The article by Se-Jin Lee and Alexandra C. McPherron investigates the regulation of myostatin activity and its role in muscle growth. Myostatin, a member of the transforming growth factor-β (TGF-β) family, is a negative regulator of skeletal muscle mass. The authors purified myostatin from mammalian cells, finding it to be a noncovalent complex of the N-terminal propeptide and a disulfide-linked dimer of the C-terminal fragments. The purified C-terminal myostatin dimer binds to activin type II receptors, specifically Act RIBB and to a lesser extent Act RIIA. This binding can be inhibited by follistatin and the myostatin propeptide. To determine the functional significance of these interactions, the authors generated transgenic mice expressing high levels of the propeptide, follistatin, or a dominant-negative form of Act RIBB. These transgenic mice exhibited significant increases in muscle mass, comparable to those seen in myostatin knockout mice. The findings suggest that blocking myostatin signaling through the propeptide, follistatin, or other molecules may be useful for enhancing muscle growth in both human therapeutic and agricultural applications. The authors propose a model where myostatin is normally maintained in a latent complex with its propeptide and other proteins, and its activity is regulated by these inhibitory factors. Release of the C-terminal dimer from these inhibitory proteins allows it to bind to receptors and activate signaling pathways, leading to muscle growth.The article by Se-Jin Lee and Alexandra C. McPherron investigates the regulation of myostatin activity and its role in muscle growth. Myostatin, a member of the transforming growth factor-β (TGF-β) family, is a negative regulator of skeletal muscle mass. The authors purified myostatin from mammalian cells, finding it to be a noncovalent complex of the N-terminal propeptide and a disulfide-linked dimer of the C-terminal fragments. The purified C-terminal myostatin dimer binds to activin type II receptors, specifically Act RIBB and to a lesser extent Act RIIA. This binding can be inhibited by follistatin and the myostatin propeptide. To determine the functional significance of these interactions, the authors generated transgenic mice expressing high levels of the propeptide, follistatin, or a dominant-negative form of Act RIBB. These transgenic mice exhibited significant increases in muscle mass, comparable to those seen in myostatin knockout mice. The findings suggest that blocking myostatin signaling through the propeptide, follistatin, or other molecules may be useful for enhancing muscle growth in both human therapeutic and agricultural applications. The authors propose a model where myostatin is normally maintained in a latent complex with its propeptide and other proteins, and its activity is regulated by these inhibitory factors. Release of the C-terminal dimer from these inhibitory proteins allows it to bind to receptors and activate signaling pathways, leading to muscle growth.