Co-Administration of Myostatin-Targeting siRNA and ActRIIB-Fc Fusion Protein Increases Masseter Muscle Mass and Fiber Size
Co-Administration of Myostatin-Targeting siRNA and ActRIIB-Fc Fusion Protein Increases Masseter Muscle Mass and Fiber Size
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DOI：
10.3177/jnsv.63.244
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发表时间：
2017-08-01
影响因子：
1.6
通讯作者：
Tanaka, Eiji
中科院分区：
文献类型：
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作者：
Bayarsaikhan, Od;Kawai, Nobuhiko;Tanaka, Eiji
肌生长抑制素是TGF-β超家族的成员，是骨骼肌细胞生长和分化的负调节剂，并以高亲和力结合激活素IIB型受体（ActRIIB）。融合至IgG的Fc结构域的ActRIIB的可溶性配体结合结构域（ActRIIB-Fc）有效地结合并抑制肌肉中的TGF-β家族成员，导致快速且显著的肌肉生长。本研究旨在评估肌生长抑制素靶向siRNA（Mstn-siRNA）和ActRIIB-Fc共递送到骨骼肌中作为萎缩性肌病的潜在治疗的有效性。将具有/不具有ActRIIB-Fc的去端胶原（ATCOL）介导的Mstn-siRNA局部注射到11周龄的雄性C57 BL/6小鼠咬肌中，每周两次。通过Mstn-siRNA和ActRIIB-Fc的组合抑制肌肉生长抑制素功能增加了鼠咬肌中的肌肉重量和肌原纤维大小。实时RT-PCR分析显示，Mstn-siRNA处理组和联合处理组的肌肉生长抑制素mRNA表达均显着下调。此外，与单独施用每种化合物相比，在组合治疗组中肌细胞生成素mRNA表达上调，而MuRF-1和Atrogin-1 mRNA表达下调。这些发现表明，双重抑制肌生长抑制素是一种潜在的有用的治疗策略，以增加肌肉质量和纤维大小，并可能是一种有用的治疗各种肌肉萎缩，包括肌营养不良症的患者。
Myostatin, a member of the TGF-beta superfamily, is a negative regulator of skeletal muscle cell growth and differentiation, and binds with high affinity to the activin type IIB receptor (ActRIIB). The soluble ligand-binding domain of ActRIIB fused to the Fc domain of IgG (ActRIIB-Fc) potently binds and inhibits TGF-beta family members in muscle, leading to rapid and marked muscle growth. The present study was designed to assess the effectiveness of the co-delivery of myostatin-targeting siRNA (Mstn-siRNA) and ActRIIB-Fc into skeletal muscle as a potential treatment of atrophic myopathies. Eleven-week-old, male C57BL/6 mice were injected with atelocollagen (ATCOL)-mediated Mstn-siRNA with/without ActRIIB-Fc locally into the masseter muscle twice a week. Inhibition of myostatin function by the combination of Mstn-siRNA and ActRIIB-Fc increased muscle weight and myofibril size in murine masseter muscle. Real-time RT-PCR analysis revealed significant downregulation of myostatin mRNA expression in both the Mstn-siRNA-treated and the combination treatment group. Furthermore, myogenin mRNA expression was upregulated in the combination treatment group, while MuRF-1 and Atrogin-1 mRNA expression was downregulated compared to administration of each compound alone. These findings suggest that double inhibition of myostatin is a potentially useful treatment strategy to increase muscle mass and fiber size and could be a useful treatment of patients with various muscle atrophies, including muscular dystrophy.