The utrophin A 5′-untranslated region confers internal ribosome entry site-mediated translational control during regeneration of skeletal muscle fibers
The utrophin A 5′-untranslated region confers internal ribosome entry site-mediated translational control during regeneration of skeletal muscle fibers
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DOI：
10.1074/jbc.m503994200
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发表时间：
2005-09-23
影响因子：
4.8
通讯作者：
Jasmin, BJ
中科院分区：
文献类型：
--
作者：
Miura, P;Thompson, J;Jasmin, BJ
Duchenne肌营养不良症患者肌肉纤维中的中营养素上调代表了一种潜在的治疗策略。因此，在试图开发药物干预措施以增加促性腺激素表达的过程中，描述肌肉中促性腺激素的调节事件是重要的。许多研究表明，在几个实验条件下，中性粒细胞营养素的丰度增加，但其mRNA没有相应的升高。在这里，我们研究在再生的肌肉纤维中，utroin的表达是否在翻译水平上受到调节。用心脏毒素处理小鼠胫骨前肌以诱导肌肉退化/再生，导致utroin A水平大幅增加(类似于14倍)，但其转录本的表达略有变化(40%)。对小鼠促性腺激素A 5‘-非翻译区的分离表明，它相对较长，具有高度的二级结构。在对照肌肉中，促性腺激素A的5‘-非编码区抑制了报告蛋白的翻译。值得注意的是，这种抑制在再生过程中被去除了，这表明再生肌肉中utroin A的表达是通过其5‘-UTR翻译调节的。利用双顺反子报告载体，我们观察到这种翻译效应涉及utroin A5‘-UTR中的一个内部核糖体进入位点。因此，内部核糖体进入位点介导的utroin A翻译至少可以部分解释再生肌肉中utroin A蛋白和转录本表达不一致的原因。这些发现为通过药物干预上调Duchenne肌营养不良症肌纤维中的utroin A水平提供了一个新的靶点。
Utrophin up-regulation in muscle fibers of Duchenne muscular dystrophy patients represents a potential therapeutic strategy. It is thus important to delineate the regulatory events presiding over utrophin in muscle in attempts to develop pharmacological interventions aimed at increasing utrophin expression. A number of studies have now shown that under several experimental conditions, the abundance of utrophin is increased without a corresponding elevation in its mRNA. Here, we examine whether utrophin expression is regulated at the translational level in regenerating muscle fibers. Treatment of mouse tibialis anterior muscles with cardiotoxin to induce muscle degeneration/regeneration led to a large (similar to 14-fold) increase in the levels of utrophin A with a modest change in expression of its transcript (40%). Isolation of the mouse utrophin A 5'-untranslated region (UTR) revealed that it is relatively long with a predicted high degree of secondary structure. In control muscles, the 5'-UTR of utrophin A caused an inhibition upon translation of a reporter protein. Strikingly, this inhibition was removed during regeneration, indicating that expression of utrophin A in regenerating muscles is translationally regulated via its 5'-UTR. Using bicistronic reporter vectors, we observed that this translational effect involves an internal ribosome entry site in the utrophin A 5'-UTR. Thus, internal ribosome entry site-mediated translation of utrophin A can, at least partially, account for the discordant expression of utrophin A protein and transcript in regenerating muscle. These findings provide a novel target for up-regulating levels of utrophin A in Duchenne muscular dystrophy muscle fibers via pharmacological interventions.