Research for the pathogenesis and therapy of dysferlinopathy: Focusing on mechanisms of plasma membrane repair

2021 Fiscal Year Final Research Report

• Project/Area Number: 18K15437
• Research Category: Grant-in-Aid for Early-Career Scientists
• Allocation Type: Multi-year Fund
• Review Section: Basic Section 52020:Neurology-related
• Research Institution: Tohoku University
• Principal Investigator: Ono Hiroya 東北大学, 医学系研究科, 大学院非常勤講師 (90803578)
• Project Period (FY): 2018-04-01 – 2022-03-31
• Keywords: 筋ジストロフィー / dysferlin / 細胞膜修復 / AMPK

Outline of Final Research Achievements

Mutations in dysferlin are responsible for a inherited muscular dystrophy known as dysferlinopathy. Using affinity purification method combined with liquid chromatography-tandem mass spectrometry, we found that AMP-activated protein kinase (AMPK)γ1 was bound to a specific region of dysferlin. Using ex vivo laser injury experiments, we demonstrated that the AMPK complex was vital for the sarcolemmal damage repair. Furthermore, it was found that the phosphorylation of AMPKα was essential for plasma membrane repair, and treatment with an AMPK activator rescued the membrane-repair impairment observed in human myotubes with dysferlinopathy and dysferlin-null mouse fibers. Finally, it was determined that treatment with the AMPK activator improved the muscle phenotype in zebrafish and mouse models of dysferlin deficiency. These findings indicate that the AMPK complex is essential for plasma membrane repair and is a potential therapeutic target for dysferlinopathy.

Free Research Field

神経筋疾患

Academic Significance and Societal Importance of the Research Achievements

国の指定難病である筋ジストロフィーは、筋肉の萎縮や筋力の低下といった障害を示す、進行性の難治性遺伝性疾患である。本研究で得られたAMPK複合体が損傷を受けた筋細胞膜の修復において重要な役割を担っているという新たな知見は、根治療法がいまだないdysferlinopathyひいては筋ジストロフィー全体の治療法の開発に結びつく可能性がある。