Transgenic inactivation of murine myostatin does not decrease the severity of disease in a model of Spinal Muscular Atrophy

Neuromuscul Disord. 2012 Mar;22(3):277-85. doi: 10.1016/j.nmd.2011.10.012. Epub 2011 Nov 10.


Spinal Muscular Atrophy (SMA) is a devastating neurodegenerative disease and is a leading genetic cause of infantile death. SMA is caused by the homozygous loss of Survival Motor Neuron-1 (SMN1). The presence of a nearly identical copy gene called SMN2 has led to the development of several strategies that are designed to elevate SMN levels, and it is clear that SMN2 is an important modifier gene. However, the possibility exists that SMN-independent strategies to lessen the severity of the SMA phenotype could provide insight into disease development as well as aid in the identification of potential therapeutic targets. Muscle enhancement has been considered an interesting target for a variety of neurodegenerative diseases, including SMA. Previously we have shown in SMA mice that delivery of recombinant follistatin resulted in an extension in survival and a general lessening of disease severity. Follistatin is known to functionally block myostatin (MSTN), a potent inhibitor of muscle development. However, follistatin is a multifaceted protein involved in a variety of cellular pathways. To determine whether MSTN inhibition was the primary pathway associated with the previously reported follistatin results, we generated an animal model of SMA in which Mstn was genetically inactivated. In this report we characterize the novel SMA/Mstn model and demonstrate that Mstn inactivation does not significantly enhance muscle development in neonatal animals, nor does it result in an amelioration of the SMA phenotype.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Age Factors
  • Animals
  • Animals, Newborn
  • Body Weight / drug effects
  • Body Weight / genetics
  • Brain / metabolism
  • Brain / pathology
  • Disease Models, Animal
  • Follistatin / therapeutic use
  • Gene Expression Regulation / drug effects
  • Gene Expression Regulation / genetics*
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Motor Activity / drug effects
  • Motor Activity / genetics
  • Motor Neurons / drug effects
  • Motor Neurons / pathology
  • Muscle, Skeletal / drug effects
  • Muscle, Skeletal / pathology
  • Muscular Atrophy, Spinal / drug therapy
  • Muscular Atrophy, Spinal / genetics
  • Muscular Atrophy, Spinal / metabolism*
  • Muscular Atrophy, Spinal / physiopathology
  • Myostatin / deficiency
  • Myostatin / metabolism*
  • Organ Size / drug effects
  • Organ Size / genetics
  • Spinal Cord / metabolism
  • Spinal Cord / pathology
  • Survival of Motor Neuron 1 Protein / genetics
  • Survival of Motor Neuron 1 Protein / metabolism*


  • Follistatin
  • Mstn protein, mouse
  • Myostatin
  • Smn1 protein, mouse
  • Survival of Motor Neuron 1 Protein