Abstract：
Most of the single point mutations of the LMNA gene are associated with distinct muscular dystrophies, marked by heterogenous phenotypes but primarily the loss and symmetric weakness of skeletal muscle tissue. The molecular mechanism and phenotype-genotype relationships in these muscular dystrophies are poorly understood. An effort has been here to delineating the adaptation of mechanical inputs into biological response by mutant cells of lamin A associated muscular dystrophy. In this study, we implement engineered smooth and pattern surfaces of particular young modulus to mimic muscle physiological range. Using fluorescence and atomic force microscopy, we present distinct architecture of the actin filament along with abnormally distorted cell and nuclear shape in mutants, which showed a tendency to deviate from wild type cells. Topographic features of pattern surface antagonize the binding of the cell with it. Correspondingly, from the analysis of genome wide expression data in wild type and mutant cells, we report differential expression of the gene products of the structural components of cell adhesion as well as LINC (linkers of nucleoskeleton and cytoskeleton) protein complexes. This study also reveals mis expressed downstream signaling processes in mutant cells, which could potentially lead to onset of the disease upon the application of engineered materials to substitute the role of conventional cues in instilling cellular behaviors in muscular dystrophies. Collectively, these data support the notion that lamin A is essential for proper cellular mechanotransduction from extracellular environment to the genome and impairment of the muscle cell differentiation in the pathogenic mechanism for lamin A associated muscular dystrophy.
摘要：
LMNA基因的大多数单点突变与明显的肌营养不良有关，以异质性表型为特征，但主要是骨骼肌组织的丢失和对称无力。这些肌营养不良的分子机制和表型-基因型关系知之甚少。本文一直在努力描述由与层粘连蛋白A相关的肌营养不良的突变细胞对机械输入的生物反应的适应性。在这项研究中,我们实施特定杨氏模量的工程光滑和图案表面来模拟肌肉生理范围。使用荧光和原子力显微镜，我们在突变体中呈现了肌动蛋白丝的独特结构以及异常扭曲的细胞和核形状，显示出偏离野生型细胞的趋势。图案表面的地形特征拮抗细胞与它的结合。相应地,从野生型和突变细胞的全基因组表达数据分析，我们报告了细胞粘附结构成分的基因产物以及LINC（核骨架和细胞骨架的接头）蛋白质复合物的差异表达。这项研究还揭示了突变细胞中表达错误的下游信号过程，在应用工程材料代替常规线索在肌肉营养不良中滴注细胞行为中的作用时，这可能会导致疾病的发作。总的来说，这些数据支持这样的观点,即在与层粘连蛋白A相关的肌营养不良的致病机制中,层粘连蛋白A对于从细胞外环境到基因组的适当细胞机械转导和肌细胞分化的损害是必不可少的。
