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Updated: Jul 19, 2025
Characterization of Neuromuscular Junctions in Mice by Combined Confocal and Super-Resolution Microscopy
Published on: December 8, 2021
DNM2 levels normalization improves muscle phenotypes of a novel mouse model for moderate centronuclear myopathy
Juliana de Carvalho Neves1, Foteini Moschovaki-Filippidou1, Johann Böhm1
1Institut de Génétique et de Biologie Moléculaire et Cellulaire (IGBMC), CNRS UMR7104, INSERM U1258, 1 rue Laurent Fries, 67404 Illkirch Cedex, France.
Abstract:
Dynamin 2 (DNM2) is a ubiquitously expressed GTPase regulating membrane trafficking and cytoskeleton dynamics. Heterozygous dominant mutations in DNM2 cause centronuclear myopathy (CNM), associated with muscle weakness and atrophy and histopathological hallmarks as fiber hypotrophy and organelles mis-position. Different severities range from the severe neonatal onset form to the moderate form with childhood onset and to the mild adult onset form. No therapy is approved for CNM. Here we aimed to validate and rescue a mouse model for the moderate form of DNM2-CNM harboring the common DNM2 R369W missense mutation. Dnm2 mice presented with increased DNM2 protein level in muscle and moderate CNM-like phenotypes with force deficit, muscle and fiber hypotrophy, impaired mTOR signaling, and progressive mitochondria and nuclei mis-position with age. Molecular analyses revealed a fiber type switch toward oxidative metabolism correlating with decreased force and alteration of mitophagy markers paralleling mitochondria structural defects. Normalization of DNM2 levels through intramuscular injection of AAV-shDnm2 targeting Dnm2 mRNA significantly improved histopathology and muscle and myofiber hypotrophy. These results showed that the Dnm2 mouse is a faithful model for the moderate form of DNM2-CNM and revealed that DNM2 normalization after a short 4-week treatment is sufficient to improve the CNM phenotypes.
Insights
This study validates a mouse model for centronuclear myopathy (CNM) caused by Dynamin 2 (DNM2) mutations. Restoring DNM2 levels improved muscle pathology and function, offering hope for CNM treatment.
Area of Science:
- Molecular biology
- Genetics
- Neuromuscular disorders
Background:
- Dynamin 2 (DNM2) is a GTPase crucial for membrane trafficking and cytoskeleton dynamics.
- Mutations in DNM2 cause centronuclear myopathy (CNM), a condition characterized by muscle weakness, atrophy, and abnormal muscle cell structure.
- Current therapeutic options for CNM are limited.
Purpose of the Study:
- To validate a mouse model for the moderate form of DNM2-related centronuclear myopathy (CNM).
- To investigate the therapeutic potential of normalizing DNM2 levels in affected muscle tissue.
Main Methods:
- Development and characterization of a mouse model (Dnm2R369W) mimicking moderate DNM2-CNM.
- Assessment of muscle histopathology, force production, and molecular signaling pathways (e.g., mTOR, mitophagy).
- Treatment of the mouse model using adeno-associated virus-mediated short hairpin RNA (AAV-shDNM2) to reduce DNM2 mRNA levels.
Main Results:
- The Dnm2R369W mice exhibited key CNM features, including muscle hypotrophy, force deficits, and mispositioned organelles.
- Molecular analysis revealed impaired mTOR signaling, altered mitophagy, and a shift towards oxidative metabolism in the mutant mice.
- Intramuscular AAV-shDNM2 treatment significantly ameliorated histopathological findings and improved muscle hypotrophy.
Conclusions:
- The Dnm2R369W mouse is a reliable model for studying moderate DNM2-CNM.
- Normalization of DNM2 levels, even with short-term intervention, can effectively improve CNM-related phenotypes in a preclinical setting.
