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Updated: Mar 11, 2026
Characterization of Neuromuscular Junctions in Mice by Combined Confocal and Super-Resolution Microscopy
Published on: December 8, 2021
Calcium homeostasis alterations in a mouse model of the Dynamin 2-related centronuclear myopathy
Bodvaël Fraysse1, Pascale Guicheney2, Marc Bitoun3
1Atlantic Gene Therapies, INSERM UMR 1089, Université de Nantes, CHU de Nantes, Nantes 44200, France.
Abstract:
Autosomal dominant centronuclear myopathy (CNM) is a rare congenital myopathy characterized by centrally located nuclei in muscle fibers. CNM results from mutations in the gene encoding dynamin 2 (DNM2), a large GTPase involved in endocytosis, intracellular membrane trafficking, and cytoskeleton regulation. We developed a knock-in mouse model expressing the most frequent DNM2-CNM mutation; i.e. the KI-Dnm2R465W model. Heterozygous (HTZ) KI-Dnm2 mice progressively develop muscle atrophy, impairment of contractile properties, histopathological abnormalities, and elevated cytosolic calcium concentration. Here, we aim at better characterizing the calcium homeostasis impairment in extensor digitorum longus (EDL) and soleus muscles from adult HTZ KI-Dnm2 mice. We demonstrate abnormal contractile properties and cytosolic Ca2+ concentration in EDL but not soleus muscles showing that calcium impairment is correlated with muscle weakness and might be a determinant factor of the spatial muscle involvement. In addition, the elevated cytosolic Ca2+ concentration in EDL muscles is associated with an increased sarcolemmal permeability to Ca2+ and releasable Ca2+ content from the sarcoplasmic reticulum. However, amplitude and kinetics characteristics of the calcium transient appear unchanged. This suggests that calcium defect is probably not a primary cause of decreased force generation by compromised sarcomere shortening but may be involved in long-term deleterious consequences on muscle physiology. Our results highlight the first pathomechanism which may explain the spatial muscle involvement occurring in DNM2-related CNM and open the way toward development of a therapeutic approach to normalize calcium content.
Insights
Centronuclear myopathy (CNM) in mice with a dynamin 2 (DNM2) mutation shows impaired muscle function and elevated calcium. This calcium imbalance, particularly in specific muscles, may explain disease progression and offers therapeutic targets.
Area of Science:
- Muscle physiology
- Genetics
- Cell biology
Background:
- Autosomal dominant centronuclear myopathy (CNM) is a rare genetic disorder affecting muscle fibers, characterized by centrally located nuclei.
- Mutations in the dynamin 2 (DNM2) gene are a common cause of CNM, impacting cellular processes like endocytosis and membrane trafficking.
- A knock-in mouse model (KI-Dnm2R465W) was developed to study the disease, exhibiting muscle atrophy and contractile dysfunction.
Purpose of the Study:
- To investigate the calcium homeostasis defects in extensor digitorum longus (EDL) and soleus muscles of adult heterozygous (HTZ) KI-Dnm2 mice.
- To correlate calcium handling abnormalities with muscle weakness and spatial disease involvement.
- To elucidate the role of calcium dysregulation in the pathomechanism of DNM2-related CNM.
Main Methods:
- Characterization of muscle contractile properties in HTZ KI-Dnm2 mice.
- Measurement of cytosolic calcium concentration (Ca2+) in EDL and soleus muscles.
- Assessment of sarcolemmal permeability and sarcoplasmic reticulum calcium content.
- Analysis of calcium transient amplitude and kinetics.
Main Results:
- HTZ KI-Dnm2 mice displayed abnormal contractile properties and elevated cytosolic Ca2+ in EDL muscles, but not soleus muscles.
- The observed calcium impairment correlated with muscle weakness and suggested a role in spatial disease manifestation.
- Elevated cytosolic Ca2+ in EDL was linked to increased sarcolemmal permeability and sarcoplasmic reticulum releasable Ca2+, while calcium transient dynamics remained unchanged.
- These findings suggest calcium defects may contribute to long-term muscle damage rather than being the primary cause of force reduction.
Conclusions:
- Calcium homeostasis impairment is a key feature in specific muscles affected by DNM2-related CNM.
- The study identifies a potential pathomechanism for spatial muscle involvement in DNM2-CNM.
- Findings pave the way for developing therapeutic strategies targeting calcium regulation in CNM.
