期刊
出版社
NATL ACAD SCIENCES
DOI: 10.1073/pnas.2109576119
关键词
congenital myopathy; membrane remodeling; gene therapy; dynamin; amphiphysin
资金
- INSERM
- CNRS
- Strasbourg University
- Agence National de la Recherche (ANR) Dynather [ANR-18-CE17-000602, ANR-10-LABX-0030-INRT]
- Agence Nationale de la Recherche [ANR-10-IDEX-0002-02]
- French infrastructure for integrated structural biology [ANR-10-INBS-05]
- Instruct-European Research Infrastructure Consortium
- Association Francaise contre les Myopathies-Telethon
- Myotubular Trust
- Sparks, The Children'sMedical Research Charity
This study identifies BIN1 as a potential therapeutic target for dominant centronuclear myopathy linked to DNM2 mutations. By increasing BIN1 expression, muscle atrophy and histopathological features can be improved, and survival can be rescued.
The mechanoenzyme dynamin 2 (DNM2) is crucial for intracellular organization and trafficking. DNM2 is mutated in dominant centronuclear myopathy (DNM2-CNM), a muscle disease characterized by defects in organelle positioning in myofibers. It remains unclear how the in vivo functions of DNM2 are regulated in muscle. Moreover, there is no therapy for DNM2-CNM to date. Here, we overexpressed human amphiphysin 2 (BIN1), a membrane remodeling protein mutated in other CNM forms, in Dnm2(RW/+) and Dnm2(RW/RW) mice modeling mild and severe DNM2-CNM, through transgenesis or with adeno-associated virus (AAV). Increasing BIN1 improved muscle atrophy and main histopathological features of Dnm2(Rw/+) mice and rescued the perinatal lethality and survival of Dnm2(RW/RW) mice. In vitro experiments showed that BIN1 binds and recruits DNM2 to membrane tubules, and that the BIN1-DNM2 complex regulates tubules fission. Overall, BIN1 is a potential therapeutic target for dominant centronuclear myopathy linked to DNM2 mutations.
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