Elucidation of the skeletal muscle regulatory mechanism of the AM-RAMP2 system and its application to sarcopenia and frailty.

• Project/Area Number: 20K07845
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Review Section: Basic Section 52010:General internal medicine-related
• Research Institution: Shinshu University
• Principal Investigator: Kawate Hisaka 信州大学, 医学部, 研究員 (20507503)
• Project Period (FY): 2020-04-01 – 2023-03-31
• Project Status: Completed (Fiscal Year 2022)
• Budget Amount: ¥4,290,000 (Direct Cost: ¥3,300,000、Indirect Cost: ¥990,000); Fiscal Year 2022: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000); Fiscal Year 2021: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000); Fiscal Year 2020: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000)
• Keywords: 骨格筋 / サルコペニア / アドレノメデュリン / RAMP2 / RAMP / フレイル

Outline of Research at the Start

我々はこれまで生理活性ペプチド、アドレノメデュリン(AM)と、その受容体活性調節タンパクRAMP2による各臓器の恒常性維持機構に注目してきた。本研究では、各種の骨格筋特異的なRAMP2遺伝子改変マウスや、サルコペニアモデルマウスなどを応用して、骨格筋におけるAM-RAMP2系の病態生理学的意義を解明すると共に、AM-RAMP2系を基軸とした、骨格筋と血管、各臓器との連携を解明する。次にAM-RAMP2系による細胞、臓器恒常性維持作用に人為的に介入し、これを操作することで、サルコペニア・フレイルの新しい予防、治療法に展開する。

Outline of Final Research Achievements

We generated a mouse model of skeletal muscle atrophy and regeneration using the cardiotoxin (CTX) to investigate the significance of adrenomedullin (AM) and its receptor activity-modifying protein, RAMP2, in the pathogenesis of skeletal muscle and sarcopenia.
RAMP2 heterozygous knockout (RAMP2+/-) mice showed delayed resolution of inflammation and delayed skeletal muscle regeneration in the tibialis anterior muscle after administration of CTX compared to wild-type mice. On the other hand, continuous administration of AM to wild-type mice suppressed inflammation and increased muscle cross-sectional area. These results indicate that the AM-RAMP2 system acts in an inhibitory manner against skeletal muscle injury.

Academic Significance and Societal Importance of the Research Achievements

超高齢化社会が進行する中で、高齢者の生活機能障害を予防し、QOLを維持することは喫緊の課題である。最近、サルコペニア・フレイルの様な新しい概念が提唱されたが、我々は、生体内の恒常性制御のメカニズムの解析を進め、その病態を解明することが重要であると考えた。
我々は生理活性ペプチド、アドレノメデュリン(AM)と、その受容体活性調節タンパクRAMP2による生体内の恒常性維持機構に注目してきた。AM, RAMP2は骨格筋にも豊富に存在するが、その機能や病態との関係は不明である。本研究ではAM-RAMP２システムのサルコペニア・フレイルにおける病態生理学的意義と治療応用の可能性を検証した。

Research Products

• [Journal Article] Receptor activity modifying protein RAMP sub-isoforms and their functional differentiation, which regulates functional diversity of adrenomedullin (2022)
  • Author(s): Shindo T, Tanaka M, Kamiyoshi A, Ichikawa-Shindo Y, Kawate H, Sakurai T
  • Journal Title: Biology(Basel) Volume: 11(5) Issue: 5 Pages: 788-788
  • DOI: 10.3390/biology11050788
  • Peer Reviewed / Open Access
• [Journal Article] Adrenomedullin ameliorates pulmonary fibrosis by regulating TGF-b-Smads signaling and myofibroblast differentiation (2021)
  • Author(s): Wei Y, Tanaka M, Sakurai T, Kamiyoshi A, Ichikawa-Shindo Y, Kawate H, Cui N, Kakihara S, Zhao Y, Aruga K, Sanjo H, Shindo T
  • Journal Title: Endocrinology Volume: 162(8) Issue: 8 Pages: 1-22
  • DOI: 10.1210/endocr/bqab090
  • Peer Reviewed
• [Journal Article] Adrenomedullin-RAMP2 and -RAMP3 systems regulate cardiac homeostasis during cardiovascular stress (2021)
  • Author(s): Cui N, Sakurai T, Kamiyoshi A, Ichikawa-Shindo Y, Kawate H, Tanaka M, Tanaka M, Wei Y, Kakihara S, Zhao Y, Aruga K, Kawagishi H, Nakada T, Yamada M, Shindo T
  • Journal Title: Endocrinology Volume: 162(3) Issue: 3 Pages: 0-0
  • DOI: 10.1210/endocr/bqab001
  • Peer Reviewed
• [Journal Article] Adrenomedullin-receptor activity-modifying protein 2 system ameliorates subretinal fibrosis by suppressing epithelial-mesenchymal transition in age-related macular degeneration (2021)
  • Author(s): Tanaka M, Kakihara S, Hirabayashi K, Imai A, Toriyama Y, Iesato Y, Sakurai T, Kamiyoshi A, Ichikawa-Shindo Y, Kawate H, Tanaka M, Cui N, Wei Y, Zhao Y, Aruga K, Yamauchi A, Murata T, Shindo T
  • Journal Title: Am J Pathol Volume: 191(4) Issue: 4 Pages: 652-668
  • DOI: 10.1016/j.ajpath.2020.12.012
  • Peer Reviewed
• [Journal Article] Adrenomedullin-RAMP2 system ameliorates pulmonary fibrosis by regulating TGF-β-Smads pathway and differentiation of myofibroblasts. (2021)
  • Author(s): Wei Y, Tanaka M, Sakurai T, Kamiyoshi A, Ichikawa-Shindo Y, Kawate H, Cui1 N, Kakihara S, Zhao Y, Aruga K, Sanjo H, Shindo T.
  • Journal Title: Endocrinology. Volume: in press
  • Peer Reviewed
• [Journal Article] Adrenomedullin-RAMP2 and -RAMP3 systems regulate cardiac homeostasis during cardiovascular stress. (2021)
  • Author(s): Cui N, Sakurai T, Kamiyoshi A, Ichikawa-Shindo Y, Kawate H, Tanaka M, Tanaka M, Wei Y, Kakihara S, Zhao Y, Aruga K, Kawagishi H, Nakada T, Yamada M, Shind T.
  • Journal Title: Endocrinology. Volume: in press
  • Peer Reviewed
• [Journal Article] Deficiency of the adrenomedullin-RAMP3 system suppresses metastasis through the modification of cancer-associated fibroblasts (2020)
  • Author(s): Dai K, Tanaka M, Kamiyoshi A, Sakurai T, Ichikawa-Shindo Y, Kawate H, Cui N, Wei Y, Tanaka M, Kakihara S, Matsui S, Shindo T
  • Journal Title: Oncogene Volume: 39(9) Issue: 9 Pages: 1914-1930
  • DOI: 10.1038/s41388-019-1112-z
  • Peer Reviewed
• [Presentation] アドレノメデュリン2の肝臓および代謝制御における病態生理学的意義 (2022)
  • Author(s): 神吉昭子、桜井敬之、新藤優佳、河手久香、田中愛、柿原伸次、Zhao Yunlu、松田順繁、Zhang Yan、Guo Qianqian、Li Peixuan、大西菜穂、笠原智、新藤隆行
  • Organizer: 第43回日本肥満学会
• [Presentation] 肥満および脂肪肝におけるアドレノメデュリン2の病態生理学的意義 (2021)
  • Author(s): 肥満および脂肪肝におけるアドレノメデュリン2の病態生理学的意義 神吉昭子、桜井敬之、新藤優佳、河手久香、田中愛、崔南奇、田中正明、Wei Yangxuan、柿原伸次、Zhao Yunlu、笠原智貴、有賀公亮、新藤隆行
  • Organizer: 第94回日本内分泌学会
• [Presentation] サルコペニア病態におけるアドレノメデュリン-RAMP系の病態生理学的意義 (2021)
  • Author(s): 有賀公亮、桜井敬之、神吉昭子、市川優佳、河手久香、田中愛、柿原伸次、Zhao Yunlu、松田順繁、新藤隆行
  • Organizer: 第25回日本心血管内分泌代謝学会
• [Presentation] Elucidation of the Significance of the Adrenomedullin-RAMP System as a Novel Therapeutic Target for Sarcopenia (2021)
  • Author(s): Aruga K, Sakurai T, Kamiyoshi A, Ichikawa-Shindo Y, Hisaka K, Tanaka M, Kakihara S, Zhao Y, Matsuda Y, Kasahara T, Shindo T.
  • Organizer: 第86回日本循環器学会
• [Presentation] Adrenomedullin-RAMP2 system regulates vascular endothelial homeostasis, which suppresses hematogenous and lymphogenous metastasis. (2021)
  • Author(s): Tanaka M, Sakurai T, Kamiyoshi A, Ichikawa-Shindo Y, Kawate H, Cui N, Wei Y, Tanaka M, Kakihara S, Zhao Y, Kasahara T, Aruga K, Shindo T.
  • Organizer: 第85回日本循環器学会
• [Presentation] Adrenomedullin-RAMP2 and -RAMP3 systems regulate cardiac homeostasis during cardiovascular stress. (2021)
  • Author(s): Cui N, Sakurai T, Kamiyoshi A, Ichikawa-Shindo Y, Kawate H, Tanaka M, Wei Y, Tanaka M, Kakihara S, Zhao Y, Kasahara T, Aruga K, Shindo T.
  • Organizer: 第85回日本循環器学会
• [Presentation] Adrenomedullin-RAMP2 system ameliorates age-related macular degeneration by suppressing choroidal neovascularization and subretinal fibrosis. (2021)
  • Author(s): Tanaka M, Kakihara S, Sakurai T, Kamiyoshi A, Ichikawa-Shindo Y, Kawate H, Tanaka M, Cui N, Wei Y, Zhao Y, Kasahara T, Aruga K, Shindo T.
  • Organizer: 第85回日本循環器学会
• [Remarks] 信州大学医学部 循環病態学教室
  • URL: http://www7a.biglobe.ne.jp/~shindo/