p62 in muscles inhibits obesity-related sarcopenia through a control of mitophagy
| Project/Area Number |
21K19694
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| Research Category |
Grant-in-Aid for Challenging Research (Exploratory)
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| Allocation Type | Multi-year Fund |
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| Review Section |
Medium-sized Section 59:Sports sciences, physical education, health sciences, and related fields
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| Research Institution | University of Tsukuba |
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Principal Investigator |
Shoda Junichi 筑波大学, 医学医療系, 客員教授 (90241827)
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| 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)
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| Project Period (FY) |
2021-07-09 – 2023-03-31
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| Project Status |
Completed (Fiscal Year 2022)
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| 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)
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| 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 |
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| 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.
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| 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.
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| 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．
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Report
(3 results)
Research Products
(16 results)
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[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.
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Journal Title
Biomed. Pharmacother.
Volume: 156
Pages: 113877-113877
DOI
Related Report
Peer Reviewed / Open Access
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[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
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Journal Title
Medicine
Volume: 100
Issue: 41
Pages: e27487-e27487
DOI
Related Report
Peer Reviewed / Open Access
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