Delivery of recombinant follistatin lessens disease severity in a mouse model of spinal muscular atrophy

Hum Mol Genet. 2009 Mar 15;18(6):997-1005. doi: 10.1093/hmg/ddn426. Epub 2008 Dec 12.


Spinal muscular atrophy (SMA) is the most common genetic cause of infant mortality. SMA is caused by loss of functional survival motor neuron 1 (SMN1), resulting in death of spinal motor neurons. Current therapeutic research focuses on modulating the expression of a partially functioning copy gene, SMN2, which is retained in SMA patients. However, a treatment strategy that improves the SMA phenotype by slowing or reversing the skeletal muscle atrophy may also be beneficial. Myostatin, a member of the TGF-beta super-family, is a potent negative regulator of skeletal muscle mass. Follistatin is a natural antagonist of myostatin, and over-expression of follistatin in mouse muscle leads to profound increases in skeletal muscle mass. To determine whether enhanced muscle mass impacts SMA, we administered recombinant follistatin to an SMA mouse model. Treated animals exhibited increased mass in several muscle groups, elevation in the number and cross-sectional area of ventral horn cells, gross motor function improvement and mean lifespan extension by 30%, by preventing some of the early deaths, when compared with control animals. SMN protein levels in spinal cord and muscle were unchanged in follistatin-treated SMA mice, suggesting that follistatin exerts its effect in an SMN-independent manner. Reversing muscle atrophy associated with SMA may represent an unexploited therapeutic target for the treatment of SMA.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Anterior Horn Cells / drug effects
  • Anterior Horn Cells / pathology
  • Disease Models, Animal
  • Drug Delivery Systems*
  • Follistatin / administration & dosage*
  • Follistatin / pharmacology
  • Follistatin / therapeutic use*
  • Humans
  • Kaplan-Meier Estimate
  • Lumbar Vertebrae / drug effects
  • Lumbar Vertebrae / pathology
  • Mice
  • Motor Activity / drug effects
  • Muscle, Skeletal / drug effects
  • Muscle, Skeletal / pathology
  • Muscular Atrophy, Spinal / drug therapy*
  • Muscular Atrophy, Spinal / pathology*
  • Muscular Atrophy, Spinal / physiopathology
  • Organ Size / drug effects
  • Recombinant Proteins / administration & dosage*
  • Recombinant Proteins / therapeutic use*
  • Spinal Cord / drug effects
  • Spinal Cord / pathology


  • Follistatin
  • Recombinant Proteins