期刊
JOURNAL OF CLINICAL INVESTIGATION
卷 127, 期 12, 页码 4477-4487出版社
AMER SOC CLINICAL INVESTIGATION INC
DOI: 10.1172/JCI90542
关键词
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资金
- animal house, histology platform and Imaging Centre of the IGBMC
- INSERM
- CNRS
- University of Strasbourg
- Agence Nationale de la Recherche [14-CE12-0009]
- SATT Conectus Alsace
- Association Francaise contre les Myopathies [15352]
- Myotubular Trust and Sparks - The Children's Medical Research Charity
- French State fund [ANR-10-LABX-0030-INRT, ANR-10-IDEX-0002-02]
- Sparks Charity [14IGB01] Funding Source: researchfish
Regulation of skeletal muscle development and organization is a complex process that is not fully understood. Here, we focused on amphiphysin 2 (BIN1, also known as bridging integrator-1) and dynamin 2 (DNM2), two ubiquitous proteins implicated in membrane remodeling and mutated in centronuclear myopathies (CNMs). We generated Bin1(-/-) Dnm2(+/-) mice to decipher the physiological interplay between BIN1 and DNM2. While Bin1(-/-) mice die perinatally from a skeletal muscle defect, Bin1(-/-) Dnm2(+/-) mice survived at least 18 months, and had normal muscle force and intracellular organization of muscle fibers, supporting BIN1 as a negative regulator of DNM2. We next characterized muscle-specific isoforms of BIN1 and DNM2. While BIN1 colocalized with and partially inhibited DNM2 activity during muscle maturation, BIN1 had no effect on the isoform of DNM2 found in adult muscle. Together, these results indicate that BIN1 and DNM2 regulate muscle development and organization, function through a common pathway, and define BIN1 as a negative regulator of DNM2 in vitro and in vivo during muscle maturation. Our data suggest that DNM2 modulation has potential as a therapeutic approach for patients with CNM and BIN1 defects. As BIN1 is implicated in cancers, arrhythmia, and late-onset Alzheimer disease, these findings may trigger research directions and therapeutic development for these common diseases.
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