Regulation of myostatin activity and muscle growth

Myostatin is a transforming growth factor-β 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.

肌抑素（myostatin）是转化生长因子-β（transforming growth factor-β）超家族成员，作为骨骼肌质量的负调控因子发挥作用。为筛选可用于促进肌肉生长的潜在肌抑素抑制剂，我们对肌抑素信号通路的调控机制开展了研究。从哺乳动物细胞中纯化获得的肌抑素蛋白，为由N端前肽与二硫键连接的C端片段二聚体以非共价结合形成的复合物。纯化的C端肌抑素二聚体可结合激活素Ⅱ型受体Act RIIB，对Act RIIA也存在较弱的结合能力。激活素结合蛋白卵泡抑素（follistatin）能够抑制肌抑素与Act RIIB的结合，当浓度升高时，肌抑素前肽同样可发挥此类抑制作用。为明确上述相互作用在体内的功能意义，我们借助骨骼肌特异性启动子，构建了分别高表达前肽、卵泡抑素或显性负效型Act RIIB的转基因小鼠。各构建体对应的独立转基因小鼠品系均出现骨骼肌质量显著增加的表型，与肌抑素基因敲除小鼠的表型相似。本研究结果提示，前肽、卵泡抑素或其他可阻断该通路信号转导的分子，可作为兼具人类治疗与农业应用价值的肌肉生长促进制剂。