INSERM U974, UMR 7215 CNRS, Institut de Myologie, UM 76 Université Pierre et Marie Curie, Paris, France.
Mol Ther. 2010 May;18(5):881-7. doi: 10.1038/mt.2009.322. Epub 2010 Jan 26.
Duchenne muscular dystrophy is characterized by muscular atrophy, fibrosis, and fat accumulation. Several groups have demonstrated that in the mdx mouse, the exon-skipping strategy can restore a quasi-dystrophin in almost 100% of the muscle fibers. On the other hand, inhibition of the myostatin pathway in adult mice has been described to enhance muscle growth and improve muscle force. Our aim was to combine these two strategies to evaluate a possible additive effect. We have chosen to inhibit the myostatin pathway using the technique of RNA interference directed against the myostatin receptor AcvRIIb mRNA (sh-AcvRIIb). The restoration of a quasi-dystrophin was mediated by the vectorized U7 exon-skipping technique (U7-DYS). Adeno-associated vectors carrying either the sh-AcvrIIb construct alone, the U7-DYS construct alone, or a combination of both constructs were injected in the tibialis anterior (TA) muscle of dystrophic mdx mice. We show that even if each separate approach has some effects on muscle physiology, the combination of the dystrophin rescue and the downregulation of the myostatin receptor is required to massively improve both the tetanic force and the specific force. This study provides a novel pharmacogenetic strategy for treatment of certain neuromuscular diseases associated with muscle wasting.
杜氏肌营养不良症的特征是肌肉萎缩、纤维化和脂肪堆积。有几个研究小组已经证明，在 mdx 小鼠中，外显子跳跃策略可以在几乎 100%的肌肉纤维中恢复准肌营养不良蛋白。另一方面，已经描述了在成年小鼠中抑制肌肉生长抑制素途径可以增强肌肉生长并改善肌肉力量。我们的目的是结合这两种策略来评估可能的附加效果。我们选择使用针对肌肉生长抑制素受体 AcvRIIb mRNA 的 RNA 干扰技术（sh-AcvRIIb）来抑制肌肉生长抑制素途径。准肌营养不良蛋白的恢复是通过载体化 U7 外显子跳跃技术（U7-DYS）介导的。携带 sh-AcvrIIb 构建体、U7-DYS 构建体或两者组合的腺相关载体被注射到肌营养不良症 mdx 小鼠的胫骨前肌（TA）中。我们表明，即使每种单独的方法对肌肉生理学都有一些影响，但肌营养不良蛋白的恢复和肌肉生长抑制素受体的下调相结合是大量提高强直力和比肌力所必需的。这项研究为治疗某些与肌肉萎缩相关的神经肌肉疾病提供了一种新的药理学基因治疗策略。
