Systemic Myostatin Inhibition via Liver-Targeted Gene Transfer in Normal and Dystrophic Mice
Systemic Myostatin Inhibition via Liver-Targeted Gene Transfer in Normal and Dystrophic Mice
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DOI：
10.1371/journal.pone.0009176
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发表时间：
2010-02-11
期刊：
影响因子：
3.7
通讯作者：
Sweeney, H. Lee
中科院分区：
文献类型：
--
作者：
Morine, Kevin J.;Bish, Lawrence T.;Sweeney, H. Lee
背景资料：肌生长抑制素抑制是一种有前途的治疗策略，以维持肌肉质量的各种疾病，包括肌营养不良症，恶病质，和肌肉减少症。以前描述的方法，以阻止肌肉生长抑制素信号包括注射传递抑制性前肽结构域或中和antibody.Methodology/主要调查结果：在这里，我们描述了一种独特的方法，肌肉生长抑制素抑制利用重组腺相关病毒过表达分泌显性负肌生长抑制素专门在小鼠的肝脏。全身性肌生长抑制素抑制导致对照C57 Bl/6小鼠和杜氏肌营养不良症的肌营养不良蛋白缺陷mdx模型中骨骼肌质量和强度增加。mdx比目鱼肌，一种更能代表人类纤维类型组成的小鼠肌肉，在力量产生方面表现出最深刻的改善，并向更快的肌球蛋白重链亚型转变。出乎意料的是，11个月大的mdx隔膜并没有被长期的肌肉生长抑制素抑制所拯救。此外，mdx小鼠治疗11个月表现出心脏肥大和功能受损的抑制剂剂量依赖manners.Conclusions/意义：肝靶向基因转移的肌肉生长抑制素抑制剂是一个有价值的工具，肌肉生长抑制素封锁的临床前研究，并提供了新的见解肌肉生长抑制素抑制横纹肌的长期影响和缺点。
Background: Myostatin inhibition is a promising therapeutic strategy to maintain muscle mass in a variety of disorders, including the muscular dystrophies, cachexia, and sarcopenia. Previously described approaches to blocking myostatin signaling include injection delivery of inhibitory propeptide domain or neutralizing antibodies.Methodology/Principal Findings: Here we describe a unique method of myostatin inhibition utilizing recombinant adeno-associated virus to overexpress a secretable dominant negative myostatin exclusively in the liver of mice. Systemic myostatin inhibition led to increased skeletal muscle mass and strength in control C57 Bl/6 mice and in the dystrophin-deficient mdx model of Duchenne muscular dystrophy. The mdx soleus, a mouse muscle more representative of human fiber type composition, demonstrated the most profound improvement in force production and a shift toward faster myosin-heavy chain isoforms. Unexpectedly, the 11-month-old mdx diaphragm was not rescued by long-term myostatin inhibition. Further, mdx mice treated for 11 months exhibited cardiac hypertrophy and impaired function in an inhibitor dose-dependent manner.Conclusions/Significance: Liver-targeted gene transfer of a myostatin inhibitor is a valuable tool for preclinical investigation of myostatin blockade and provides novel insights into the long-term effects and shortcomings of myostatin inhibition on striated muscle.