Expanded CTG repeats within the DMPK 3′ UTR causes severe skeletal muscle wasting in an inducible mouse model for myotonic dystrophy
Expanded CTG repeats within the DMPK 3′ UTR causes severe skeletal muscle wasting in an inducible mouse model for myotonic dystrophy
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DOI：
10.1073/pnas.0708519105
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发表时间：
2008-02-19
影响因子：
11.1
通讯作者：
Cooper, Thomas A.
中科院分区：
文献类型：
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作者：
Orengo, James P.;Chambon, Pierre;Cooper, Thomas A.
严重的骨骼肌萎缩是强直性肌营养不良1型（DM 1）患者经历的最衰弱的症状。我们提出了一种DM 1小鼠模型，在DMPK外显子15的背景下，CTG重复序列的大片段具有诱导性和骨骼肌特异性表达。这些小鼠概括了与DM 1骨骼肌相关的许多发现，如CUG RNA灶与Muscleblind样1（MBNL 1）蛋白共定位，发育调节的可变剪接事件的失调，肌强直，特征性组织学异常和CUGBP 1蛋白水平升高。重要的是，这种DM 1小鼠模型重现了严重的肌肉萎缩，这在MBNL 1耗竭是主要特征的模型中尚未报道。使用这些小鼠，我们发现了以前未描述的选择性剪接事件，这些事件对CUGBP 1而不是MBNL有反应，并且发现这些事件在DM 1个体中被错误调节。我们的研究结果表明，CUGBP 1蛋白水平的增加与DMPK-CUG RNA表达相关，表明CUGBP 1特异性剪接或细胞质功能在肌肉萎缩中的作用。
Severe skeletal muscle wasting is the most debilitating symptom experienced by individuals with myotonic dystrophy type 1 (DM1). We present a DM1 mouse model with inducible and skeletal muscle-specific expression of large tracts of CTG repeats in the context of DMPK exon 15. These mice recapitulate many findings associated with DM1 skeletal muscle, such as CUG RNA foci with Muscleblind-like 1 (MBNL1) protein colocalization, misregulation of developmentally regulated alternative splicing events, myotonia, characteristic histological abnormalities, and increased CUGBP1 protein levels. Importantly, this DM1 mouse model recapitulates severe muscle wasting, which has not been reported in models in which depletion of MBNL1 is the main feature. Using these mice, we discovered previously undescribed alternative splicing events that are responsive to CUGBP1 and not MBNL, and these events were found to be misregulated in individuals with DM1. Our results indicate that increased CUGBP1 protein levels are associated with DMPK-CUG RNA expression, suggesting a role for CUGBP1-specific splicing or cytoplasmic functions in muscle wasting.