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.
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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

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Figure 2

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In vivo analyses of cardiac function with micromanometry and sonomicrome...
In vivo analyses of cardiac function with micromanometry and sonomicrometry in mice aged 4–6 weeks. (a) Representative LV pressure-volume loops recorded at steady state are shown for WT (blue), Lmna+/– (green), and Lmna–/– (red) mice. Steady-state LV end-diastolic pressure (EDP) plotted against LV end-diastolic volume (EDV) (b) and stress-strain relationships (c) for WT (diamonds, n = 9) Lmna+/– mice (squares, n = 11), and Lmna–/– mice (triangles, n = 6). Volume data are normalized to body weight; data are shown as mean ± SD. Functional and morphologic characteristics of cardiac myocytes isolated from mice aged 4–6 weeks were also assessed. (d) Representative recordings of Ca2+ transients (top panel) and shortening (lower panel) in single myocytes. Intracellular Ca2+ concentration was measured as the change in the 405:485 nm emission ratio for Indo-1. 0.25 represents the magnitude of the Ca2+ transient. Lmna–/– myocytes have similar baseline and peak intracellular Ca2+ concentrations to WT and Lmna+/– myocytes but significantly reduced shortening. (e) Lmna–/– myocytes are shorter and thinner than WT and Lmna+/– myocytes but the length/width ratios are similar. Scale bar: 20 μm.