AMPK Complex Activation Promotes Sarcolemmal Repair in Dysferlinopathy

Hiroya Ono, Naoki Suzuki, Shin ichiro Kanno, Genri Kawahara, Rumiko Izumi, Toshiaki Takahashi, Yasuo Kitajima, Shion Osana, Naoko Nakamura, Tetsuya Akiyama, Kensuke Ikeda, Tomomi Shijo, Shio Mitsuzawa, Ryoichi Nagatomi, Nobukazu Araki, Akira Yasui, Hitoshi Warita, Yukiko K. Hayashi, Katsuya Miyake, Masashi Aoki

Research output: Contribution to journalArticle

Abstract

Mutations in dysferlin are responsible for a group of progressive, recessively inherited muscular dystrophies known as dysferlinopathies. Using recombinant proteins and affinity purification methods combined with liquid chromatography-tandem mass spectrometry (LC-MS/MS), we found that AMP-activated protein kinase (AMPK)γ1 was bound to a region of dysferlin located between the third and fourth C2 domains. Using ex vivo laser injury experiments, we demonstrated that the AMPK complex was vital for the sarcolemmal damage repair of skeletal muscle fibers. Injury-induced AMPK complex accumulation was dependent on the presence of Ca2+, and the rate of accumulation was regulated by dysferlin. 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 immortalized human myotubes with reduced expression of dysferlin and dysferlin-null mouse fibers. Finally, it was determined that treatment with the AMPK activator metformin 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.

Original languageEnglish
Pages (from-to)1133-1153
Number of pages21
JournalMolecular Therapy
Volume28
Issue number4
DOIs
Publication statusPublished - 2020 Apr 8

Keywords

  • AMPK
  • dysferlin
  • membrane repair
  • mouse model
  • muscular dystrophy
  • zebrafish

ASJC Scopus subject areas

  • Molecular Medicine
  • Molecular Biology
  • Genetics
  • Pharmacology
  • Drug Discovery

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