Pioglitazone suppresses neuronal and muscular degeneration caused by polyglutamine-expanded androgen receptors

Hum Mol Genet. 2015 Jan 15;24(2):314-29. doi: 10.1093/hmg/ddu445. Epub 2014 Aug 28.


Spinal and bulbar muscular atrophy (SBMA) is a neuromuscular disease caused by the expansion of a CAG repeat in the androgen receptor (AR) gene. Mutant AR has been postulated to alter the expression of genes important for mitochondrial function and induce mitochondrial dysfunction. Here, we show that the expression levels of peroxisome proliferator-activated receptor-γ (PPARγ), a key regulator of mitochondrial biogenesis, were decreased in mouse and cellular models of SBMA. Treatment with pioglitazone (PG), an activator of PPARγ, improved the viability of the cellular model of SBMA. The oral administration of PG also improved the behavioral and histopathological phenotypes of the transgenic mice. Furthermore, immunohistochemical and biochemical analyses demonstrated that the administration of PG suppressed oxidative stress, nuclear factor-κB (NFκB) signal activation and inflammation both in the spinal cords and skeletal muscles of the SBMA mice. These findings suggest that PG is a promising candidate for the treatment of SBMA.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Disease Models, Animal
  • Humans
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Mice, Transgenic
  • Muscle, Skeletal / drug effects*
  • Muscle, Skeletal / metabolism
  • Muscular Disorders, Atrophic / drug therapy*
  • Muscular Disorders, Atrophic / genetics
  • Muscular Disorders, Atrophic / metabolism
  • Neurons / drug effects*
  • Neurons / metabolism
  • Peptides / metabolism*
  • Peroxisome Proliferator-Activated Receptors / genetics
  • Peroxisome Proliferator-Activated Receptors / metabolism
  • Pioglitazone
  • Receptors, Androgen / genetics*
  • Receptors, Androgen / metabolism
  • Spinal Cord / drug effects
  • Spinal Cord / metabolism
  • Thiazolidinediones / administration & dosage*
  • Trinucleotide Repeat Expansion / drug effects


  • Peptides
  • Peroxisome Proliferator-Activated Receptors
  • Receptors, Androgen
  • Thiazolidinediones
  • polyglutamine
  • Pioglitazone