Myostatin, also known as growth and differentiation factor-8 (GDF8), belongs to the transforming growth factor (TGF)-β superfamily (1, 2). Similar to other TGF-β superfamily members, myostatin

is synthesized as a precursor protein that is biologically inactive. Production of mature myostatin occurs through dimerization of the precursor and subsequent proteolytic processing. Cleavage by furin-like protease is responsible of separating the N-terminal propeptide from the C-terminal mature myostatin, while cleavage of the latent propeptide by the bone morphogenetic protein-1/tolloid (BMP1/TLD) family of metalloproteinases is responsible for activation of latent myostatin (3). Inhibitors,research,lifescience,medical The C-terminal dimeric 26-kDa protein acts as mature myostatin. Mice with targeted deletion of the myostatin gene show dramatic and widespread increases in Inhibitors,research,lifescience,medical skeletal muscle mass (2). Both muscle fiber hypertrophy and muscle cell hyperplasia are observed. Myostatin signals through two types of transmembrane serine/threonine kinase receptors, namely activin type II receptors (ACVR2B and ACVR2A) and activin receptor-like kinases 4 and 5 (ALK4 and 5). Its

intracellular signaling pathway is similar to those of activin and TGF-β, and mediated by the Smad proteins Smad2 and Smad3 (1, 2, 4). Myostatin negatively regulates G1-to-S progression in the cell cycle and maintains the quiescent Inhibitors,research,lifescience,medical status of satellite cells (5). As a result, increased numbers of satellite cells are present

in myostatin-deficient mice (5). Involvement of the MAP kinase pathway as well as the Smad pathway is a characteristic of Inhibitors,research,lifescience,medical the myostatin-regulated skeletal muscle differentiation program (6). However, the precise mechanism of action and the skeletal-muscle specific signaling of myostatin have not yet been fully elucidated. Myostatin Inhibition as a Therapeutic Strategy for Muscular Dystrophy Interestingly, inhibition of myostatin activity is capable of increasing muscle mass and strength in the postnatal period and even in Inhibitors,research,lifescience,medical adults. These observations selleck suggest that targeting of myostatin would be a suitable therapy for degenerative muscle diseases, such as muscular dystrophy and cachexia, and may be able to prevent muscle wasting due to aging (1, 2, 7). In fact, antibody-mediated myostatin blockade in mdx mice, a model for Duchenne muscular dystrophy, was found to ameliorate the pathophysiology and muscle weakness (8). Myostatin propeptide-mediated Phosphoprotein phosphatase amelioration of the symptoms in mdx mice, limb-girdle muscular dystrophy (LGMD) 1C model mice with caveolin-3 gene mutations and LGMD2A model mice with calpain 3 gene mutations has also been reported (9–11). However, elimination of myostatin did not recover the pathology in laminin-α2-deficient model mice and rather increased their mortality (12). Thus, the effectiveness of myostatin inhibition depends on the disease state (Table ​(Table1).1).