Silva-Rojas, Roberto;
Nattarayan, Vasugi;
Jaque-Fernandez, Francisco;
Gomez-Oca, Raquel;
Menuet, Alexia;
Reiss, David;
Goret, Marie;
... Laporte, Jocelyn; + view all
(2022)
Mice with muscle-specific deletion of Bin1 recapitulate centronuclear myopathy and acute downregulation of dynamin 2 improves their phenotypes.
Molecular Therapy
, 30
(2)
pp. 868-880.
10.1016/j.ymthe.2021.08.006.
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Mice with muscle-specific deletion of Bin1 recapitulate centronuclear myopathy and acute downregulation of dynamin 2 improve.pdf - Published Version Download (3MB) | Preview |
Abstract
Mutations in the BIN1 (Bridging Interactor 1) gene, encoding the membrane remodeling protein amphiphysin 2, cause centronuclear myopathy (CNM) associated with severe muscle weakness and myofiber disorganization and hypotrophy. There is no available therapy, and the validation of therapeutic proof of concept is impaired by the lack of a faithful and easy-to-handle mammalian model. Here, we generated and characterized the Bin1mck−/− mouse through Bin1 knockout in skeletal muscle. Bin1mck−/− mice were viable, unlike the constitutive Bin1 knockout, and displayed decreased muscle force and most histological hallmarks of CNM, including myofiber hypotrophy and intracellular disorganization. Notably, Bin1mck−/− myofibers presented strong defects in mitochondria and T-tubule networks associated with deficient calcium homeostasis and excitation-contraction coupling at the triads, potentially representing the main pathomechanisms. Systemic injection of antisense oligonucleotides (ASOs) targeting Dnm2 (Dynamin 2), which codes for dynamin 2, a BIN1 binding partner regulating membrane fission and mutated in other forms of CNM, improved muscle force and normalized the histological Bin1mck−/− phenotypes within 5 weeks. Overall, we generated a faithful mammalian model for CNM linked to BIN1 defects and validated Dnm2 ASOs as a first translatable approach to efficiently treat BIN1-CNM.
| Type: | Article |
|---|---|
| Title: | Mice with muscle-specific deletion of Bin1 recapitulate centronuclear myopathy and acute downregulation of dynamin 2 improves their phenotypes |
| Location: | United States |
| Open access status: | An open access version is available from UCL Discovery |
| DOI: | 10.1016/j.ymthe.2021.08.006 |
| Publisher version: | https://doi.org/10.1016/j.ymthe.2021.08.006 |
| Language: | English |
| Additional information: | This article is available under the Creative Commons CC-BY-NC-ND license, https://creativecommons.org/licenses/by-nc-nd/4.0/, and permits non-commercial use of the work as published, without adaptation or alteration provided the work is fully attributed. |
| Keywords: | Myopathy; antisense oligonucleotides; membrane curvature; dynamin; amphiphysin; therapy; MTM1; myotubular myopathy; myotubularin; t-tubule |
| UCL classification: | UCL UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Life Sciences UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Life Sciences > Div of Biosciences UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Life Sciences > Div of Biosciences > Cell and Developmental Biology |
| URI: | https://discovery-pp.ucl.ac.uk/id/eprint/10203966 |
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