Prenatal flutamide enhances survival in a myogenic mouse model of spinal bulbar muscular atrophy

Neurodegener Dis. 2011;8(1-2):25-34. doi: 10.1159/000313682. Epub 2010 Aug 4.


Background: Spinal bulbar muscular atrophy (SBMA) is caused by a CAG repeat expansion mutation in the androgen receptor (AR) gene, and mutant AR is presumed to act in motoneurons to cause SBMA. However, we found that mice overexpressing wild-type (wt) AR solely in skeletal muscle fibers display the same androgen-dependent disease phenotype as when mutant AR is broadly expressed, challenging the assumptions that only an expanded AR can induce disease and that SBMA is strictly neurogenic. We have previously reported that AR toxicity was ligand dependent in our model, and that very few transgenic (tg) males survived beyond birth.

Methods: We tested whether the AR antagonist flutamide could block perinatal toxicity. tg males were treated prenatally with flutamide and assessed for survival and motor behavior in adulthood.

Results: Prenatal treatment with flutamide rescued tg male pups from perinatal death, and, as adults, such perinatally rescued tg males showed an SBMA phenotype that was comparable to that of previously described untreated tg males. Moreover, tg males carrying a mutant endogenous allele for AR--the testicular feminization mutation (tfm)--and thus having functional AR only in muscle fibers nevertheless displayed the same androgen-dependent disease phenotype as adults.

Conclusions: These mice represent an excellent model to study the myogenic contribution to SBMA as they display many of the core features of disease as other mouse models. These data demonstrate that AR acting exclusively in muscle fibers is sufficient to induce SBMA symptoms and that flutamide is protective perinatally.

Publication types

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

MeSH terms

  • Alleles
  • Anatomy, Cross-Sectional
  • Androgen Antagonists / therapeutic use*
  • Animals
  • Behavior, Animal / drug effects
  • Bulbo-Spinal Atrophy, X-Linked / pathology
  • Bulbo-Spinal Atrophy, X-Linked / prevention & control*
  • Disease Models, Animal
  • Female
  • Flutamide / therapeutic use*
  • Gene Expression
  • Male
  • Mice
  • Mice, Transgenic
  • Muscle, Skeletal / pathology
  • NAD / metabolism
  • Pregnancy
  • Receptors, Androgen / genetics
  • Receptors, Androgen / physiology
  • Reverse Transcriptase Polymerase Chain Reaction
  • Survival


  • Androgen Antagonists
  • Receptors, Androgen
  • NAD
  • Flutamide