Activation of latent myostatin by the BMP-1/tolloid family of metalloproteinases
Activation of latent myostatin by the BMP-1/tolloid family of metalloproteinases
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DOI：
10.1073/pnas.2534946100
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发表时间：
2003-12-23
影响因子：
11.1
通讯作者：
Leet, SI
中科院分区：
文献类型：
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作者：
Wolfman, NM;McPherron, AC;Leet, SI
肌生长抑制素是转化生长因子13家族成员，其作为骨骼肌生长的负调节剂。肌肉生长抑制素在成年小鼠的血液中以与其他蛋白质（包括其前肽）非共价结合的复合物形式循环，这些蛋白质使C末端二聚体保持在潜在的非活性状态。这种潜在形式的肌生长抑制素可以在体外通过酸处理激活;然而，体内激活潜在肌生长抑制素的机制尚不清楚。在这里，我们表明，骨形态发生蛋白-1/tolloid（BMP-1/BMP）家族的金属蛋白酶的成员可以切割该复合物中的肌生长抑制素前肽，从而激活潜在的肌生长抑制素。此外，我们表明，一种突变形式的前肽抗裂解BMP-1/BMP蛋白酶可以导致肌肉质量显着增加时，注射到成年小鼠。这些发现提高了BMP-1/BMP家族成员可能参与体内激活潜伏性肌生长抑制素的可能性，并且能够抑制这些蛋白酶的分子可能是用于增加人类治疗和农业应用的肌肉质量的有效试剂。
Myostatin is a transforming growth factor 13 family member that acts as a negative regulator of skeletal muscle growth. Myostatin circulates in the blood of adult mice in a noncovalently held complex with other proteins, including its propeptide, which maintain the C-terminal dimer in a latent, inactive state. This latent form of myostatin can be activated in vitro by treatment with acid; however, the mechanisms by which latent myostatin is activated in vivo are unknown. Here, we show that members of the bone morphogenetic protein-1/tolloid (BMP-1/TLD) family of metalloproteinases can cleave the myostatin propeptide in this complex and can thereby activate latent myostatin. Furthermore, we show that a mutant form of the propeptide resistant to cleavage by BMP-1/TLD proteinases can cause significant increases in muscle mass when injected into adult mice. These findings raise the possibility that members of the BMP-1/TLD family may be involved in activating latent myostatin in vivo and that molecules capable of inhibiting these proteinases may be effective agents for increasing muscle mass for both human therapeutic and agricultural applications.