Myostatin is a transforming growth factor-li family member that acts as a negative regulator of musclegrowth. Mice engineered to lack myostatin have about twice the muscle mass of normal animals as a resultof a combination of muscle fiber hyperplasia and hypertrophy. Increased muscling also occurs in both cattleand humans with naturally occurring mutations in the myostatin gene. These findings have raised thepossibility that agents capable of blocking myostatin activity may be effective in increasing muscle mass andstrength in patients with muscular dystrophy. The overall aim of this proposal is to identify strategies fordeveloping therapeutic agents targeting myostatin activity. Myostatin is known to circulate in the blood in alatent, inactive complex with other proteins, including the myostatin propeptide, FLRG, and Gasp-1. Thecomplex with the propeptide can be activated by proteolytic cleavage of the propeptide by members of theBMP-1/tolloid family of metalloproteases. The specific protease responsible for activating latent myostatin invivo is not known. The regulatory roles played by each of the various myostatin binding proteins are also notknown. The major goal of this proposal is to elucidate the mechanisms by which myostatin activity isregulated extracellularly.
The specific aims are: to generate and characterize mice in which genes encodingeach member of the BMP-1/tolloid family are disrupted either individually or in combination in skeletal muscleand to characterize the interactions of myostatin with its known binding proteins. The results of theseexperiments should provide important insights into how myostatin activity is normally regulated and therebyprovide valuable information for identifying strategies for blocking myostatin signaling. If successful, theseexperiments will provide the framework for developing new therapeutic agents capable of increasing musclemass in patients with muscular dystrophy.
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