Metalloprotease activation of myostatin, and methods of modulating myostatin activity

Abstract

It has been determined that metalloprotease cleavage of a myostatin pro peptide results in activation of a latent inactive myostatin to an active form. Accordingly, methods of identifying agents that modulate metalloprotease mediated activation of myostatin are provided, as are agents identified using such methods. Also provided are methods of modulating muscle growth in an organism by increasing or decreasing metalloprotease mediated cleavage of a myostatin pro peptide.

1 . A method of modulating myostatin activation, comprising contacting a latent myostatin complex comprising a myostatin pro peptide and a myostatin C-terminal fragment, and a metalloprotease that can cleave the myostatin pro peptide, with an agent that increases or decreases proteolytic cleavage of the pro peptide by the metalloprotease, thereby modulating myostatin activation.  
     
     
         2 . The method of  claim 1 , wherein the metalloprotease is a bone morphogenic protein-1/tolloid (BMP-1/TLD) family member.  
     
     
         3 . The method of  claim 2 , wherein the BMP-1/TLD family member is tolloid-like protein-2 (TLL-2).  
     
     
         4 . The method of  claim 2 , wherein the BMP-1/TLD family member is mammalian TLL-2 (mTLL-2).  
     
     
         5 . The method of  claim 1 , which comprises increasing myostatin activation, said method comprising contacting the latent myostatin complex and metalloprotease with an agent that increases proteolytic cleavage of the pro peptide by the metalloprotease, thereby increasing myostatin activation.  
     
     
         6 . The method of  claim 1 , wherein said contacting is performed on a sample in vitro.  
     
     
         7 . The method of  claim 6 , wherein the sample comprises a cell sample, a tissue sample, or a biological fluid sample.  
     
     
         8 . The method of  claim 1 , wherein said contacting is performed in vivo, said method comprising administering the agent to a subject.  
     
     
         9 . The method of  claim 8 , wherein the agent decreases proteolytic cleavage of the pro peptide by the metalloprotease, thereby reducing or inhibiting myostatin activation.  
     
     
         10 . The method of  claim 9 , wherein, in the subject, muscle mass is increased, fat content is decreased, or a combination thereof.  
     
     
         11 . The method of  claim 10 , wherein the subject is an animal raised as a food source.  
     
     
         12 . The method of  claim 11 , wherein the animal is a mammalian species, an avian species, or a piscine species.  
     
     
         13 . The method of  claim 12 , wherein mammalian species is an ovine species, a porcine species, or a bovine species.  
     
     
         14 . The method of  claim 12 , wherein the avian species is a chicken or a turkey.  
     
     
         15 . The method of  claim 8 , wherein the subject is a human subject.  
     
     
         16 .- 66 . (canceled)