Targeting the Activin Type IIB Receptor to Improve Muscle Mass and Function in the mdx Mouse Model of Duchenne Muscular Dystrophy
Targeting the Activin Type IIB Receptor to Improve Muscle Mass and Function in the mdx Mouse Model of Duchenne Muscular Dystrophy
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DOI：
10.1016/j.ajpath.2010.11.071
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发表时间：
2011-03-01
影响因子：
6
通讯作者：
Khurana, Tejvir
中科院分区：
文献类型：
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作者：
Pistilli, Emidio E.;Bogdanovich, Sasha;Khurana, Tejvir
激活素受体IIB型（ActRIIB）是转化生长因子-α超家族成员（包括肌生长抑制素）的跨膜受体，其参与骨骼肌质量的负调节。我们测试了翻译假设，即阻断配体与ActRIIB结合12周将刺激mdx小鼠的骨骼肌生长并改善肌肉功能。使用新型抑制剂靶向ActRIIB，所述新型抑制剂包含ActRIIB的细胞外部分与鼠IgG的Fc部分融合（sActRIIB），浓度为1.0和10.0 mg/kg（-1）体重。治疗12周后，10.0 mg/kg（-1）剂量导致体重增加27%，同时瘦肌肉质量增加33%。用任一剂量的sActRIIB治疗后，小鼠离体趾长伸肌的绝对力产生更高，并且在较低剂量（1.0 mg/kg（-1））后比力显著更高，表明肌肉功能改善。与对照小鼠相比，用sActRIIB治疗的小鼠的循环肌酸激酶水平显著较低。这些数据显示，靶向ActRIIB改善了DMD的mdx小鼠模型中的骨骼肌质量和功能强度，为使用该分子治疗骨骼肌病变提供了治疗原理。(Am J Pathol 2011，178：1287-1297; DOI：10.1016/j.ajpath.2010.11.071）
The activin receptor type IIB (ActRIIB) is a transmembrane receptor for transforming growth factor-a superfamily members, including myostatin, that are involved in the negative regulation of skeletal muscle mass. We tested the translational hypothesis that blocking ligand binding to ActRIIB for 12 weeks would stimulate skeletal muscle growth and improve muscle function in the mdx mouse. ActRIIB was targeted using a novel inhibitor comprised of the extracellular portion of the ActRIIB fused to the Fc portion of murine IgG (sActRIIB), at concentrations of 1.0 and 10.0 mg/kg(-1) body weight. After 12 weeks of treatment, the 10.0 mg/kg(-1) dose caused a 27% increase in body weight with a concomitant 33% increase in lean muscle mass. Absolute force production of the extensor digitorum longus muscle ex vivo was higher in mice after treatment with either dose of sActRIIB, and the specific force was significantly higher after the lower dose (1.0 mg/kg(-1)), indicating functional improvement in the muscle. Circulating creatine kinase levels were significantly lower in mice treated with sActRIIB, compared with control mice. These data show that targeting the ActRIIB improves skeletal muscle mass and functional strength in the mdx mouse model of DMD, providing a therapeutic rationale for use of this molecule in treating skeletal myopathies. (Am J Pathol 2011, 178:1287-1297; DOI: 10.1016/j.ajpath.2010.11.071)