Use of Follistatin-Like Related Gene (FLRG) to Increase Muscle Mass

Abstract

The present relates to use of follistatin-like related gene (FLRG) to increase muscle mass in a subject. As such, methods of ameliorating the severity of a pathologic condition characterized, at least in part, by a decreased amount, development or metabolic activity of muscle are provided. In addition transgenic non-human mammals expressing FLRG and having increased muscle mass as compared to a corresponding mammal having a myostatin-null mutation or a decreased level of myostatin are provided.

1 . A transgenic non-human mammal whose genome contains a nucleic acid sequence comprising FLRG and a regulatory element comprising a muscle-specific promoter operably linked and integrated into the genome of the mammal, wherein the nucleic acid sequence is expressed so as to result in elevated levels of FLRG and an increase in muscle mass in the mammal as compared to a corresponding mammal whose genome contains a myostatin-null mutation or a decreased level of myostatin as compared with normal basal levels. 
     
     
         2 . The transgenic non-human mammal of  claim 1 , wherein the muscle tissue growth of the transgenic non-human mammal is at least two-fold greater than the muscle tissue growth of the corresponding mammal whose genome lacks FLRG and contains a myostatin-null mutation or a decreased level of myostatin as compared with normal basal level. 
     
     
         3 . The transgenic non-human mammal of  claim 1 , wherein the regulatory element comprises a myosin light chain promoter and an enhancer. 
     
     
         4 . The transgenic non-human mammal of  claim 1 , wherein the regulatory element comprises a myosin light chain promoter and myosin light chain 1/3 enhancer. 
     
     
         5 . The transgenic non-human mammal of  claim 1 , wherein the genome of the corresponding mammal contains a truncated Activin Type II receptor gene that encodes a truncated dominant engative Activin Type II receptor lacking kinase activity. 
     
     
         6 . The transgenic non-human mammal of  claim 5 , wherein the Activin Type II receptor is an Activin RITA or an Activin RIIB. 
     
     
         7 . The transgenic non-human mammal of  claim 1 , wherein the mammal is murine, ovine, porcine, or bovine. 
     
     
         8 . A transgenic non-human mammal whose genome contains a myostatin-null mutation or a decreased level of myostatin as compared with normal basal levels, a nucleic acid sequence comprising FLRG, and a regulatory element comprising a muscle-specific promoter operably linked and integrated into the genome of the mammal, wherein the nucleic acid sequence is expressed so as to result in elevated levels of FLRG and an increase in muscle mass in the mammal as compared to a corresponding mammal whose genome contains a myostatin-null mutation or a decreased level of myostatin alone. 
     
     
         9 . The transgenic non-human mammal of  claim 5 , wherein the muscle tissue growth of the transgenic non-human mammal is at least two-fold greater than the muscle tissue growth of the corresponding mammal whose genome lacks FLRG and contains a myostatin-null mutation or a decreased level of myostatin as compared with normal basal level. 
     
     
         10 . The transgenic non-human mammal of  claim 8 , wherein the regulatory element comprises a myosin light chain promoter and an enhancer. 
     
     
         11 . The transgenic non-human mammal of  claim 8 , wherein the regulatory element comprises a myosin light chain promoter and myosin light chain 1/3 enhancer. 
     
     
         12 . The transgenic non-human mammal of  claim 8 , wherein either or both of the genomes of the transgenic non-human mammal and the corresponding mammal contains a truncated Activin Type II receptor gene that encodes a truncated dominant negative Activin Type II receptor lacking kinase activity. 
     
     
         13 . The transgenic non-human mammal of  claim 12 , wherein the Activin Type II receptor is an Activin RIIA or an Activin RIIB 
     
     
         14 . The transgenic non-human mammal of  claim 8 , wherein the mammal is murine, ovine, porcine, or bovine.