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PMID: 14755333 Published · ppublish English Journal Article Research Support, Non-U.S. Gov't

Defects in nuclear structure and function promote dilated cardiomyopathy in lamin A/C-deficient mice.

The Journal of clinical investigation ·Vol. 113 ·No. 3 ·2004-02-00 ·Pages 357-69

Nikolova V, Leimena C, McMahon AC, Tan JC, Chandar S, Jogia D, Kesteven SH, Michalicek J, Otway R, Verheyen F, Rainer S, Stewart CL, Martin D, Feneley MP, Fatkin D

Abstract

Laminopathies are a group of disorders caused by mutations in the LMNA gene that encodes the nuclear lamina proteins, lamin A and lamin C; their pathophysiological basis is unknown. We report that lamin A/C-deficient (Lmna(-/-)) mice develop rapidly progressive dilated cardiomyopathy (DCM) characterized by left ventricular (LV) dilation and reduced systolic contraction. Isolated Lmna(-/-) myocytes show reduced shortening with normal baseline and peak amplitude of Ca(2+) transients. Lmna(-/-) LV myocyte nuclei have marked alterations of shape and size with central displacement and fragmentation of heterochromatin; these changes are present but less severe in left atrial nuclei. Electron microscopy of Lmna(-/-) cardiomyocytes shows disorganization and detachment of desmin filaments from the nuclear surface with progressive disruption of the cytoskeletal desmin network. Alterations in nuclear architecture are associated with defective nuclear function evidenced by decreased SREBP1 import, reduced PPARgamma expression, and a lack of hypertrophic gene activation. These findings suggest a model in which the primary pathophysiological mechanism in Lmna(-/-) mice is defective force transmission resulting from disruption of lamin interactions with the muscle-specific desmin network and loss of cytoskeletal tension. Despite severe DCM, defects in nuclear function prevent Lmna(-/-) cardiomyocytes from developing compensatory hypertrophy and accelerate disease progression.

MeSH Terms
Animals Apoptosis/genetics,physiology Cardiomyopathy, Dilated/genetics,pathology,physiopathology Cell Nucleus/pathology Echocardiography Electrocardiography Lamin Type A/deficiency,genetics Mice Myocardium/pathology Myocytes, Cardiac/pathology Time Factors
Chemicals
Lamin Type A
Authors & Affiliations
15 authors, click to expand affiliations / ORCID
Nikolova Vesna
Molecular Cardiology Program, Victor Chang Cardiac Research Institute, Darlinghurst, New South Wales, Australia.
Leimena Christiana
McMahon Aisling C
Tan Ju Chiat
Chandar Suchitra
Jogia Dilesh
Kesteven Scott H
Michalicek Jan
Otway Robyn
Verheyen Fons
Rainer Stephen
Stewart Colin L
Martin David
Feneley Michael P
Fatkin Diane
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Article Info
Journal
The Journal of clinical investigation
Abbr.
J Clin Invest
ISSN
0021-9738
DOI
10.1172/JCI19448
Published
2004-02-00
Pages
357-69
Language
English
Region
United States
NLM ID
7802877
PMCID
PMC324538
Subset
IM
Corrections
CommentIn
PMID: 14755330
External Links
PubMed source DOI: 10.1172/JCI19448 PMC Full Text View journal details
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