PDF(Pubmed)
Abstract：
Duchenne muscular dystrophy (DMD) is a progressive muscle disease that results in muscle wasting, wheelchair dependence, and eventual death due to cardiac and respiratory complications. In addition to muscle fragility, dystrophin deficiency also results in multiple secondary dysfunctions, which may lead to the accumulation of unfolded proteins causing endoplasmic reticulum (ER) stress and the unfolded protein response (UPR). The purpose of this investigation was to understand how ER stress and the UPR are modified in muscle from D2-mdx mice, an emerging DMD model, and from humans with DMD. We hypothesized that markers of ER stress and the UPR are upregulated in D2-mdx and human dystrophic muscles compared to their healthy counterparts. Immunoblotting in diaphragms from 11-month-old D2-mdx and DBA mice indicated increased ER stress and UPR in dystrophic diaphragms compared to healthy, including increased relative abundance of ER stress chaperone CHOP, canonical ER stress transducers ATF6 and pIRE1α S724, and transcription factors that regulate the UPR such as ATF4, XBP1s, and peIF2α S51. The publicly available Affymetrix dataset (GSE38417) was used to analyze the expression of ER stress and UPR-related transcripts and processes. Fifty-eight upregulated genes related to ER stress and the UPR in human dystrophic muscles suggest pathway activation. Further, based on analyses using iRegulon, putative transcription factors that regulate this upregulation profile were identified, including ATF6, XBP1, ATF4, CREB3L2, and EIF2AK3. This study adds to and extends the emerging knowledge of ER stress and the UPR in dystrophin deficiency and identifies transcriptional regulators that may be responsible for these changes and be of therapeutic interest.
摘要：
杜氏肌营养不良症（DMD）是一种进行性肌肉疾病，导致肌肉萎缩，轮椅依赖，最终死于心脏和呼吸系统并发症.除了肌肉脆弱,肌营养不良蛋白缺乏也会导致多种继发性功能障碍，这可能导致未折叠蛋白的积累，引起内质网（ER）应激和未折叠蛋白反应（UPR）。这项研究的目的是了解D2-mdx小鼠肌肉中的ER应激和UPR是如何改变的，一种新兴的DMD模型，来自患有DMD的人类。我们假设，与健康的肌肉相比，D2-mdx和人类营养不良的肌肉中ER应激和UPR的标志物上调。11个月大的D2-mdx和DBA小鼠的隔膜免疫印迹表明，与健康相比，营养不良性隔膜的ER应激和UPR增加，包括ER应激伴侣CHOP的相对丰度增加，规范的ER应激传感器ATF6和pIRE1αS724，以及调节UPR的转录因子，如ATF4，XBP1s，和PEIF2αS51。公开可用的Affymetrix数据集(GSE38417)用于分析ER应激和UPR相关转录本和过程的表达。58个与人营养不良肌肉中ER应激和UPR相关的上调基因表明途径激活。Further,基于使用iPregion的分析，鉴定了调节这种上调谱的推定转录因子，包括ATF6、XBP1、ATF4、CREB3L2和EIF2AK3。这项研究增加并扩展了肌萎缩蛋白缺乏中ER应激和UPR的新兴知识，并确定了可能负责这些变化并具有治疗意义的转录调节因子。
