Development of a therapy for immobilization induced muscle atrophy by targeting Smads

2019 Fiscal Year Final Research Report

• Project/Area Number: 17K10941
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: Orthopaedic surgery
• Research Institution: Keio University
• Principal Investigator: KANAJI Arihiko 慶應義塾大学, 医学部(信濃町), 講師 (20286511)
• Co-Investigator(Kenkyū-buntansha): 宮本 健史 慶應義塾大学, 医学部(信濃町), 特任教授 (70383768)
• Project Period (FY): 2017-04-01 – 2020-03-31
• Keywords: 整形外科

Outline of Final Research Achievements

Muscle atrophy is a risk for fall leading to fragility fractures in elderly. Thus, inhibiting muscle atrophy in elderly is mandatory. We have previously demonstrated that Smad2 and Smad3 proteins accumulated in atrophic muscles in an immobilization induced muscle atrophy model in mice. Muscle specific targeting Smad2 and Smad3 resulted in significant inhibition of the immobilization induced muscle atrophy in mice. To determine if Smad2 and Smad3 could be inhibited globally in adults, we tried to establish Smad3 flox mice. We successfully established the Smad3 flox mice. Smad2 flox mice were already gifted by a collaborator. Now we successfully generated inducible Smad2 and Smad3 doubly deficient mice in adults. We found that Smad2 and Smad3 could be targeted in adult mice. We also screened Smad3 inhibitors by a drug repositioning screen, and identified some agents as Smad3 inhibiting chemical compounds.

Free Research Field

整形外科

Academic Significance and Societal Importance of the Research Achievements

現在、様々な分子が筋萎縮に対する治療標的と考えられているが筋萎縮に対する治療薬は存在しない。我々はSmad2/Smad3が不動性筋萎縮の治療標的であることを見出していたが、Smad2/Smad3のノックアウトマウスは胎生致死であるため、アダルトにおける筋萎縮の治療標的としては有用であるかが不明であった。今回のスタディでは、Smad2/Smad3はアダルトにおいて治療標的となり得ることを明らかにした点で学術的意義がある。また人為的にSmad2/Smad3を抑制するための薬剤も同定できており、今後の筋萎縮の治療法の開発にもつなげ得る成果を得た点において、社会的意義があると考えている。