Abstract

Mutations in the lamin A/C gene 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. Lamin A/C deficient fibroblasts were subjected to mechanical strain to measure nuclear mechanical properties and strain-induced signalling. We found that lamin A/C deficient fibroblasts are characterized by impaired nuclear mechanics and mechanotransduction, reflected by increased nuclear deformations, increased nuclear fragility, attenuated expression of mechanosensitive genes, and impaired transcriptional activation, leading to impaired viability of mechanically strained cells. Lamins and other nuclear envelope proteins can thus affect several levels of the mechanotransduction cascade, altering nuclear and cytoskeletal mechanics as well as playing an important role in mechanically activated gene regulation. Individual mutations in the lamin A/C gene could potentially selectively interfere with any of these functions, explaining the tissue-specific effects observed in the laminopathies.