Peripheral androgen receptor gene suppression rescues disease in mouse models of spinal and bulbar muscular atrophy.

Academic Article


  • Spinal and bulbar muscular atrophy (SBMA) is caused by the polyglutamine androgen receptor (polyQ-AR), a protein expressed by both lower motor neurons and skeletal muscle. Although viewed as a motor neuronopathy, data from patients and mouse models suggest that muscle contributes to disease pathogenesis. Here, we tested this hypothesis using AR113Q knockin and human bacterial artificial chromosome/clone (BAC) transgenic mice that express the full-length polyQ-AR and display androgen-dependent weakness, muscle atrophy, and early death. We developed antisense oligonucleotides that suppressed AR gene expression in the periphery but not the CNS after subcutaneous administration. Suppression of polyQ-AR in the periphery rescued deficits in muscle weight, fiber size, and grip strength, reversed changes in muscle gene expression, and extended the lifespan of mutant males. We conclude that polyQ-AR expression in the periphery is an important contributor to pathology in SBMA mice and that peripheral administration of therapeutics should be explored for SBMA patients.
  • Published In

  • Cell Reports  Journal
  • Keywords

  • Animals, Body Weight, Disease Models, Animal, Gene Knock-In Techniques, Hand Strength, Humans, Male, Mice, Mice, Inbred C57BL, Mice, Transgenic, Muscle Fibers, Skeletal, Muscle, Skeletal, Muscular Disorders, Atrophic, Oligonucleotides, Antisense, Phenotype, Receptors, Androgen, Survival Rate, Testosterone, Transcriptome
  • Digital Object Identifier (doi)

    Author List

  • Lieberman AP; Yu Z; Murray S; Peralta R; Low A; Guo S; Yu XX; Cortes CJ; Bennett CF; Monia BP
  • Start Page

  • 774
  • End Page

  • 784
  • Volume

  • 7
  • Issue

  • 3