Transgenic expression of a myostatin inhibitor derived from follistatin increases skeletal muscle mass and ameliorates dystrophic pathology in mdx mice
Transgenic expression of a myostatin inhibitor derived from follistatin increases skeletal muscle mass and ameliorates dystrophic pathology in mdx mice
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DOI：
10.1096/fj.07-8673com
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发表时间：
2008-02-01
期刊：
影响因子：
4.8
通讯作者：
Tsuchida, Kunihiro
中科院分区：
文献类型：
--
作者：
Nakatani, Masashi;Takehara, Yuka;Tsuchida, Kunihiro
肌生长抑制素是骨骼肌生长的有效负调节剂。因此，肌生长抑制素抑制剂通过恢复骨骼肌质量和抑制肌肉变性的进展为肌营养不良症提供了一种新的治疗策略。已知的肌生长抑制素抑制剂包括肌生长抑制素前肽、卵泡抑素、卵泡抑素相关蛋白和肌生长抑制素抗体。虽然卵泡抑素显示出有效的肌肉生长抑制素抑制活性，但它也作为激活素的有效抑制剂。由于激活素参与各种器官的多种功能，卵泡抑素对其的阻断将影响骨骼肌以外的多种组织。在本研究中，我们报告了一种来源于卵泡抑素的肌生长抑制素抑制剂的特性，它不影响激活素信号传导。卵泡抑素与激活素和肌肉生长抑制素的解离常数（Kd）分别为1.72 nM和12.3 nM。相比之下，卵泡抑素衍生的肌生长抑制素抑制剂（命名为FS I-I）对激活素和肌生长抑制素的解离常数（Kd）分别为64.3 μ M和46.8 nM。在骨骼肌特异性启动子的控制下，表达FS I-I的转基因小鼠表现出骨骼肌质量和强度的增加。观察到增生和肥大。我们将FS I-I转基因小鼠与mdx小鼠（Duchenne肌营养不良症模型）杂交。值得注意的是，mdx/FS I-I小鼠的骨骼肌显示增大和细胞浸润减少。在mdx/FS I-I小鼠中也恢复了肌肉强度。这些结果表明，FS I-I的肌生长抑制素阻断剂对肌营养不良症具有治疗潜力。
Myostatin is a potent negative regulator of skeletal muscle growth. Therefore, myostatin inhibition offers a novel therapeutic strategy for muscular dystrophy by restoring skeletal muscle mass and suppressing the progression of muscle degeneration. The known myostatin inhibitors include myostatin propeptide, follistatin, follistatin-related proteins, and myostatin antibodies. Although follistatin shows potent myostatin-inhibiting activities, it also acts as an efficient inhibitor of activins. Because activins are involved in multiple functions in various organs, their blockade by follistatin would affect multiple tissues other than skeletal muscles. In the present study, we report the characterization of a myostatin inhibitor derived from follistatin, which does not affect activin signaling. The dissociation constants (K-d) of follistatin to activin and myostatin are 1.72 nM and 12.3 nM, respectively. By contrast, the dissociation constants (K-d) of a follistatin-derived myostatin inhibitor, designated FS I-I, to activin and myostatin are 64.3 mu M and 46.8 nM, respectively. Transgenic mice expressing FS I-I, under the control of a skeletal muscle-specific promoter showed increased skeletal muscle mass and strength. Hyperplasia and hypertrophy were both observed. We crossed FS I-I transgenic mice with mdx mice, a model for Duchenne muscular dystrophy. Notably, the skeletal muscles in the mdx/FS I-I mice showed enlargement and reduced cell infiltration. Muscle strength is also recovered in the mdx/FS I-I mice. These results indicate that myostatin blockade by FS I-I has a therapeutic potential for muscular dystrophy.