Transgenic expression of a myostatin inhibitor derived from follistatin increases skeletal muscle mass and ameliorates dystrophic pathology in mdx mice

FASEB J. 2008 Feb;22(2):477-87. doi: 10.1096/fj.07-8673com. Epub 2007 Sep 24.


Myostatin is a potent negative regulator of skeletal muscle growth. Therefore, myostatin inhibition offers a novel therapeutic strategy for muscular dystrophy by restoring skeletal muscle mass and suppressing the progression of muscle degeneration. The known myostatin inhibitors include myostatin propeptide, follistatin, follistatin-related proteins, and myostatin antibodies. Although follistatin shows potent myostatin-inhibiting activities, it also acts as an efficient inhibitor of activins. Because activins are involved in multiple functions in various organs, their blockade by follistatin would affect multiple tissues other than skeletal muscles. In the present study, we report the characterization of a myostatin inhibitor derived from follistatin, which does not affect activin signaling. The dissociation constants (K(d)) of follistatin to activin and myostatin are 1.72 nM and 12.3 nM, respectively. By contrast, the dissociation constants (K(d)) of a follistatin-derived myostatin inhibitor, designated FS I-I, to activin and myostatin are 64.3 microM and 46.8 nM, respectively. Transgenic mice expressing FS I-I, under the control of a skeletal muscle-specific promoter showed increased skeletal muscle mass and strength. Hyperplasia and hypertrophy were both observed. We crossed FS I-I transgenic mice with mdx mice, a model for Duchenne muscular dystrophy. Notably, the skeletal muscles in the mdx/FS I-I mice showed enlargement and reduced cell infiltration. Muscle strength is also recovered in the mdx/FS I-I mice. These results indicate that myostatin blockade by FS I-I has a therapeutic potential for muscular dystrophy.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Cell Line
  • Follistatin / metabolism*
  • Gene Expression Regulation* / drug effects
  • Humans
  • Kinetics
  • Mice
  • Mice, Inbred mdx
  • Mice, Transgenic
  • Muscle, Skeletal
  • Muscular Dystrophies / genetics
  • Muscular Dystrophies / metabolism*
  • Muscular Dystrophies / pathology*
  • Muscular Dystrophies / physiopathology
  • Mutation / genetics
  • Myostatin
  • Protein Binding
  • Transforming Growth Factor beta / antagonists & inhibitors*
  • Transforming Growth Factor beta / pharmacology*


  • Follistatin
  • MSTN protein, human
  • Mstn protein, mouse
  • Myostatin
  • Transforming Growth Factor beta