Leiden University Medical Center (LUMC), Department of Human Genetics, 2333 ZC Leiden, The Netherlands.
Hum Gene Ther. 2012 Dec;23(12):1269-79. doi: 10.1089/hum.2012.056. Epub 2012 Sep 24.
Adeno-associated virus (AAV)-U7-mediated skipping of dystrophin-exon-23 restores dystrophin expression and muscle function in the mdx mouse model of Duchenne muscular dystrophy. Soluble activin receptor IIB (sActRIIB-Fc) inhibits signaling of myostatin and homologous molecules and increases muscle mass and function of wild-type and mdx mice. We hypothesized that combined treatment with AAV-U7 and sActRIIB-Fc may synergistically improve mdx muscle function. Bioactivity of sActRIIB-Fc on skeletal muscle was first demonstrated in wild-type mice. In mdx mice we show that AAV-U7-mediated dystrophin restoration improved specific muscle force and resistance to eccentric contractions when applied alone. Treatment of mdx mice with sActRIIB-Fc increased body weight, muscle mass and myofiber size, but had little effect on muscle function. Combined treatment stimulated muscle growth comparable to the effect of sActRIIB-Fc alone and dystrophin rescue was similar to AAV-U7 alone. Moreover, combined treatment improved maximal tetanic force and the resistance to eccentric contraction to similar extent as AAV-U7 alone. In conclusion, combination of dystrophin exon skipping with sActRIIB-Fc brings together benefits of each treatment; however, we failed to evidence a clear synergistic effect on mdx muscle function.
腺相关病毒 (AAV)-U7 介导的肌营养不良蛋白外显子 23 跳跃恢复了杜氏肌营养不良症 mdx 小鼠模型中的肌营养不良蛋白表达和肌肉功能。可溶性激活素受体 IIB (sActRIIB-Fc) 抑制肌肉生长抑制素和同源分子的信号传导，增加野生型和 mdx 小鼠的肌肉质量和功能。我们假设 AAV-U7 和 sActRIIB-Fc 的联合治疗可能会协同改善 mdx 肌肉功能。首先在野生型小鼠中证明了 sActRIIB-Fc 对骨骼肌的生物活性。在 mdx 小鼠中，我们表明，AAV-U7 介导的肌营养不良蛋白恢复单独应用时可改善特定肌肉力量和抵抗离心收缩的能力。sActRIIB-Fc 治疗 mdx 小鼠增加了体重、肌肉质量和肌纤维大小，但对肌肉功能影响不大。联合治疗刺激肌肉生长的效果与 sActRIIB-Fc 单独治疗相当，且肌营养不良蛋白恢复与 AAV-U7 单独治疗相似。此外，联合治疗还可改善最大强直力和抵抗离心收缩的能力，与 AAV-U7 单独治疗的效果相似。总之，肌营养不良蛋白外显子跳跃与 sActRIIB-Fc 的联合治疗结合了每种治疗的益处；然而，我们未能证明对 mdx 肌肉功能有明显的协同作用。
