Department of Cellular and Molecular Medicine, Faculty of Medicine, University of Ottawa, 451 Smyth Road, Ottawa, ON, K1H 8M5, Canada.
Centre for Neuromuscular Disease, 451 Smyth Road, Ottawa, ON, K1H 8M5, Canada.
Nat Commun. 2020 Apr 24;11(1):1990. doi: 10.1038/s41467-020-15971-w.
Up-regulation of utrophin in muscles represents a promising therapeutic strategy for the treatment of Duchenne Muscular Dystrophy. We previously demonstrated that eEF1A2 associates with the 5'UTR of utrophin A to promote IRES-dependent translation. Here, we examine whether eEF1A2 directly regulates utrophin A expression and identify via an ELISA-based high-throughput screen, FDA-approved drugs that upregulate both eEF1A2 and utrophin A. Our results show that transient overexpression of eEF1A2 in mouse muscles causes an increase in IRES-mediated translation of utrophin A. Through the assessment of our screen, we reveal 7 classes of FDA-approved drugs that increase eEF1A2 and utrophin A protein levels. Treatment of mdx mice with the 2 top leads results in multiple improvements of the dystrophic phenotype. Here, we report that IRES-mediated translation of utrophin A via eEF1A2 is a critical mechanism of regulating utrophin A expression and reveal the potential of repurposed drugs for treating DMD via this pathway.
肌内肌联蛋白的上调代表了治疗杜氏肌营养不良症的一种很有前途的治疗策略。我们之前证明，eEF1A2 与肌联蛋白 A 的 5'UTR 结合，以促进 IRES 依赖性翻译。在这里，我们研究了 eEF1A2 是否直接调节肌联蛋白 A 的表达，并通过基于 ELISA 的高通量筛选鉴定出可上调 eEF1A2 和肌联蛋白 A 的 FDA 批准药物。我们的结果表明，eEF1A2 在小鼠肌肉中的瞬时过表达导致肌联蛋白 A 的 IRES 介导的翻译增加。通过对我们的筛选进行评估，我们揭示了 7 类可增加 eEF1A2 和肌联蛋白 A 蛋白水平的 FDA 批准药物。用这两种最佳先导化合物治疗 mdx 小鼠可改善多种肌肉营养不良表型。在这里，我们报告说，eEF1A2 通过 IRES 介导的肌联蛋白 A 翻译是调节肌联蛋白 A 表达的关键机制，并揭示了通过该途径重新利用药物治疗 DMD 的潜力。
