Mice with muscle-specific deletion of Bin1 recapitulate centronuclear myopathy and acute downregulation of dynamin 2 improves their phenotypes.
Mol Ther
; 30(2): 868-880, 2022 02 02.
Article
in En
| MEDLINE
| ID: mdl-34371181
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.
Key words
Full text:
1
Collection:
01-internacional
Database:
MEDLINE
Main subject:
Myopathies, Structural, Congenital
/
Dynamin II
Limits:
Animals
Language:
En
Journal:
Mol Ther
Journal subject:
BIOLOGIA MOLECULAR
/
TERAPEUTICA
Year:
2022
Document type:
Article
Affiliation country:
Francia