Lamin A/C deficiency causes defective nuclear mechanics and mechanotransduction

TLDR

Mutations in LMNA cause a spectrum of diseases, yet the tissue‑specific effects remain unclear, suggesting that defective lamin A/C may heighten cellular mechanical sensitivity. The study aimed to determine how lamin A/C influences mechanotransduction by applying mechanical strain to lamin A/C‑deficient mouse embryo fibroblasts and assessing nuclear mechanics and signaling responses. Mechanical strain was imposed on Lmna‑/‑ fibroblasts while nuclear mechanical properties and strain‑induced signaling pathways were measured. Lmna‑/‑ cells exhibited greater nuclear deformation, impaired mechanotransduction, reduced viability under strain, and attenuated NF‑κB–mediated transcription despite increased factor binding, indicating that lamin A/C deficiency disrupts nuclear mechanics and mechanically activated gene expression, which may underlie the tissue‑specific manifestations of laminopathies.

Abstract

Mutations in the lamin A/C gene (LMNA) cause a variety of human diseases including Emery-Dreifuss muscular dystrophy, dilated cardiomyopathy, and Hutchinson-Gilford progeria syndrome. The tissue-specific effects of lamin mutations are unclear, in part because the function of lamin A/C is incompletely defined, but the many muscle-specific phenotypes suggest that defective lamin A/C could increase cellular mechanical sensitivity. To investigate the role of lamin A/C in mechanotransduction, we subjected lamin A/C-deficient mouse embryo fibroblasts to mechanical strain and measured nuclear mechanical properties and strain-induced signaling. We found that Lmna-/- cells have increased nuclear deformation, defective mechanotransduction, and impaired viability under mechanical strain. NF-kappaB-regulated transcription in response to mechanical or cytokine stimulation was attenuated in Lmna-/- cells despite increased transcription factor binding. Lamin A/C deficiency is thus associated with both defective nuclear mechanics and impaired mechanically activated gene transcription. These findings suggest that the tissue-specific effects of lamin A/C mutations observed in the laminopathies may arise from varying degrees of impaired nuclear mechanics and transcriptional activation.