AMPK Complex Activation Promotes Sarcolemmal Repair in Dysferlinopathy
| Autor: | Nobukazu Araki, Masashi Aoki, Naoki Suzuki, Hiroya Ono, Katsuya Miyake, Kensuke Ikeda, Naoko Nakamura, Hitoshi Warita, Yukiko K. Hayashi, Tomomi Shijo, Shio Mitsuzawa, Tetsuya Akiyama, Yasuo Kitajima, Ryoichi Nagatomi, Shin Ichiro Kanno, Akira Yasui, Genri Kawahara, Toshiaki Takahashi, Shion Osana, Rumiko Izumi |
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| Rok vydání: | 2019 |
| Předmět: |
muscular dystrophy
AMPK Dysferlinopathy mouse model AMP-Activated Protein Kinases Cell Line Dysferlin 03 medical and health sciences Mice 0302 clinical medicine Sarcolemma Protein Domains Drug Discovery Genetics medicine Animals Humans Phosphorylation Protein kinase A Muscle Skeletal Molecular Biology 030304 developmental biology Pharmacology 0303 health sciences biology Activator (genetics) Myogenesis Chemistry Lasers Plasma membrane repair medicine.disease zebrafish Metformin Cell biology dysferlin Disease Models Animal Muscular Dystrophies Limb-Girdle membrane repair 030220 oncology & carcinogenesis Mutation biology.protein Molecular Medicine Original Article |
| Zdroj: | Molecular Therapy |
| ISSN: | 1525-0024 |
| Popis: | 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. Mutations in dysferlin are responsible for a group of progressive, recessively inherited muscular dystrophies known as dysferlinopathies. Using affinity purification methods combined with LC/MS/MS, Ono et al. found that AMPKγ1 was bound to dysferlin. The AMPK complex is essential for sarcolemmal repair and is a potential therapeutic target for dysferlinopathy. |
| Databáze: | OpenAIRE |
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