Defects in nuclear structure and function promote dilated cardiomyopathy in lamin A/C–deficient mice
Vesna Nikolova, … , Michael P. Feneley, Diane Fatkin
Vesna Nikolova, … , Michael P. Feneley, Diane Fatkin
Published February 1, 2004
Citation Information: J Clin Invest. 2004;113(3):357-369. https://doi.org/10.1172/JCI19448.
View: Text | PDF
Article Cardiology

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 Ca2+ 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 PPARγ 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

Vesna Nikolova, Christiana Leimena, Aisling C. McMahon, Ju Chiat Tan, Suchitra Chandar, Dilesh Jogia, Scott H. Kesteven, Jan Michalicek, Robyn Otway, Fons Verheyen, Stephen Rainer, Colin L. Stewart, David Martin, Michael P. Feneley, Diane Fatkin

×

Figure 5

Options: View larger image (or click on image) Download as PowerPoint
Disruption of the lamin-desmin intermediate filament network in lamin A/...
Disruption of the lamin-desmin intermediate filament network in lamin A/C–deficient mice. Attachment sites of desmin filaments to the LV cardiomyocyte nuclear surface were identified using immunogold-labeled desmin Ab’s and electron microscopy. Approximately 30 nuclei from WT mice (n = 3), Lmna+/– mice (n = 3), and Lmna–/– mice (n = 3) aged 2 weeks and 4–6 weeks were evaluated. In WT mice (a), desmin filaments (black dots) generally appear as well-defined bands connecting the cytoskeleton with the nuclear surface through nuclear pores (insets). Disorganization of the desmin filaments with detachment from the nuclear surface (with or without widening of the gap between the nuclear and myofibril borders) was observed in 4 (13%) Lmna+/– nuclei (b) and 16 (59%) Lmna–/– nuclei (d), but in none of the WT nuclei at 4–6 weeks. These changes were evident in 14 (50%) Lmna–/– nuclei (c) at 2 weeks; scale bar = 0.25 μm. Immunostaining with a desmin Ab (e–h) shows normal Z disc striations and intercalated discs in WT and Lmna+/– mice, but progressive disorganization of the desmin filament network in 2-week-old (g) and 4- to 6-week-old (h) Lmna–/– mice. Scale bar: 5 μm.