TY - JOUR
T1 - Pioglitazone suppresses neuronal and muscular degeneration caused by polyglutamine-expanded androgen receptors
AU - Iida, Madoka
AU - Katsuno, Masahisa
AU - Nakatsuji, Hideaki
AU - Adachi, Hiroaki
AU - Kondo, Naohide
AU - Miyazaki, Yu
AU - Tohnai, Genki
AU - Ikenaka, Kensuke
AU - Watanabe, Hirohisa
AU - Yamamoto, Masahiko
AU - Kishida, Ken
AU - Sobue, Gen
N1 - Publisher Copyright:
© The Author 2014.
Copyright:
Copyright 2015 Elsevier B.V., All rights reserved.
PY - 2015/1/15
Y1 - 2015/1/15
N2 - 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.
AB - 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.
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U2 - 10.1093/hmg/ddu445
DO - 10.1093/hmg/ddu445
M3 - Article
C2 - 25168383
AN - SCOPUS:84922466241
VL - 24
SP - 314
EP - 329
JO - Human Molecular Genetics
JF - Human Molecular Genetics
SN - 0964-6906
IS - 2
M1 - ddu445
ER -