title: Defects in nuclear structure and function promote dilated cardiomyopathy in lamin A/C-deficient mice.
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.
authors.affiliation: Molecular Cardiology Program, Victor Chang Cardiac Research Institute, Darlinghurst, New South Wales, Australia.
authors.forename: Vesna
authors.initials: V
authors.lastname: Nikolova
authors.forename: Christiana
authors.initials: C
authors.lastname: Leimena
authors.forename: Aisling C
authors.initials: AC
authors.lastname: McMahon
authors.forename: Ju Chiat
authors.initials: JC
authors.lastname: Tan
authors.forename: Suchitra
authors.initials: S
authors.lastname: Chandar
authors.forename: Dilesh
authors.initials: D
authors.lastname: Jogia
authors.forename: Scott H
authors.initials: SH
authors.lastname: Kesteven
authors.forename: Jan
authors.initials: J
authors.lastname: Michalicek
authors.forename: Robyn
authors.initials: R
authors.lastname: Otway
authors.forename: Fons
authors.initials: F
authors.lastname: Verheyen
authors.forename: Stephen
authors.initials: S
authors.lastname: Rainer
authors.forename: Colin L
authors.initials: CL
authors.lastname: Stewart
authors.forename: David
authors.initials: D
authors.lastname: Martin
authors.forename: Michael P
authors.initials: MP
authors.lastname: Feneley
authors.forename: Diane
authors.initials: D
authors.lastname: Fatkin
mesh_terms: 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
chemical_list: D034904:Lamin Type A