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p62 in muscles inhibits obesity-related sarcopenia through a control of mitophagy

Research Project

Project/Area Number 21K19694
Research Category

Grant-in-Aid for Challenging Research (Exploratory)

Allocation TypeMulti-year Fund
Review Section Medium-sized Section 59:Sports sciences, physical education, health sciences, and related fields
Research InstitutionUniversity of Tsukuba

Principal Investigator

Shoda Junichi  筑波大学, 医学医療系, 客員教授 (90241827)

Co-Investigator(Kenkyū-buntansha) 鈴木 英雄  筑波大学, 医学医療系, 准教授 (00400672)
石井 亜紀子  筑波大学, 医学医療系, 講師 (10400681)
岡田 浩介  筑波大学, 医学医療系, 准教授 (80757526)
Project Period (FY) 2021-07-09 – 2023-03-31
Project Status Completed (Fiscal Year 2022)
Budget Amount *help
¥6,500,000 (Direct Cost: ¥5,000,000、Indirect Cost: ¥1,500,000)
Fiscal Year 2022: ¥2,470,000 (Direct Cost: ¥1,900,000、Indirect Cost: ¥570,000)
Fiscal Year 2021: ¥4,030,000 (Direct Cost: ¥3,100,000、Indirect Cost: ¥930,000)
Keywords肥満 / サルコペニア / サルコペニア肥満 / p62 / mitophagy / autophagy / 運動療法 / 遺伝子改変マウス
Outline of Research at the Start

肥満者の血中には筋mitochondria (Mt)由来の成分分子が増加しており, 筋Mtの障害が推測される.サルコペニア形成には,機能不全に陥ったMtの分解機構であるmitophagyの障害が関与する. p62はmitophagy開始の起点因子として役割を演じる.p62遺伝子欠失マウスでは,成熟期には高度肥満とサルコペニア形成に至る. p62はmitophagy制御を介してサルコペニアの抑制因子として役割を演じることが示唆される.本研究では各種p62遺伝子改変マウスを活用して,p62による新しいmitophagy制御機構の解明とmitophagy制御によるサルコペニアの抑止効果を探索する.

Outline of Final Research Achievements

A maintenance of skeletal muscles in obese subjects is an important issue because of poor survival outcome of sarcopenic obesity. In this study, we aimed to determine the effects of muscle p62 on skeletal muscle mass and muscle strength. We generated muscle-specific p62 gene rescue mice (p62-mRes), which express p62 only in muscle and were derived from p62-knock out mice (p62KIKI) using the cre/loxp system. p62KIKI and p62-mRes mice were fed an HFD for 20 weeks. HFD-feeding caused severe obesity in both p62KIKI and p62-mRes mice, but there was no effect of muscle p62 on body mass. Limb skeletal muscle mass, grip strength, and the cross-sectional area of muscle fibers were higher in p62-mRes mice than in p62KIKI. The glucose tolerance and insulin sensitivity of the p62-mRes mice were also superior. The maintenance of skeletal muscle mass and function induced by p62 in muscle reduces insulin resistance in obese mice and protects against steatohepatitis via a muscle-liver axis.

Academic Significance and Societal Importance of the Research Achievements

サルコペニア肥満は,予後不良の疾病病態であるが,日常臨床の現場においてその対策は十分に機能しているとは言い難い.本研究では,筋のp62が肥満の病態下で,体組成には影響せず,骨格筋量・筋力の維持,インスリン抵抗性に対して防御的に機能することを見出した.これらの結果は,肥満者に対する筋p62を標的とした新たなサルコペニア予防・治療法の構築につながる可能性があり,大きな発展が期待される.

Report

(3 results)
  • 2022 Annual Research Report   Final Research Report ( PDF )
  • 2021 Research-status Report
  • Research Products

    (16 results)

All 2022 2021

All Journal Article (8 results) (of which Peer Reviewed: 8 results,  Open Access: 8 results) Presentation (8 results)

  • [Journal Article] p62/Sqstm1 Rescue in Muscle Retards the Progression of Steatohepatitis in p62/Sqstm1-null Mice Fed a High-fat Diet.2022

    • Author(s)
      Miura I, Okada K, Ishii A, Warabi E, Watahiki T, To K, Shimano H, Ariizumi S, Shoda J.
    • Journal Title

      Front Physiol.

      Volume: 13 Pages: 993995-993995

    • DOI

      10.3389/fphys.2022.993995

    • Related Report
      2022 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] Antioxidative Self-Assembling Nanoparticles Attenuate the Development of Steatohepatitis and Inhibit Hepatocarcinogenesis in Mice2022

    • Author(s)
      Watahiki Takahisa、Okada Kosuke、Miura Ikuru、To Keii、Tanaka Seiya、Warabi Eiji、Kanno Naomi、Yamagata Kenji、Gotoh Naohiro、Suzuki Hideo、Ariizumi Shunichi、Tsuchiya Kiichiro、Nagasaki Yukio、Shoda Junichi
    • Journal Title

      Antioxidants

      Volume: 11 Issue: 10 Pages: 1939-1939

    • DOI

      10.3390/antiox11101939

    • Related Report
      2022 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] Hepatic Niemann-Pick C1-Like 1 exacerbates non-alcoholic fatty liver disease by re-absorbing specific biliary oxysterols.2022

    • Author(s)
      Yamanashi Y, Takada T, Tanaka Y, Ogata Y, Toyoda Y, Ito SM, Kitani, Oshida N, Okada K, Shoda J, Suzuki H.
    • Journal Title

      Biomed. Pharmacother.

      Volume: 156 Pages: 113877-113877

    • DOI

      10.1016/j.biopha.2022.113877

    • Related Report
      2022 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] Effect of a sulforaphane supplement on muscle soreness and damage induced by eccentric exercise in young adults: A pilot study2021

    • Author(s)
      Komine S, Miura I, Shoda J, TokinoyaK, Oh S, Miyashita N, Omori H
    • Journal Title

      Physiol Reps

      Volume: 9 Issue: 24 Pages: 15130-15130

    • DOI

      10.14814/phy2.15130

    • Related Report
      2021 Research-status Report
    • Peer Reviewed / Open Access
  • [Journal Article] Association of dietary habits and physical activity levels with non-alcoholic fatty liver disease with advanced liver fibrosis2021

    • Author(s)
      Yabe Y, Kim T, Oh S, Oshida N, Hasegawa N, Kamimaki T, Someya N, Shoda J
    • Journal Title

      Int J Environ Res and Public Health

      Volume: 18 Issue: 17 Pages: 8918-8918

    • DOI

      10.3390/ijerph18178918

    • Related Report
      2021 Research-status Report
    • Peer Reviewed / Open Access
  • [Journal Article] The prevalence and clinical implications of pancreatic fat accumulation identified during a medical check-up2021

    • Author(s)
      Okada K, Watahiki T, Horie M, Takayama T, Aida Y, To K, Shida T, Ishige K, Suzuki H, Nishiyama H, Shoda J
    • Journal Title

      Medicine

      Volume: 100 Issue: 41 Pages: e27487-e27487

    • DOI

      10.1097/md.0000000000027487

    • Related Report
      2021 Research-status Report
    • Peer Reviewed / Open Access
  • [Journal Article] Prevention of non-alcoholic steatohepatitis by long-term exercise via the induction of phenotypic changes in Kupffer cells of hyperphagic obese mice2021

    • Author(s)
      Miura I, Komine S, Okada K, Wada S, Warabi E, Uchida F, Oh S, Suzuki H, Mizokami Y, Shoda J
    • Journal Title

      Physiol Reps

      Volume: 9 Issue: 9

    • DOI

      10.14814/phy2.14859

    • Related Report
      2021 Research-status Report
    • Peer Reviewed / Open Access
  • [Journal Article] Weight-loss-independent benefits of exercise on liver steatosis and stiffness in Japanese men with NAFLD2021

    • Author(s)
      Oh Sechang、Tsujimoto Takehiko、Kim Bokun、Uchida Fumihiko、Suzuki Hideo、Iizumi Seiichiro、Isobe Tomonori、Sakae Takeji、Tanaka Kiyoji、Shoda Junichi
    • Journal Title

      JHEP Reports

      Volume: 3 Issue: 3 Pages: 100253-100253

    • DOI

      10.1016/j.jhepr.2021.100253

    • Related Report
      2021 Research-status Report
    • Peer Reviewed / Open Access
  • [Presentation] 骨格筋のp62は筋-肝連関を介して脂肪性肝炎の炎症・線維化を抑制する2022

    • Author(s)
      三浦征, 岡田浩介, 石井亜紀子, 正田純一
    • Organizer
      第108回日本消化器病学会総会
    • Related Report
      2022 Annual Research Report
  • [Presentation] 骨格筋のNrf2は筋-肝連関を介してマウスNASHの肝炎症・線維化を抑制する2022

    • Author(s)
      三浦征, 岡田浩介, 正田純一
    • Organizer
      第58回日本肝臓学会総会
    • Related Report
      2022 Annual Research Report
  • [Presentation] 非アルコール性脂肪性肝炎に対する筋Nrf2の防御的役割2022

    • Author(s)
      三浦征, 岡田浩介, 石井亜紀子, 綿引隆久, 陶経緯, 正田純一
    • Organizer
      日本筋学会第8回学術集会
    • Related Report
      2022 Annual Research Report
  • [Presentation] 肥満における骨格筋量・筋力の低下と耐糖能異常に対するp62の役割2022

    • Author(s)
      三浦征, 岡田浩介, 石井亜紀子, 正田純一
    • Organizer
      第77回日本体力医学会大会
    • Related Report
      2022 Annual Research Report
  • [Presentation] 骨格筋のNrf2は筋-肝連関を介してNASHの発症を抑止する2022

    • Author(s)
      三浦征, 岡田浩介, 石井亜紀子, 綿引隆久, 陶経緯, 正田純一
    • Organizer
      第26回日本肝臓学会大会(JDDW2022)
    • Related Report
      2022 Annual Research Report
  • [Presentation] p62およびNrf2遺伝子二重欠失マウスは,腸内細菌叢の変化に関連したlipopolysaccharide増加により脂肪性肝炎を自然発症する2021

    • Author(s)
      岡田 浩介,綿引 隆久,正田 純一
    • Organizer
      第107回日本消化器病学会総会
    • Related Report
      2021 Research-status Report
  • [Presentation] NASH進行とNASH肝癌におけるautophagy調節因子p62の役割2021

    • Author(s)
      陶 経緯,綿引 隆久,岡田 浩介,石毛 和紀,鈴木 英雄,有泉 俊一,山本 雅一,正田 純一
    • Organizer
      第25回日本肝臓学会大会
    • Related Report
      2021 Research-status Report
  • [Presentation] 骨格筋のp62は骨格筋機能を改善させ脂肪性肝炎の炎症・線維化を減弱する2021

    • Author(s)
      三浦 征,岡田 浩介,石井 亜紀子,正田 純一
    • Organizer
      第7回日本筋学会学術集会
    • Related Report
      2021 Research-status Report

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Published: 2021-07-13   Modified: 2024-01-30  

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