Blocking the myostatin signal with a dominant negative receptor improves the success of human myoblast transplantation in dystrophic mice

Mol Ther. 2011 Jan;19(1):204-10. doi: 10.1038/mt.2010.171. Epub 2010 Aug 10.


Duchenne muscular dystrophy (DMD) is a recessive disease caused by a dystrophin gene mutation. Myoblast transplantation permits to introduce the dystrophin gene in dystrophic muscle fibers. However, the success of this approach is reduced by the short duration of the regeneration following the transplantation, which reduces the number of hybrid fibers. Myostatin (MSTN) is a negative regulator of skeletal muscle development and responsible for limiting regeneration. It binds with high affinity to the activin type IIB receptor (ActRIIB). Our aim was to verify whether the success of the myoblast transplantation is enhanced by blocking the MSTN signal with expression of a dominant negative mutant of ActRIIB (dnActRIIB). In vitro, blocking MSTN activity with a lentivirus carrying dnActRIIB increased proliferation and fusion of human myoblasts because MSTN regulates the expression of several myogenic regulatory factors. In vivo, myoblasts infected with the dnActRIIB lentivirus were transplanted in immunodeficient dystrophic mice. Dystrophin immunostaining of tibialis anterior (TA) cross-sections of these mice 1 month post-transplantation revealed more human dystrophin-positive myofibers following the transplantation of dnActRIIB myoblasts than of control myoblasts. Thus, blocking the MSTN signal with dnActRIIB improved the success of myoblast transplantation by increasing the myoblast proliferation and fusion and changed the expression of myogenic regulatory factors.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Activin Receptors, Type II / genetics
  • Activin Receptors, Type II / metabolism*
  • Animals
  • Cell Fusion / methods
  • Cell Proliferation / drug effects
  • Dystrophin / genetics*
  • Dystrophin / metabolism*
  • Humans
  • Lentivirus / genetics
  • Lentivirus / metabolism
  • Mice
  • Mice, Inbred C57BL
  • Mice, Inbred mdx
  • Muscle Fibers, Skeletal / metabolism
  • Muscle Fibers, Skeletal / transplantation
  • Muscular Dystrophy, Animal / genetics
  • Muscular Dystrophy, Animal / metabolism
  • Muscular Dystrophy, Animal / therapy*
  • MyoD Protein / genetics
  • Myoblasts / cytology
  • Myoblasts / drug effects
  • Myoblasts / transplantation*
  • Myogenic Regulatory Factors / metabolism
  • Myostatin / antagonists & inhibitors*
  • Myostatin / metabolism
  • Signal Transduction / genetics


  • Dystrophin
  • MyoD Protein
  • MyoD1 myogenic differentiation protein
  • Myogenic Regulatory Factors
  • Myostatin
  • Activin Receptors, Type II
  • activin receptor type II-A