Myostatin propeptide-mediated amelioration of dystrophic pathophysiology
Myostatin propeptide-mediated amelioration of dystrophic pathophysiology
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DOI：
10.1096/fj.04-2796com
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发表时间：
2005-04-01
期刊：
影响因子：
4.8
通讯作者：
Khurana, TS
中科院分区：
文献类型：
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作者：
Bogdanovich, S;Perkins, KJ;Khurana, TS
肌肉生长抑制素 (GDF8) 的突变导致肌肉质量显着增加，表明这种转化生长因子-β (TGF-β) 超家族成员对肌肉生长具有负调节作用。因此，肌肉生长抑制素阻断提供了一种逆转杜氏肌营养不良症 (DMD) 中肌肉萎缩的策略，而无需诉诸基因操作。在这里，我们证明使用通过与 IgG-Fc 融合而稳定的肌生长抑制素前肽进行药理学阻断可改善 DMD mdx 小鼠模型的病理生理学。比力改善所证明的功能益处超过了之前使用肌生长抑制素抗体介导的阻断所报道的功能益处。更重要的是，使用前肽阻断策略消除了抗独特型反应的可能性，随着时间的推移，抗独特型反应可能会限制抗体介导的肌生长抑制素阻断策略的有效性。这项研究为治疗与肌肉萎缩相关的疾病（如 DMD）提供了一种新的药理学策略，并且由于它使用肌生长抑制素的内源性抑制剂，因此应有助于规避与传统基因或细胞疗法相关的技术障碍和毒性。
Mutations in myostatin (GDF8) cause marked increases in muscle mass, suggesting that this transforming growth factor-beta (TGF-beta) superfamily member negatively regulates muscle growth. Myostatin blockade therefore offers a strategy for reversing muscle wasting in Duchenne's muscular dystrophy (DMD) without resorting to genetic manipulation. Here, we demonstrate that pharmacological blockade using a myostatin propeptide stabilized by fusion to IgG-Fc improved pathophysiology of the mdx mouse model of DMD. Functional benefits evidenced by specific force improvement, exceeded those reported previously using myostatin antibody-mediated blockade. More importantly, use of a propeptide blockade strategy obviates possibilities of anti-idiotypic responses that could potentially limit the effectiveness of antibody-mediated myostatin blockade strategies over time. This study provides a novel pharmacological strategy for treatment of diseases associated with muscle wasting such as DMD and since it uses an endogenous inhibitor of myostatin should help circumvent technical hurdles and toxicity associated with conventional gene or cell based therapies.