The role of mitochondrial quality control in skeletal muscle atrophy

• Project/Area Number: 24500868
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: Applied health science
• Research Institution: Juntendo University
• Principal Investigator: FURUYA Norihiko 順天堂大学, 医学(系)研究科(研究院), 助教 (50401188)
• Project Period (FY): 2012-04-01 – 2015-03-31
• Project Status: Completed (Fiscal Year 2014)
• Budget Amount: ¥5,330,000 (Direct Cost: ¥4,100,000、Indirect Cost: ¥1,230,000); Fiscal Year 2014: ¥1,300,000 (Direct Cost: ¥1,000,000、Indirect Cost: ¥300,000); Fiscal Year 2013: ¥1,300,000 (Direct Cost: ¥1,000,000、Indirect Cost: ¥300,000); Fiscal Year 2012: ¥2,730,000 (Direct Cost: ¥2,100,000、Indirect Cost: ¥630,000)
• Keywords: 筋萎縮 / 遅筋 / Parkin介在性マイトファジー / ミトコンドリア / プロテアソーム / 酸化ストレス / NFE2L1 / オートファジー

Outline of Final Research Achievements

Skeletal muscle atrophy is thought to result from hyperactivation of intracellular protein degradation pathways, including autophagy and the ubiquitin–proteasome system. However, the precise contributions of these pathways to muscle atrophy are unclear. Here, we found that Parkin-mediated mitochondrial autophagy (mitophagy) deficiency in denervated slow-twitch soleus muscles delayed skeletal muscle atrophy, reduced mitochondrial activity, and induced oxidative stress. In both autophagy-deficient and Parkin KO soleus muscles, denervation caused the accumulation of polyubiquitinated proteins. Denervation induced proteasomal activation via NFE2L1 nuclear translocation in control mice, whereas it had little effect in autophagy-deficient and Parkin KO mice. These results suggest that Parkin-mediated mitophagy plays an essential role in the activation of proteasomes during denervation atrophy in slow-twitch muscles.

Research Products

• [Journal Article] CHCHD2 mutations in autosomal dominant late-onset Parkinson’s disease: a genome-wide linkage and sequencing study. (2015)
  • Author(s): Funayama M, Ohe K, Amo T, Furuya N, Yamaguchi J, Saiki S, Yuanzhe L, Ogaki K, Ando M, Yoshinon H, Tomiyama H, Nishioka K, Hasegawa K, Saiki H, Satake W, Mogushi K, Sasaki R, Kokubo Y, Kuzuhara S, Toda T, Mizuno Y, Uchiyama Y, Ohno K, Hattori N.
  • Journal Title: Lancet Neurol Volume: 14 Issue: 3 Pages: 274-282
  • DOI: 10.1016/s1474-4422(14)70266-2
  • Peer Reviewed / Open Access
• [Journal Article] A treadmill exercise reactivates the signaling of the mammalian target of rapamycin (mTor) in the skeletal muscles of starved mice. (2014)
  • Author(s): Zheng, D.M., Bian, Z., Furuya, N., Oliva Trejo, J.A., Takeda-Ezaki, M., Takahashi, K., Hiraoka, Y., Mineki, R., Taka, H., Ikeda, S., Komatsu, M., Fujimura, T., Ueno, T., Ezaki, J.
  • Journal Title: Biochem. Biophys. Res. Commun. Volume: 456 Issue: 1 Pages: 519-526
  • DOI: 10.1016/j.bbrc.2014.11.118
  • Peer Reviewed / Open Access
• [Journal Article] PARK2/Parkin-mediated mitochondrial clearance contributes to proteasome activation during slow-twitch muscle atrophy via NFE2L1 nuclear translocation. (2014)
  • Author(s): Furuya, N., Ikeda, S.I., Sato, S., Soma, S., Ezaki, J., Oliva Trejo, J.A., Takeda-Ezaki, M., Fujimura, T., Arikawa-Hirasawa, E., Tada, N., Komatsu, M., Tanaka, K., Kominami, E., Hattori, N., Ueno, T.
  • Journal Title: Autophagy Volume: 10 Pages: 50-60
  • Peer Reviewed
• [Journal Article] p150glued-associated disorders are caused by activation of intrinsic apoptotic pathway. (2014)
  • Author(s): Ishikawa, K.I., Saiki, S., Furuya, N., Yamada, D., Imamichi, Y., Li, Y., Kawajiri, S., Hironori, S., Tsuboi, Y, Hattori, N.
  • Journal Title: PLOS ONE Volume: in press
  • NAID: 40020259609
  • Peer Reviewed
• [Journal Article] Perilipin-mediated lipid droplet formation in adipocytes promotes sterol regulatory element-binding protein-1 processing and triacylglyceride accumulation (2013)
  • Author(s): Y. Takahashi, A. Shinoda, N. Furuya, E. Harada, N. Arimura, I. Ichi, Y. Fujiwara, J. Inoue, R. Sato
  • Journal Title: PLoS One Volume: 29 Issue: 5 Pages: e64605-e64605
  • DOI: 10.1371/journal.pone.0064605
  • Peer Reviewed
• [Journal Article] Ferulic Acid Induces Mammalian Target of Rapamycin Inactivation in Cultured Mammalian Cells (2013)
  • Author(s): Zehua, B. et al.
  • Journal Title: Biological and Pharmaceutical Bulletin Volume: 36 Issue: 1 Pages: 120-124
  • DOI: 10.1248/bpb.b12-00695
  • NAID: 130001869764
  • ISSN: 0918-6158, 1347-5215
  • Peer Reviewed
• [Presentation] Parkin介在性マイトファジーにおけるCALCOCO2/NDP52の役割 (2014)
  • Author(s): 古屋徳彦、住吉克彦、安藤真矢、服部信孝
  • Organizer: 第 8 回オートファジー研究会・第 2 回新学術「オートファジー」班会議
  • Place of Presentation: シャトレーゼ ガトーキングダム サッポロ、札幌
  • Year and Date: 2014-11-10 – 2014-11-11
• [Presentation] Parkin-mediated mitochondrial clearance contributes to the proteasome activation during slow-twitch muscle atrophy via NFE2L1 nuclear translocation (2014)
  • Author(s): Norihiko Furuya, Shin-Ichi Ikeda, Shigeto Sato, Sanae Soma, Junji Ezaki, Juan Alejandro Oliva Trejo, Mitsue Takeda-Ezaki, Tsutomu Fujimura, Eri Arikawa-Hirasawa, Norihiro Tada, Masaaki Komatsu, Keiji Tanaka, Eiki Kominami, Nobutaka Hattori and Takashi Ueno
  • Organizer: Gordon Research Conference "Autophagy in Stress, Development & Disease"
  • Place of Presentation: イタリア共和国ルッカ
• [Presentation] 遅筋萎縮におけるParkin介在性マイトファジーの役割 (2013)
  • Author(s): 古屋 徳彦
  • Organizer: 第7回オートファジー研究会 兼 新学術領域「オートファジー」第1回班会議
  • Place of Presentation: 静岡県掛川市
• [Presentation] Parkin-mediated mitophagy in slow-twitch skeletal muscle atrophy (2012)
  • Author(s): Norihiko Furuya
  • Organizer: The 6th International Symposium on Autophagy 2012
  • Place of Presentation: Bankoku Shinryokan, Okinawa, Japan
  • Invited
• [Presentation] 遅筋萎縮におけるミトコンドリア品質管理機構の役割 (2012)
  • Author(s): 古屋徳彦
  • Organizer: 精神・神経疾患研究開発費23-5「筋ジストロフィーおよび関連疾患の診断・治療開発を目指した基盤研究」班会議
  • Place of Presentation: JA共済ビルカンファレンスホール、東京
• [Remarks] 順天堂大学医学部付属順天堂医院脳神経内科
  • URL: http://www.juntendo-neurology.com