Mechanism of skeletal muscle disorders in myotonic dystrophy

2022 Fiscal Year Final Research Report

• Project/Area Number: 19K17007
• Research Category: Grant-in-Aid for Early-Career Scientists
• Allocation Type: Multi-year Fund
• Review Section: Basic Section 52020:Neurology-related
• Research Institution: Osaka University
• Principal Investigator: Hasuike Yuhei 大阪大学, 大学院医学系研究科, 招へい教員 (90838351)
• Project Period (FY): 2019-04-01 – 2023-03-31
• Keywords: 筋強直性ジストロフィー / 骨格筋障害

Outline of Final Research Achievements

Myotonic dystrophy type 1 (DM1) is a dominantly inherited disorder due to a toxic gain of function of RNA transcripts containing expanded CUG repeats (CUGexp). Although the involvement of cellular senescence, a critical component of aging, was suggested in studies of DM1 patient-derived cells, the detailed mechanism of cellular senescence caused by CUGexp RNA remains unelucidated.Here, we developed a DM1 cell model that conditionally expressed CUGexp RNA in human primary cells so that we could perform a detailed assessment that eliminated the variability in primary cells from different origins. Our DM1 model cells demonstrated that CUGexp RNA expression induced cellular senescence by a telomere-independent mechanism. Furthermore, the toxic RNA expression caused mitochondrial dysfunction, excessive reactive oxygen species production, and DNA damage and response. This study provides unequivocal evidence of the induction of premature senescence by CUGexp RNA in our DM1 model cells.

Free Research Field

神経内科学

Academic Significance and Societal Importance of the Research Achievements

DM1患者は、筋肉の衰え、認知機能障害、白内障、前頭部禿頭、内分泌異常などの早老症に類似した症状を呈する。本研究では、最適なヒトDM1細胞モデルを作成し、異常RNAの発現がテロメア非依存的なメカニズムで細胞老化を誘導することを実証した。また、その老化メカニズムの一端を明らかにした。異常伸長リピートをもつRNAに起因する老化誘導因子を標的とした介入は、DM1における早老症と類似した症状に対する治療薬につながる可能性がある。