Elucidation of Inflammation Mechanism for Muscle Wasting Treatment in Chronic Heart Failure

2018 Fiscal Year Final Research Report

• Project/Area Number: 16K16607
• Research Category: Grant-in-Aid for Young Scientists (B)
• Allocation Type: Multi-year Fund
• Research Field: Applied health science
• Research Institution: Juntendo University
• Principal Investigator: Kadoguchi Tomoyasu 順天堂大学, 医学(系)研究科(研究院), 博士研究員 (10762049)
• Project Period (FY): 2016-04-01 – 2019-03-31
• Keywords: 筋萎縮 / 酸化ストレス / NADPH oxidase / アンジオテンシンII / 心不全 / 骨格筋

Outline of Final Research Achievements

We examined whether NADPH oxidase 4 (NOX4) is associated with muscle wasting in Ang II-infusion mice. Either saline or Ang II was infused into WT and Nox4 KO mice via osmotic minipump for 4 weeks. At 4 weeks after Ang II-infusion, body and skeletal muscle weight, and myocyte cross-sectional area significantly decreased in WTA mice compared to WTV mice. These changes were significantly attenuated in KOA mice. Protein degradation and synthesis markers in skeletal muscle significantly increased and decreased in WTA mice compared to WTV mice, respectively. Moreover, NF-E2-related factor 2 (Nrf2) regulated genes and protein expression level of Nrf2 in nuclear fraction significantly decreased in WTA mice compared to WTV mice. These parameters were significantly ameliorated in KOA mice (all p values <0.05). NOX4 induces muscle wasting by Ang II via downregulation of Nrf2 pathway, suggesting that the NOX4-Nrf2 axis plays an essential role in the development of muscle wasting.

Free Research Field

健康科学

Academic Significance and Societal Importance of the Research Achievements

これまで、NOX4由来のROSは肺疾患および腎疾患の病態発症・進展における役割が示されてきたが、心不全による骨格筋萎縮におけるNOX4およびNrf2の役割は明らかではなかった。本研究では、NOX4欠損マウスを用いることにより、心不全における骨格筋萎縮に対するNOX4およびNrf2の役割が明らかとなる。NOX4由来のROSによるNrf2低下が、心不全における骨格筋萎縮に関与する可能性に着目した研究は、国内外では取り組みがない。したがって、骨格筋におけるNOX4由来のROS適正化は、心不全における骨格筋萎縮の治療の可能性を模索するものである。