Muscle fiber type specific dystrphic phenotype in murine model of nuclear envelopathies and NQO1 as a target for potential therapy

2020 Fiscal Year Final Research Report

• Project/Area Number: 18K15052
• Research Category: Grant-in-Aid for Early-Career Scientists
• Allocation Type: Multi-year Fund
• Review Section: Basic Section 48040:Medical biochemistry-related
• Research Institution: Tokyo Medical University
• Principal Investigator: Wada Eiji 東京医科大学, 医学部, 講師 (60756948)
• Project Period (FY): 2018-04-01 – 2021-03-31
• Keywords: 核膜病 / 骨格筋線維タイプ / ミトコンドリア / メカニカルストレス / DNAダメージ / 核

Outline of Final Research Achievements

Nuclear envelopathies are tissue-selective diseases that affect differently in organ systems. Mutations in nuclear envelope proteins, emerin (EMD) and lamin A/C (LMNA) genes, cause myopathy called Emery-Dreifuss muscular dystrophy (EDMD). Since there was no suitable model existed, the underlying molecular mechanism of skeletal muscle involvement in EDMD has not been clarified. Recently, we generated double mutant (Emd-null/LmnaH222P/H222P mutant; EH) mice which show the progression of muscular dystrophy before appearance of cardiac dysfunction similar to EDMD patients. From a micro-array analysis, some genes related to mitochondria functions are altered, especially in a NQO1 levels. In this study, several potential drugs for upregulating NQO1 levels are administered to evaluate the effectiveness in skeletal muscle phenotype in EH mice.

Free Research Field

筋生理学、筋疾患

Academic Significance and Societal Importance of the Research Achievements

筋ジストフィーは骨格筋の 壊死 ・再生を主病変とする遺伝性筋疾患の総称であり、その中でエメリー・ドレイフス型筋ジストロフィー（EDMD）は核膜関連タンパク質の遺伝子異常で起こる希少筋疾患である。これまで骨格筋の病態メカニズムが不明であったこともあり、有効な治療法は確立されていない。我々はEDMDの骨格筋病態を良く再現するモデルマウスを有しており、本研究ではEDMDにおける骨格筋病態メカニズムの解明とミトコンドリアの機能回復をターゲットにした候補治療薬の探索を行った。