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AMPK Complex Activation Promotes Sarcolemmal Repair in Dysferlinopathy
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...
Autores principales: | , , , , , , , , , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
American Society of Gene & Cell Therapy
2020
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7132631/ https://www.ncbi.nlm.nih.gov/pubmed/32087766 http://dx.doi.org/10.1016/j.ymthe.2020.02.006 |
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author | Ono, Hiroya Suzuki, Naoki Kanno, Shin-ichiro Kawahara, Genri Izumi, Rumiko Takahashi, Toshiaki Kitajima, Yasuo Osana, Shion Nakamura, Naoko Akiyama, Tetsuya Ikeda, Kensuke Shijo, Tomomi Mitsuzawa, Shio Nagatomi, Ryoichi Araki, Nobukazu Yasui, Akira Warita, Hitoshi Hayashi, Yukiko K. Miyake, Katsuya Aoki, Masashi |
author_facet | Ono, Hiroya Suzuki, Naoki Kanno, Shin-ichiro Kawahara, Genri Izumi, Rumiko Takahashi, Toshiaki Kitajima, Yasuo Osana, Shion Nakamura, Naoko Akiyama, Tetsuya Ikeda, Kensuke Shijo, Tomomi Mitsuzawa, Shio Nagatomi, Ryoichi Araki, Nobukazu Yasui, Akira Warita, Hitoshi Hayashi, Yukiko K. Miyake, Katsuya Aoki, Masashi |
author_sort | Ono, Hiroya |
collection | PubMed |
description | 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 Ca(2+), 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. |
format | Online Article Text |
id | pubmed-7132631 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2020 |
publisher | American Society of Gene & Cell Therapy |
record_format | MEDLINE/PubMed |
spelling | pubmed-71326312021-04-08 AMPK Complex Activation Promotes Sarcolemmal Repair in Dysferlinopathy Ono, Hiroya Suzuki, Naoki Kanno, Shin-ichiro Kawahara, Genri Izumi, Rumiko Takahashi, Toshiaki Kitajima, Yasuo Osana, Shion Nakamura, Naoko Akiyama, Tetsuya Ikeda, Kensuke Shijo, Tomomi Mitsuzawa, Shio Nagatomi, Ryoichi Araki, Nobukazu Yasui, Akira Warita, Hitoshi Hayashi, Yukiko K. Miyake, Katsuya Aoki, Masashi Mol Ther Original Article 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 Ca(2+), 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. American Society of Gene & Cell Therapy 2020-04-08 2020-02-12 /pmc/articles/PMC7132631/ /pubmed/32087766 http://dx.doi.org/10.1016/j.ymthe.2020.02.006 Text en © 2020 The Author(s) http://creativecommons.org/licenses/by-nc-nd/4.0/ This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/). |
spellingShingle | Original Article Ono, Hiroya Suzuki, Naoki Kanno, Shin-ichiro Kawahara, Genri Izumi, Rumiko Takahashi, Toshiaki Kitajima, Yasuo Osana, Shion Nakamura, Naoko Akiyama, Tetsuya Ikeda, Kensuke Shijo, Tomomi Mitsuzawa, Shio Nagatomi, Ryoichi Araki, Nobukazu Yasui, Akira Warita, Hitoshi Hayashi, Yukiko K. Miyake, Katsuya Aoki, Masashi AMPK Complex Activation Promotes Sarcolemmal Repair in Dysferlinopathy |
title | AMPK Complex Activation Promotes Sarcolemmal Repair in Dysferlinopathy |
title_full | AMPK Complex Activation Promotes Sarcolemmal Repair in Dysferlinopathy |
title_fullStr | AMPK Complex Activation Promotes Sarcolemmal Repair in Dysferlinopathy |
title_full_unstemmed | AMPK Complex Activation Promotes Sarcolemmal Repair in Dysferlinopathy |
title_short | AMPK Complex Activation Promotes Sarcolemmal Repair in Dysferlinopathy |
title_sort | ampk complex activation promotes sarcolemmal repair in dysferlinopathy |
topic | Original Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7132631/ https://www.ncbi.nlm.nih.gov/pubmed/32087766 http://dx.doi.org/10.1016/j.ymthe.2020.02.006 |
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