Muscle-dominant wild-type TDP-43 transgenic mice as a novel model of sporadic inclusion body myositis

2018 Fiscal Year Final Research Report

• Project/Area Number: 16K09674
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: Neurology
• Research Institution: Kumamoto University
• Principal Investigator: YAMASHITA Satoshi 熊本大学, 大学院生命科学研究部(医), 准教授 (20457592)
• Research Collaborator: ANDO yukio ; TAKEDA naoki ; TAWARA nozomu ; DOKI tsukasa ; MATSUO yoshimasa
• Project Period (FY): 2016-04-01 – 2019-03-31
• Keywords: 封入体筋炎 / TDP-43 / Tubular aggregate / NT5C1A / ミトコンドリア

Outline of Final Research Achievements

Muscle histology of inclusion body myositis (IBM) demonstrates inflammatory findings and degenerative features including accumulation of TDP-43. However, whether sarcoplasmic accumulation of TDP-43 is a primary trigger of muscle degeneration or a secondary event resulting from muscle degeneration in IBM remained unclear. Our study aimed to discover whether muscle-dominant expression of TDP-43 is a primary cause of muscle degeneration. We generated wild-type TDP-43 transgenic mice driven by a creatine kinase 8 promoter. The mice showed increased serum levels of myogenic enzymes. Muscle histology demonstrated myopathic changes including fiber size variation, abundant tubular aggregates, and TDP-43 aggregation. Proteomic analysis identified increased SR/ ER-resident proteins as well as cytosolic 5'-nucleotidase 1A. Muscle-dominant wild-type TDP-43 expression indeed caused myotoxicity featuring tubular aggregates and TDP-43-positive inclusions.

Free Research Field

神経筋疾患

Academic Significance and Societal Importance of the Research Achievements

封入体筋炎（IBM）は高齢者に好発する筋疾患であり、加齢に伴って起こる筋症＝サルコぺニアのモデルとなる点でも今後注目すべき疾患である。本疾患の骨格筋では、筋萎縮性側索硬化症などの神経変性疾患に共通してTDP-43が沈着しており、TDP-43プロテイノパチーの一型でもある。本マウスを用いて、TDP-43の筋線維内凝集を抑制する低分子化合物スクリーニングシステムを構築し、IBMの根治的治療法を探索することは、高齢者の運動機能を著しく低下させるサルコぺニアやALSなどの神経変性疾患の治療法開発に展開可能であると期待される。