Identification of RARgamma-activated muscle hypertrophic factor and its regulatory mechanism

2019 Fiscal Year Final Research Report

• Project/Area Number: 17H03820
• Research Category: Grant-in-Aid for Scientific Research (B)
• Allocation Type: Single-year Grants
• Section: 一般
• Research Field: Food science
• Research Institution: Osaka Prefecture University
• Principal Investigator: Yamaji Ryoichi 大阪府立大学, 生命環境科学研究科, 教授 (00244666)
• Project Period (FY): 2017-04-01 – 2020-03-31
• Keywords: ビタミンA / レチノイン酸 / レチノイン酸受容体 / 骨格筋 / 肥大 / 分泌タンパク質 / トランスグルタミナーゼ2 / mTORシグナル

Outline of Final Research Achievements

We have found that dietary provitamin A β-carotene increased soleus muscle mass with hypertrophy by activating the retinoic acid receptor (RAR) γ in mice. In myotube cells, ATRA increased transglutaminase 2 (TG2) expression in an RARγ-dependent manner and TG2 was secreted into extracellular space. The expression of TG2 was also increased in an RARγ-dependent manner in the soleus muscle of β-carotene-fed mice. Extracellular TG2 activated mTOR signaling pathway through GPR56, promoted protein synthesis, and induced hypertrophy of myotubes. TG2 mutant lacking TG activity exerted the same effects as wild-type TG2. Intraperitoneally administration of TG2 increased soleus muscle mass in mice. These results indicated that TG2 expression was upregulated through ATRA-mediated RARγ and that extracellular TG2 induced myotube hypertrophy by activating mTOR signaling-mediated protein synthesis through GPR56, independent of transglutaminase activity.

Free Research Field

分子栄養学

Academic Significance and Societal Importance of the Research Achievements

骨格筋の量的・質的な維持・増加を食品成分により調節することは生涯自立した健全な生活をおくるための対策となる。β-カロテンを含むカロテノイドの血中濃度が高い高齢者では歩行速度が速く、筋力も強いが、分子機構は不明であった。本研究で見出したRARγ依存的に発現するTG2が分泌因子として筋肥大に寄与することはビタミンAの新規な機能の解明であり、学術的価値は高い。またβ-カロテンを含むビタミンA前駆体を活用して骨格筋の量的・質的な維持・増加を目指す食品成分や薬の開発への発展性も持ち、ロコモティブシンドローム（運動器症候群）やメタボリックシンドローム（代謝性症候群）への対応策にもなり、社会的意義も高い。