A centronuclear myopathy-dynamin 2 mutation impairs skeletal muscle structure and function in mice

Area of Science:

• Muscle Biology
• Genetics
• Cellular Biology

Background:

• Autosomal dominant centronuclear myopathy (AD-CNM) is linked to mutations in the dynamin 2 (DNM2) gene.
• DNM2 plays a critical role in endocytosis and intracellular membrane trafficking.

Purpose of the Study:

• To investigate the pathomechanisms of AD-CNM by creating a knock-in mouse model with a common DNM2 mutation (KI-Dnm2(R465W)).
• To analyze the resulting myopathy's characteristics, including muscle involvement, cellular abnormalities, and potential therapeutic targets.

Main Methods:

• Generated heterozygous (HTZ) and homozygous (HMZ) KI-Dnm2(R465W) mice.
• Assessed muscle contractile properties, histology, gene expression, and protein localization in muscle fibers.
• Examined clathrin-mediated endocytosis in embryonic fibroblasts.

Main Results:

• HTZ mice developed progressive myopathy with muscle atrophy, mitochondrial/reticular network abnormalities, and altered calcium levels.
• DNM2 localized to trafficking regions, and dysferlin accumulation was observed in HTZ muscle fibers and patient biopsies.
• HMZ mice exhibited embryonic lethality, likely due to impaired endocytosis.

Conclusions:

• The KI-Dnm2(R465W) mouse model recapitulates key features of DNM2-related myopathy.
• Dysferlin accumulation in muscle is a potential new biomarker for DNM2-CNM.
• This model is crucial for studying DNM2 function, disease mechanisms, and therapeutic strategies for AD-CNM.