Link between MHC Fiber Type and Restoration of Dystrophin Expression and Key Components of the DAPC by Tricyclo-DNA-Mediated Exon Skipping.
Link between MHC Fiber Type and Restoration of Dystrophin Expression and Key Components of the DAPC by Tricyclo-DNA-Mediated Exon Skipping.
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DOI：
10.1016/j.omtn.2017.10.014
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发表时间：
2017-12-15
期刊：
影响因子：
--
通讯作者：
Patel K
中科院分区：
文献类型：
--
作者：
Omairi S;Hau KL;Collin-Hooper H;Montanaro F;Goyenvalle A;Garcia L;Patel K
由三环-DNA（tc-DNA）反义寡核苷酸介导的外显子跳跃已显示在mdx（杜氏肌营养不良症的小鼠模型）中诱导显著水平的肌营养不良蛋白恢复。这转化为肌肉、心肺功能、心脏和CNS的关键疾病指标的显著改善。在这里，我们研究肌纤维类型之间的关系，肌球蛋白重链（MHC）的配置文件的基础上，和能力的tc-DNA恢复不仅肌营养不良蛋白，但也肌营养不良蛋白相关的糖蛋白复合物（DAPC）的其他成员。我们首先在未治疗的mdx肌肉中分析了这种关系，我们发现所有纤维类型都以无偏的方式支持肌营养不良蛋白阳性状态的逆转事件。重要的是，我们发现只有一小部分回复纤维表达DAPC的其他成员。然而，蛋白质水平的免疫印迹分析显示，这些组件的强大的表达，未能正确定位到肌膜。然后，我们表明，TC-DNA治疗导致几乎所有的纤维不仅表达肌营养不良蛋白，但也DAPC的其他关键成分。重要的是，我们的工作表明，MHC纤维类型不偏向任何这些重要蛋白质的表达。这项工作还强调了先前报道的tc-DNA治疗后肌肉生理学的改善是由于所有MHCII纤维中肌营养不良蛋白复合物以相同的效率完全恢复所致。
Exon skipping mediated by tricyclo-DNA (tc-DNA) antisense oligonucleotides has been shown to induce significant levels of dystrophin restoration in mdx, a mouse model of Duchenne muscular dystrophy. This translates into significant improvement in key disease indicators in muscle, cardio-respiratory function, heart, and the CNS. Here we examine the relationship between muscle fiber type, based on myosin heavy chain (MHC) profile, and the ability of tc-DNA to restore not only dystrophin but also other members of the dystrophin-associated glycoprotein complex (DAPC). We first profiled this relationship in untreated mdx muscle, and we found that all fiber types support reversion events to a dystrophin-positive state, in an unbiased manner. Importantly, we show that only a small fraction of revertant fibers expressed other members of the DAPC. Immunoblot analysis of protein levels, however, revealed robust expression of these components, which failed to correctly localize to the sarcolemma. We then show that tc-DNA treatment leads to nearly all fibers expressing not only dystrophin but also other key components of the DAPC. Of significance, our work shows that MHC fiber type does not bias the expression of any of these important proteins. This work also highlights that the improved muscle physiology following tc-DNA treatment reported previously results from the complete restoration of the dystrophin complex in all MHCII fibers with equal efficiencies.
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DOI：
10.1083/jcb.200604179
发表时间：
2007-03-26
期刊：
The Journal of cell biology
影响因子：
--
作者：
Rezniczek GA;Konieczny P;Nikolic B;Reipert S;Schneller D;Abrahamsberg C;Davies KE;Winder SJ;Wiche G
通讯作者：
Wiche G
影响因子：
6
作者：
Chretien, F;Dreyfus, PA;Gherardi, RK
通讯作者：
Gherardi, RK
影响因子：
2.7
作者：
ANDERSON, JE;BRESSLER, BH;OVALLE, WK
通讯作者：
OVALLE, WK
DOI：
10.1111/j.1748-1716.1980.tb06515.x
发表时间：
1980-01-01
期刊：
ACTA PHYSIOLOGICA SCANDINAVICA
影响因子：
--
作者：
KOVANEN, V;SUOMINEN, H;HEIKKINEN, E
通讯作者：
HEIKKINEN, E
影响因子：
7.8
作者：
Ohlendieck, K;Ervasti, J M;Snook, J B;Campbell, K P
通讯作者：
Campbell, K P