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Influence of heterozygous Hsf-1 depletion on the skeletal muscle pathology of spinal and bulbar muscular atrophy (SBMA)

  • P2-317
  • 近藤 直英 / Naohide Kondo:1 勝野 雅央 / Masahisa Katsuno:1 足立 弘明 / Hiroaki Adachi:2 佐橋 健太郎 / Kentaro Sahashi:1 宮崎 雄 / Yu Miyazaki:1 飯田 円 / Madoka Iida:1 藤内 玄規 / Genki Tohnai:1 石垣 診祐 / Shinsuke Ishigaki:1 藤岡 祐介 / Yusuke Fujioka:1 田中 章景 / Fumiaki Tanaka:3 祖父江 元 / Gen Sobue:1 
  • 1:名古屋大院医神経内科 / Dept Neurol, Univ of Nagoya, Nagoya, Japan 2:産業医大院医神経内科 / Dept Neurol, Univ of Occupational and Environmental Health, School of Medicine, Kokura, Japan 3:横浜市大院医神経内科 / Dept Neurol and Stroke, Univ of Yokohama City, Yokohama, Japan 

Objective: Heat shock factor-1 (Hsf-1) controls the expression levels of heat shock proteins (hsps), that play a defensive role on the neurodegeneration by solubilizing and refolding pathogenic proteins. To reveal the function of Hsf-1 on the skeletal muscle pathology of spinal and bulbar muscular atrophy (SBMA), an adult-onset motor neuron disease, here we investigate the changes in hsp regulation in the skeletal muscle of heterozygous Hsf-1 knockout SBMA mice. Methods: We performed western blotting and Immunohistochemistry of skeletal muscle from wild-type; AR-97Q (SBMA model: 97Q Tg/-, Hsf-1 +/+); and AR-97Q Hsf-1 +/- (heterozygous Hsf-1 knockout SBMA: 97Q Tg/-, Hsf-1 +/-) mice using anti-Hsf-1, anti-Hsp72, anti-Nfya, anti-Sp1, anti-p53, anti-Tbp and anti-polyglutamine antibodies. Results: While Hsp72, the inducible form of Hsp70, was downregulated in the spinal cord on western blot analysis, the expression level of this chaperone in skeletal muscle was unaffected despite Hsf-1 depletion. Additionally, the reduction of Hsf-1 did not enhance the pathogenic AR accumulations in the skeletal muscle of SBMA model mice. Surprisingly, Nfya and Sp1 were upregulated in the skeletal muscle of AR-97Q mice compared with wild-type mice both in immunohistochemistry and western blot analysis. Furthermore, this phenomenon was enhanced by the heterozygous Hsf-1 depletion. In contrast to the skeletal muscle, neither Nfya nor Sp1 was upregulated by Hsf-1 depletion in the spinal cord of AR-97Q or in heterozygous Hsf-1 knockout AR-97Q mice. Conclusions: These results suggest that skeletal muscle of SBMA mice may have a compensative mechanism on the pathogenic AR-mediated dysregulation of hsps.

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