Recovery of function in a myogenic mouse model of spinal bulbar muscular atrophy

Neurobiol Dis. 2009 Apr;34(1):113-20. doi: 10.1016/j.nbd.2008.12.009. Epub 2008 Dec 31.

Abstract

With this paper, we deliberately challenge the prevailing neurocentric theory of the etiology of spinal bulbar muscular atrophy (SBMA). We offer data supporting an alternative view that androgen receptor (AR) acts in skeletal muscles to cause the symptoms of SBMA. While SBMA has been linked to a CAG repeat expansion in the AR gene and mutant AR is presumed to act in motoneurons to cause SBMA, we find that over-expression of wild type AR solely in skeletal muscle fibers results in the same androgen-dependent disease phenotype as when mutant AR is broadly expressed. Like other recent SBMA mouse models, transgenic (tg) females in our model exhibit a motor phenotype only when exposed to androgens, and this motor dysfunction is independent of motoneuronal or muscle fiber cell death. Muscles from symptomatic females also show denervation-like changes in gene expression comparable to a knock-in model of SBMA. Furthermore, once androgen treatment ends, tg females rapidly recover motor function and muscle gene expression, demonstrating the strict androgen-dependence of the disease phenotype in our model. Our results argue that SBMA may be caused by AR acting in muscle.

Publication types

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

MeSH terms

  • Analysis of Variance
  • Androgens / pharmacology
  • Animals
  • Bulbo-Spinal Atrophy, X-Linked / drug therapy
  • Bulbo-Spinal Atrophy, X-Linked / pathology
  • Bulbo-Spinal Atrophy, X-Linked / physiopathology*
  • Disease Models, Animal
  • Female
  • Gene Expression
  • Male
  • Mice
  • Mice, Transgenic
  • Motor Activity / drug effects
  • Motor Activity / physiology
  • Motor Neurons / physiology
  • Muscle, Skeletal / drug effects
  • Muscle, Skeletal / pathology
  • Muscle, Skeletal / physiopathology*
  • Receptors, Androgen / metabolism*
  • Recovery of Function
  • Testosterone / pharmacology

Substances

  • Androgens
  • Receptors, Androgen
  • Testosterone