RA sarcopenia therapy targeting the lower leg slow-twitch muscle molecular chaperone-myokine induction therapy

• Project/Area Number: 19K19914
• Research Category: Grant-in-Aid for Early-Career Scientists
• Allocation Type: Multi-year Fund
• Review Section: Basic Section 59010:Rehabilitation science-related
• Research Institution: Kyoto Prefectural University of Medicine
• Principal Investigator: Toyama Shogo 京都府立医科大学, 医学(系)研究科(研究院), 客員講師 (00388183)
• Project Period (FY): 2019-04-01 – 2022-03-31
• Project Status: Completed (Fiscal Year 2021)
• Budget Amount: ¥3,900,000 (Direct Cost: ¥3,000,000、Indirect Cost: ¥900,000); Fiscal Year 2020: ¥1,950,000 (Direct Cost: ¥1,500,000、Indirect Cost: ¥450,000); Fiscal Year 2019: ¥1,950,000 (Direct Cost: ¥1,500,000、Indirect Cost: ¥450,000)
• Keywords: 関節リウマチ / サルコペニア / 遅筋 / 運動 / 整形外科学 / 骨格筋 / 速筋 / 分子シャペロン / マイオカイン / 下腿筋

Outline of Research at the Start

高齢や疾患にともない全身の低筋肉量と低機能が特徴であるサルコペニアは、高齢化の著しい日本社会においては無視できない喫緊の課題である。運動を十分に行うことが、もっとも根本的な治療法であるが、実際には合併症などで運動ができないことが多く、運動以外の治療法の開発が求められてきた。われわれはラットを用いて、独自の方法による分子シャペロンを通じた大量マイオカイン誘導両方の開発を計画した。これが確立されれば、低負荷の運動にわれわれの方法を併用することで、安全にかつ効果の高い筋肉増強効果を局所だけでなく、全身にも得られる可能性があると考えた。本研究は、この目的の第一歩の研究である。

Outline of Final Research Achievements

Using an animal arthritis model, we analyzed the effects of arthritis on fast-twitch and slow-twitch muscles. Muscle atrophy and fibrosis occurred in the soleus muscle, which is rich in slow-twitch muscle fibers, compared to the extensor digitorum longus muscle, which is rich in fast-twitch muscle fibers. Next, the effects of treadmill running were examined. Eif4e, an anabolic marker of muscle protein, was increased in the soleus muscle at 2 weeks after immunosensitization, and atrogin-1, a catabolic marker, was increased at 6 weeks after immunosensitization, depending on the presence or absence of exercise and the muscle. Four weeks of exercise also prevented muscle atrophy in slow-twitch muscles. We hypothesized that treadmill running may prevent atrophy and fibrosis of slow-twitch muscles by modulating the metabolic cycle of the muscles.

Academic Significance and Societal Importance of the Research Achievements

関節リウマチ(rheumatoid arthritis; RA)に対する薬物治療の進歩により関節炎の寛解が得られるようになったが、依然としてサルコペニアの罹患率が高くRA患者のADL障害の大きな要因となっている。一方、遅筋は速筋の約5倍マイオカインを分泌することがこれまで明らかになっており、遅筋の比率が高い下腿への刺激
が全身の筋肥大をもたらすことができれば、サルコペニアの有効な治療法になり得ると考えた。

Research Products

• [Journal Article] Treadmill running prevents atrophy differently in fast- versus slow-twitch muscles in a rat model of rheumatoid arthritis (2021)
  • Author(s): Yoichiro Kamada , Shogo Toyama , Yuji Arai , Hiroaki Inoue , Shuji Nakagawa , Yuta Fujii Kenta Kaihara , Tsunao Kishida , Osam Mazda , Kenji Takahashi
  • Journal Title: J Muscle Res Cell Motil . Volume: Dec;42(3-4) Issue: 3-4 Pages: 429-441
  • DOI: 10.1007/s10974-021-09610-0
  • Peer Reviewed / Open Access
• [Journal Article] Treadmill Running in Established Phase Arthritis Inhibits Joint Destruction in Rat Rheumatoid Arthritis Models (2019)
  • Author(s): Fujii Yuta、Inoue Hiroaki、Arai Yuji、Shimomura Seiji、Nakagawa Shuji、Kishida Tsunao、Tsuchida Shinji、Kamada Yoichiro、Kaihara Kenta、Shirai Toshiharu、Terauchi Ryu、Toyama Shogo、Ikoma Kazuya、Mazda Osam、Mikami Yasuo
  • Journal Title: International Journal of Molecular Sciences Volume: 20 Issue: 20 Pages: 5100-5100
  • DOI: 10.3390/ijms20205100
  • Peer Reviewed / Open Access
• [Presentation] Effect of treadmill running on slow-twitch muscle atrophy in a rat model of arthritis (2022)
  • Author(s): Kamada Y, Inoue A, Toyama S, Inoue H, Nakagawa S, Fujii Y, Kaihara K, Cha R, Arai Y, Mazda O, Takahashi K
  • Organizer: 2022 ORS annual meeting
  • Int'l Joint Research
• [Presentation] 関節炎モデルラットを用いた筋線維タイプ別の運動効果の比較 (2021)
  • Author(s): 鎌田陽一郎，遠山将吾，井上裕章，中川周士，藤井雄太，貝原健太，新井祐志，松田 修，高橋謙治
  • Organizer: 第36回日本整形外科学会基礎学術集会
• [Presentation] Analysis of the effect of cationic hyaluronic acid on articular cartilage (2021)
  • Author(s): Kamada Y, Inoue H, Nakagawa S, Fujii Y, Kaihara K, Arai Y, Mazda O, Takahashi K
  • Organizer: 2021 OARSI annual meeting
  • Int'l Joint Research
• [Presentation] Analysis of muscle atrophy and fibrosis in fast and slow muscles in a rat model of arthritis (2021)
  • Author(s): Yoichiro Kamada, Shogo Toyama, Hiroaki Inoue, Shuji Nakagawa, Yuta Fujii, Kenta Kaihara, Yuji Arai, Osam Mazda, Kenji Takahashi
  • Organizer: 67th Annual Meeting of Orthopaedic Research Society
  • Int'l Joint Research
• [Presentation] Treadmill Running Suppressed Joint Destruction In A Rheumatoid Arthritis Rat Model (2020)
  • Author(s): Yuta Fujii; Hiroaki Inoue; Yuji Arai; Seiji Shimomura; Shuji Nakagawa; Shinji Tsuchida; Yoichiro Kamada; Kenta Kaihara; Osam Mazda; Yasuo Mikami
  • Organizer: 2020 Annual Meeting of Orthopaedic Research Society
  • Int'l Joint Research