Orengo James P, Chambon Pierre, Metzger Daniel, Mosier Dennis R, Snipes G Jackson, Cooper Thomas A
Department of Pathology, Baylor College of Medicine, One Baylor Plaza, Houston, TX 77030, USA.
Proc Natl Acad Sci U S A. 2008 Feb 19;105(7):2646-51. doi: 10.1073/pnas.0708519105. Epub 2008 Feb 13.
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.
严重骨骼肌萎缩是1型强直性肌营养不良症（DM1）患者经历的最使人衰弱的症状。我们展示了一种DM1小鼠模型，在DMPK外显子15的背景下，大片段CTG重复序列可诱导且在骨骼肌中特异性表达。这些小鼠重现了许多与DM1骨骼肌相关的发现，如CUG RNA病灶与类肌肉盲蛋白1（MBNL1）蛋白共定位、发育调控的可变剪接事件失调、肌强直、特征性组织学异常以及CUGBP1蛋白水平升高。重要的是，这种DM1小鼠模型重现了严重的肌肉萎缩，而在以MBNL1缺失为主要特征的模型中尚未有此报道。利用这些小鼠，我们发现了以前未描述的对CUGBP1而非MBNL有反应的可变剪接事件，并且这些事件在DM1患者中失调。我们的结果表明，CUGBP1蛋白水平升高与DMPK - CUG RNA表达相关，提示CUGBP1特异性剪接或细胞质功能在肌肉萎缩中起作用。
