Mouse model of muscleblind-like 1 overexpression: skeletal muscle effects and therapeutic promise
Mouse model of muscleblind-like 1 overexpression: skeletal muscle effects and therapeutic promise
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DOI：
10.1093/hmg/dds306
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发表时间：
2012-11-01
影响因子：
3.5
通讯作者：
Ranum, Laura P. W.
中科院分区：
文献类型：
--
作者：
Chamberlain, Christopher M.;Ranum, Laura P. W.
强直性肌营养不良（DM）是由CTG或CCTG扩增突变引起的多系统疾病。有强有力的证据表明，DM 1 CUG和DM 2 CCUG扩增转录物隔离肌盲样（MBNL）蛋白，MBNL功能的丧失会导致疾病的选择性剪接异常。由于认为MBNL 1损失在疾病中起重要作用，并且MBNL 1的局部AAV递送部分地挽救了DM小鼠中的骨骼肌病理，因此对MBNL 1过表达作为治疗策略存在强烈兴趣。我们开发了第一个转基因MBNL 1过表达小鼠模型（MBNL 1-OE），以测试多系统MBNL 1过表达的安全性和有效性。首先，我们证明MBNL 1过表达在骨骼肌中通常耐受良好。其次，我们展示了令人惊讶的结果，即在多器官系统中MBNL 1调节基因的选择性剪接的过早转变与生命相容，并且不会导致胚胎死亡。第三，我们第一次证明了早期和长期MBNL 1过表达可以预防DM 1小鼠中CUG诱导的肌强直、肌病和选择性剪接异常。总之，MBNL 1过表达可能是治疗DM骨骼肌特征的有价值的策略。
Myotonic dystrophy (DM) is a multisystemic disease caused by CTG or CCTG expansion mutations. There is strong evidence that DM1 CUG and DM2 CCUG expansion transcripts sequester muscleblind-like (MBNL) proteins and that loss of MBNL function causes alternative splicing abnormalities that contribute to disease. Because MBNL1 loss is thought to play an important role in disease and localized AAV delivery of MBNL1 partially rescues skeletal muscle pathology in DM mice, there is strong interest in MBNL1 overexpression as a therapeutic strategy. We developed the first transgenic MBNL1 overexpression mouse model (MBNL1-OE) to test the safety and efficacy of multisystemic MBNL1 overexpression. First, we demonstrate that MBNL1 overexpression is generally well-tolerated in skeletal muscle. Second, we show the surprising result that premature shifts in alternative splicing of MBNL1-regulated genes in multiple organ systems are compatible with life and do not cause embryonic lethality. Third, we show for the first time that early and long-term MBNL1 overexpression prevents CUG-induced myotonia, myopathy and alternative splicing abnormalities in DM1 mice. In summary, MBNL1 overexpression may be a valuable strategy for treating the skeletal muscle features of DM.