Defects in nuclear structure and function promote dilated cardiomyopathy in lamin A/C-deficient mice.
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.
Nikolova
Vesna
V
Molecular Cardiology Program, Victor Chang Cardiac Research Institute, Darlinghurst, New South Wales, Australia.
Leimena
Christiana
C
McMahon
Aisling C
AC
Tan
Ju Chiat
JC
Chandar
Suchitra
S
Jogia
Dilesh
D
Kesteven
Scott H
SH
Michalicek
Jan
J
Otway
Robyn
R
Verheyen
Fons
F
Rainer
Stephen
S
Stewart
Colin L
CL
Martin
David
D
Feneley
Michael P
MP
Fatkin
Diane
D
D000818:Animals; D017209:Apoptosis / Q000235:genetics / Q000502:physiology; D002311:Cardiomyopathy, Dilated / Q000235:genetics* / Q000473:pathology / Q000503:physiopathology; D002467:Cell Nucleus / Q000473:pathology; D004452:Echocardiography; D004562:Electrocardiography; D034904:Lamin Type A / Q000172:deficiency* / Q000235:genetics; D051379:Mice; D009206:Myocardium / Q000473:pathology; D032383:Myocytes, Cardiac / Q000473:pathology; D013997:Time Factors
D034904:Lamin Type A