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 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.

Lamin A/C haploinsufficiency causes dilated cardiomyopathy and apoptosis-triggered cardiac conduction system disease

“…Lamin deficiency causes abnormal nuclear architecture [20,21]: on electronmicroscopy, Lmna +/-nuclei had irregularities of shape and peripheral heterochromatin clumping [21]. We confirmed this and found that nuclei from both isolated conduction and non-conduction system myocytes of Lmna +/-mice were elongated and dysmorphic (Figure 4).…”

“…Prior studies demonstrated apoptosis in ventricular myocytes from Lmna -/-mice as the probable cause for early-onset DCM and heart failure [21]. We found no apoptotic myocytes in cardiac ventricles of young adult Lmna +/-mice, despite their physical proximity to apoptotic AV nodal myocytes ( Figure 5).…”

“…Juvenile, homozygous lamin-null (Lmna -/-) mice are runted, have skeletal muscle atrophy [20], DCM [21], and die by 8 weeks, recapitulating some features of human Emery-Dreifuss muscular dystrophy, DCM and progeria. In contrast, heterozygous mutant mice, which replicate the mutant gene dosage found in humans, are reported as indistinguishable from wildtype mice [21]. Whether this reflects fundamental differences in lamin biology, survival differences, or incomplete phenotyping is unclear.…”

Beyond membrane channelopathies: alternative mechanisms underlying complex human disease

“…Altered lamin due to a LMNA gene mutation will develop an abnormal interaction with associated proteins resulting in disorganized cell structure and in-turn cell dysfunction [79][80][81][82] . Nikolova et al, demonstrated that in lamin A/C deficient mice the intermediate filament protein desmin, important in maintaining structural integrity of the cell, became disorganized and detached from the nuclear surface [79,83] .…”

Inner nuclear membrane and signal transduction

“…Lammerding et al [2004] have shown that fibroblasts from lamin A/C null mice have nuclear structural defects and attenuated NFkappaB-regulated transcription in response to mechanical or cytokine stimulation. Lamin A/C null mice develop cardiomyopathy and skeletal muscle abnormalities similar to human Emery-Dreifuss muscular dystrophy [Sullivan et al, 1999;Nikolova et al, 2004]. Hence, abnormal signal transduction may play a role the development of striated muscle disease with loss of A-type lamins.…”