Blocking extracellular activation of myostatin as a strategy for treating muscle wasting.
Blocking extracellular activation of myostatin as a strategy for treating muscle wasting.
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DOI：
10.1038/s41598-018-20524-9
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发表时间：
2018-02-02
影响因子：
4.6
通讯作者：
Donovan A
中科院分区：
文献类型：
--
作者：
Pirruccello-Straub M;Jackson J;Wawersik S;Webster MT;Salta L;Long K;McConaughy W;Capili A;Boston C;Carven GJ;Mahanthappa NK;Turner KJ;Donovan A
许多生长因子与细胞外基质紧密结合，通过调节的处理和释放导致细胞刺激。Myostatin和GDF11是转化生长因子β家族中密切相关的成员，它们的激活需要两次蛋白水解性切割才能从原结构域释放生长因子。传统上，通过靶向生长因子-受体相互作用来特异性调节肌肉生长抑素和GDF11的活性一直是具有挑战性的。在这里，我们证明了一种新的阻断myostatin和GDF11的策略，即抑制生长因子的释放，在体外和体内都特异性和有效地抑制信号转导。我们开发了选择性结合myostatin和GDF11前体形式的人单抗，包括抑制myostatin蛋白分解激活和防止体内肌肉萎缩的亚群。最有效的肌肉抑制素激活阻断抗体促进了肌肉的强健生长，并导致健康小鼠肌肉性能的显著提高。总之，我们表明，阻断生长因子的细胞外激活是防止信号传递的有效方法，为一种新的治疗策略提供了概念证明，该策略可以应用于转化生长因子β家族的其他成员。
Many growth factors are intimately bound to the extracellular matrix, with regulated processing and release leading to cellular stimulation. Myostatin and GDF11 are closely related members of the TGFβ family whose activation requires two proteolytic cleavages to release the growth factor from the prodomain. Specific modulation of myostatin and GDF11 activity by targeting growth factor-receptor interactions has traditionally been challenging. Here we demonstrate that a novel strategy for blocking myostatin and GDF11, inhibition of growth factor release, specifically and potently inhibits signaling both in vitro and in vivo. We developed human monoclonal antibodies that selectively bind the myostatin and GDF11 precursor forms, including a subset that inhibit myostatin proteolytic activation and prevent muscle atrophy in vivo. The most potent myostatin activation-blocking antibodies promoted robust muscle growth and resulted in significant gains in muscle performance in healthy mice. Altogether, we show that blocking the extracellular activation of growth factors is a potent method for preventing signaling, serving as proof of concept for a novel therapeutic strategy that can be applied to other members of the TGFβ family of growth factors.
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影响因子：
7.2
作者：
Hinck AP;Mueller TD;Springer TA
通讯作者：
Springer TA
影响因子：
29
作者：
Egerman MA;Cadena SM;Gilbert JA;Meyer A;Nelson HN;Swalley SE;Mallozzi C;Jacobi C;Jennings LL;Clay I;Laurent G;Ma S;Brachat S;Lach-Trifilieff E;Shavlakadze T;Trendelenburg AU;Brack AS;Glass DJ
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Glass DJ
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作者：
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Pap, Thomas
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作者：
Holzbaur, Erika L. F.;Howland, David S.;Walsh, Frank S.
通讯作者：
Walsh, Frank S.
影响因子：
4.8
作者：
Hill, JJ;Davies, MV;Qiu, YC
通讯作者：
Qiu, YC