Department of Medical Sciences, Institute of Biomedicine (iBiMED), University of Aveiro, 3810-193 Aveiro, Portugal.
Int J Mol Sci. 2022 Jan 4;23(1):522. doi: 10.3390/ijms23010522.
Myotonic dystrophy type 1 (DM1) is a hereditary and multisystemic disease characterized by myotonia, progressive distal muscle weakness and atrophy. The molecular mechanisms underlying this disease are still poorly characterized, although there are some hypotheses that envisage to explain the multisystemic features observed in DM1. An emergent hypothesis is that nuclear envelope (NE) dysfunction may contribute to muscular dystrophies, particularly to DM1. Therefore, the main objective of the present study was to evaluate the nuclear profile of DM1 patient-derived and control fibroblasts and to determine the protein levels and subcellular distribution of relevant NE proteins in these cell lines. Our results demonstrated that DM1 patient-derived fibroblasts exhibited altered intracellular protein levels of lamin A/C, LAP1, SUN1, nesprin-1 and nesprin-2 when compared with the control fibroblasts. In addition, the results showed an altered location of these NE proteins accompanied by the presence of nuclear deformations (blebs, lobes and/or invaginations) and an increased number of nuclear inclusions. Regarding the nuclear profile, DM1 patient-derived fibroblasts had a larger nuclear area and a higher number of deformed nuclei and micronuclei than control-derived fibroblasts. These results reinforce the evidence that NE dysfunction is a highly relevant pathological characteristic observed in DM1.
肌强直性营养不良 1 型（DM1）是一种遗传性多系统疾病，其特征为肌强直、进行性远端肌肉无力和萎缩。尽管有一些假说设想可以解释 DM1 中观察到的多系统特征，但这种疾病的分子机制仍未得到充分描述。一种新兴假说认为，核膜（NE）功能障碍可能导致肌肉疾病，特别是 DM1。因此，本研究的主要目的是评估 DM1 患者来源的成纤维细胞和对照成纤维细胞的核形态，并确定这些细胞系中相关 NE 蛋白的蛋白水平和亚细胞分布。我们的结果表明，与对照成纤维细胞相比，DM1 患者来源的成纤维细胞表现出细胞内层粘连蛋白 A/C、LAP1、SUN1、nesprin-1 和 nesprin-2 的蛋白水平改变。此外，结果显示这些 NE 蛋白的位置发生改变，同时伴有核变形（泡状、叶状和/或内陷）和核内包涵体数量增加。关于核形态，与对照来源的成纤维细胞相比，DM1 患者来源的成纤维细胞具有更大的核面积和更多的畸形核和微核。这些结果进一步证实了 NE 功能障碍是 DM1 中观察到的一个高度相关的病理特征。
