Viscoelastic behavior of cardiomyocytes carrying LMNA mutations.

Abstract

Background: Laminopathies are genetic diseases caused by mutations in the nuclear lamina.

Objective: Given the clinical impact of laminopathies, understanding mechanical properties of cells bearing lamin mutations will lead to advancement in the treatment of heart failure.

Methods: Atomic force microscopy (AFM) was used to analyze the viscoelastic behavior of neonatal rat ventricular myocyte cells expressing three human lamin A/C gene (LMNA) mutations.

Results: Cell storage modulus was characterized, by two plateaus, one in the low frequency range, a second one at higher frequencies. The loss modulus instead showed a "bell" shape with a relaxation toward fluid properties at lower frequencies. Mutations shifted the relaxation to higher frequencies, rendering the networks more solid-like. This increase of stiffness with mutations (solid like behavior) was at frequencies around 1 Hz, close to the human heart rate.

Conclusions: These features resulted from a combination of the properties of cytoskeleton filaments and their temporary cross-linker. Our results substantiate that cross-linked filaments contribute, for the most part, to the mechanical strength of the cytoskeleton of the cell studied and the relaxation time is determined by the dissociation dynamics of the cross-linking proteins. The severity of biomechanical defects due to these LMNA mutations correlated with the severity of the clinical phenotype.