Myostatin (MSTN) is a secreted protein that normally acts to suppress muscle growth. Mice genetically engineered to lack MSTN activity have dramatic increases in muscle mass as a result of a combination of muscle fiber hypertrophy and increased fiber numbers. Moreover, administration of a number of different MSTN inhibitors to wild type mice can also promote muscle growth, demonstrating that MSTN plays a critical role in regulating muscle growth in adult animals. As a result, there has been considerable interest in the possibility that inhibitors of MSTN signaling might be effective in enhancing muscle strength and regeneration in patients with muscle degenerative diseases. Following processing of the MSTN precursor protein, the mature C-terminal dimer remains non-covalently bound to the N-terminal propeptide, which maintains MSTN in an inactive, latent state. A variety of biochemical and genetic studies have demonstrated that members of the BMP-1/tolloid family of metalloproteases play a critical role in regulating MSTN latency by cleaving and thereby inactivating the propeptide. Hence, inhibition of these proteases could be an effective therapeutic strategy to prevent activation of latent MSTN and thereby promote muscle growth. Moreover, the potential benefits of targeting these proteases could extend well beyond just MSTN inhibition, as these proteases are also known to act on other substrates besides MSTN that may play a role in muscle degenerative diseases. In particular, these proteases are capable of cleaving the TGF-ss binding protein, LTBP-1, thereby activating TGF-ss from its latent state, which may be significant with respect to therapeutic development given that inhibition of TGF-ss signaling has been shown to improve muscle regeneration in mdx mice. Furthermore, the BMP-1/tolloid proteases appear to be the enzymes responsible for processing procollagens into the mature species capable of forming collagen fibrils, raising the possibility that these enzymes may play a role in the development of fibrosis in a variety of disease settings. Hence, inhibitors of BMP-1/tolloid proteases have the potential to provide clinical benefit in patients with muscle degenerative diseases by targeting several different molecular pathways. The overall aims of this project are to validate the beneficial effects of inhibiting BMP-1/tolloid proteases in the setting of muscle degeneration and to initiate the development of a biologic agent capable of targeting these enzymes.
The Specific Aims are: to assess the potential beneficial effects of targeting BMP-1/tolloid metalloproteases in mdx mice and to determine whether the BMP-1/tolloid inhibitor, sFRP2, can increase muscle growth either when expressed as a transgene in skeletal muscle or when administered systemically to mice. If successful, these studies will identify a novel therapeutic agent with the potential to promote muscle growth and improve clinical outcome in patients with muscular dystrophy.
Myostatin is a protein that normally acts to limit muscle growth. The goal of this project is to develop therapeutic agents capable of blocking myostatin activity and promoting muscle growth in patients with muscle degenerative diseases.
| Lee, Se-Jin (2010) Extracellular Regulation of Myostatin: A Molecular Rheostat for Muscle Mass. Immunol Endocr Metab Agents Med Chem 10:183-194 |
