Use of mRNA expression signatures to discover small molecule inhibitors of skeletal muscle atrophy.
Use of mRNA expression signatures to discover small molecule inhibitors of skeletal muscle atrophy.
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DOI：
10.1097/mco.0000000000000159
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发表时间：
2015-05
影响因子：
3.1
通讯作者：
Dyle MC
中科院分区：
文献类型：
--
作者：
Adams CM;Ebert SM;Dyle MC
在这里，我们讨论了最近开发的一种实验策略，用于发现具有预防和治疗骨骼肌萎缩潜力的小分子。肌肉萎缩涉及并需要骨骼肌基因表达的广泛变化，骨骼肌基因表达的变化产生复杂但可测量的骨骼肌mRNA水平的正、负变化模式（即肌肉萎缩的mRNA表达特征）。许多具有生物活性的小分子产生自己特有的mRNA表达特征，通过识别其特征近似于肌肉萎缩特征的小分子，人们可以识别出具有预防和/或逆转肌肉萎缩潜力的小分子。与传统的药物发现方法不同，该策略不依赖于预定义的分子靶标，而是利用肌肉萎缩的复杂性来识别对抗萎缩肌肉中整个病理变化的小分子。我们讨论了如何使用这一策略来识别两种天然化合物，熊果酸和番茄碱，减少肌肉萎缩和改善骨骼肌功能。基于mRNA表达特征的发现策略可以阐明保存和恢复肌肉质量和功能的新方法。
Here, we discuss a recently developed experimental strategy for discovering small molecules with potential to prevent and treat skeletal muscle atrophy. Muscle atrophy involves and requires widespread changes in skeletal muscle gene expression, which generate complex but measurable patterns of positive and negative changes in skeletal muscle mRNA levels (a.k.a. mRNA expression signatures of muscle atrophy). Many bioactive small molecules generate their own characteristic mRNA expression signatures, and by identifying small molecules whose signatures approximate mirror images of muscle atrophy signatures, one may identify small molecules with potential to prevent and/or reverse muscle atrophy. Unlike a conventional drug discovery approach, this strategy does not rely on a predefined molecular target but rather exploits the complexity of muscle atrophy to identify small molecules that counter the entire spectrum of pathological changes in atrophic muscle. We discuss how this strategy has been used to identify two natural compounds, ursolic acid and tomatidine, that reduce muscle atrophy and improve skeletal muscle function. Discovery strategies based on mRNA expression signatures can elucidate new approaches for preserving and restoring muscle mass and function.