Department of Engineering and Architecture, University of Trieste, Trieste, Italy.
University of Colorado Anschutz Medical Campus - Aurora, CO, Cardiovascular Institute, USA.
Biorheology. 2020;57(1):1-14. doi: 10.3233/BIR-190229.
Laminopathies are genetic diseases caused by mutations in the nuclear lamina.
Given the clinical impact of laminopathies, understanding mechanical properties of cells bearing lamin mutations will lead to advancement in the treatment of heart failure.
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.
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.
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.
核纤层病是由核纤层蛋白基因突变引起的遗传疾病。
鉴于核纤层病的临床影响，了解携带核纤层蛋白基因突变的细胞的力学特性将有助于推进心力衰竭的治疗。
原子力显微镜（AFM）用于分析表达三种人类 lamin A/C 基因（LMNA）突变的新生大鼠心室肌细胞的粘弹行为。
细胞储能模量表现为两个平台，一个在低频范围内，另一个在较高频率。损耗模量则呈现出“钟形”，在较低频率下向流体性质松弛。突变将弛豫移至较高频率，使网络更具固态。这种随着突变而增加的硬度（固态行为）出现在约 1 Hz 的频率，接近人类的心率。
这些特征源于细胞骨架丝及其临时交联剂的特性组合。我们的结果证实，交联丝在很大程度上贡献了所研究细胞的细胞骨架的机械强度，而弛豫时间则由交联蛋白的解离动力学决定。由于这些 LMNA 突变引起的生物力学缺陷的严重程度与临床表型的严重程度相关。
