau
Christina
C
Brown
Diana N
DN
Pak
Yuexia
Y
Wang
Antoine
A
Muchir
Howard J
HJ
Worman
Luis F
LF
Santana
Warren C
WC
Ladiges
Peter S
PS
Rabinovitch
Brian K
BK
Kennedy
D000818:Animals; D003593:Cytoplasm / Q000378:metabolism; D003893:Desmin / Q000378:metabolism; D004562:Electrocardiography / Q000379:methods; D006352:Heart Ventricles / Q000166:cytology; D034904:Lamin Type A / Q000235:genetics* / Q000502:physiology*; D051379:Mice; D008822:Mice, Transgenic; D019950:Mitogen-Activated Protein Kinase 1 / Q000378:metabolism; D048052:Mitogen-Activated Protein Kinase 3 / Q000378:metabolism; D008957:Models, Genetic; D032342:Muscle Cells / Q000378:metabolism; D032383:Myocytes, Cardiac / Q000166:cytology*; D010641:Phenotype; D019076:Transgenes
D003893:Desmin; D034904:Lamin Type A; C535148:Mapk1 protein, mouse; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3