Lee S J, McPherron A C
Department of Molecular Biology and Genetics, Johns Hopkins University School of Medicine, 725 North Wolfe Street, Baltimore, MD 21205, USA.
Proc Natl Acad Sci U S A. 2001 Jul 31;98(16):9306-11. doi: 10.1073/pnas.151270098. Epub 2001 Jul 17.
Myostatin is a transforming growth factor-beta family member that acts as a negative regulator of skeletal muscle mass. To identify possible myostatin inhibitors that may have applications for promoting muscle growth, we investigated the regulation of myostatin signaling. Myostatin protein purified from mammalian cells consisted of a noncovalently held complex of the N-terminal propeptide and a disulfide-linked dimer of C-terminal fragments. The purified C-terminal myostatin dimer was capable of binding the activin type II receptors, Act RIIB and, to a lesser extent, Act RIIA. Binding of myostatin to Act RIIB could be inhibited by the activin-binding protein follistatin and, at higher concentrations, by the myostatin propeptide. To determine the functional significance of these interactions in vivo, we generated transgenic mice expressing high levels of the propeptide, follistatin, or a dominant-negative form of Act RIIB by using a skeletal muscle-specific promoter. Independent transgenic mouse lines for each construct exhibited dramatic increases in muscle mass comparable to those seen in myostatin knockout mice. Our findings suggest that the propeptide, follistatin, or other molecules that block signaling through this pathway may be useful agents for enhancing muscle growth for both human therapeutic and agricultural applications.
肌肉生长抑制素是转化生长因子-β家族成员，作为骨骼肌质量的负调节因子。为了鉴定可能用于促进肌肉生长的肌肉生长抑制素抑制剂，我们研究了肌肉生长抑制素信号通路的调节。从哺乳动物细胞中纯化的肌肉生长抑制素蛋白由非共价结合的N端前肽复合物和C端片段的二硫键连接二聚体组成。纯化的C端肌肉生长抑制素二聚体能够结合激活素II型受体Act RIIB，在较小程度上还能结合Act RIIA。肌肉生长抑制素与Act RIIB的结合可被激活素结合蛋白卵泡抑素抑制，在较高浓度下也可被肌肉生长抑制素前肽抑制。为了确定这些相互作用在体内的功能意义，我们使用骨骼肌特异性启动子生成了表达高水平前肽、卵泡抑素或Act RIIB显性负性形式的转基因小鼠。每个构建体的独立转基因小鼠品系均表现出与肌肉生长抑制素基因敲除小鼠相当的肌肉质量显著增加。我们的研究结果表明，前肽、卵泡抑素或其他阻断该信号通路的分子可能是用于人类治疗和农业应用中增强肌肉生长的有用药物。
