Related Experiment Video
Updated: May 14, 2026
Modeling Charcot-Marie-Tooth Disease In Vitro by Transfecting Mouse Primary Motoneurons
Published on: January 7, 2019
Viral-mediated expression of desmin mutants to create mouse models of myofibrillar myopathy
Pierre Joanne1, Oussama Chourbagi1, Christophe Hourdé2
1Université Paris Diderot, Sorbonne Paris Cité, CNRS EAC4413, Unit of Functional and Adaptive Biology, Laboratory of Stress and Pathologies of the Cytoskeleton, 75013, Paris, France.
Background:
The clinical features of myofibrillar myopathies display a wide phenotypic heterogeneity. To this date, no studies have evaluated this parameter due to the absence of pertinent animal models. By studying two mutants of desmin, which induce subtle phenotypic differences in patients, we address this issue using an animal model based on the use of adeno-associated virus (AAV) vectors carrying mutated desmin cDNA.
Methods:
After preparation of the vectors, they were injected directly into the tibialis anterior muscles of C57BL/6 mice to allow expression of wild-type (WT) or mutated (R406W or E413K) desmin. Measurements of maximal force were carried out on the muscle in situ and then the injected muscles were analyzed to determine the structural consequences of the desmin mutations on muscle structure (microscopic observations, histology and immunohistochemistry).
Results:
Injection of AAV carrying WT desmin results in the expression of exogenous desmin in 98% of the muscle fibers without any pathological or functional perturbations. Exogenous WT and endogenous desmin are co-localized and no differences were observed compared to non-injected muscle. Expression of desmin mutants in mouse muscles induce morphological changes of muscle fibers (irregular shape and size) and the appearance of desmin accumulations around the nuclei (for R406W) or in subsarcolemmal regions of fibers (for E413K). These accumulations seem to occur and disrupt the Z-line, and a strong regeneration was observed in muscle expressing the R406W desmin, which is not the case for E413K. Moreover, both mutants of desmin studied here induce a decrease in muscle force generation capacity.
Conclusions:
In this study we show that AAV-mediated expression of desmin mutants in mouse muscles recapitulate the aggregation features, the decrease in contractile function and the morphological changes observed in patients with myofibrillar myopathy. More importantly, our results suggest that the R406W desmin mutant induces a robust muscle regeneration, which is not the case for the E413K mutant. This difference could help to explain the phenotypic differences observed in patients. Our results highlight the heterogeneous pathogenic mechanisms between different desmin mutants and open the way for new advances in the study of myofibrillar myopathies.
Insights
This study uses an animal model to show how desmin mutations cause myofibrillar myopathy, with one mutant (R406W) triggering muscle regeneration unlike the other (E413K). These findings help explain patient differences and advance myofibrillar myopathy research.
Area of Science:
- Muscle biology
- Genetics
- Biochemistry
Background:
- Myofibrillar myopathies exhibit diverse clinical features, but a lack of suitable animal models has hindered research.
- This study investigates desmin mutations, known to cause subtle patient phenotype variations, using a novel adeno-associated virus (AAV) animal model.
Purpose of the Study:
- To develop and utilize an AAV-based animal model to explore the functional and structural consequences of specific desmin mutations.
- To investigate the differential effects of desmin mutants (R406W and E413K) on muscle integrity and regeneration.
Main Methods:
- Adeno-associated virus (AAV) vectors carrying wild-type (WT) or mutated desmin cDNA (R406W, E413K) were injected into mouse tibialis anterior muscles.
- Muscle force generation was measured in situ, followed by microscopic, histological, and immunohistochemical analyses to assess structural changes and desmin aggregation.
Main Results:
- AAV-mediated WT desmin expression showed no adverse effects, with exogenous and endogenous desmin co-localizing.
- Desmin mutants induced fiber morphological changes, desmin accumulations (perinuclear for R406W, subsarcolemmal for E413K), Z-line disruption, and decreased muscle force.
- Muscle expressing R406W desmin exhibited significant regeneration, whereas E413K did not.
Conclusions:
- AAV-mediated expression of desmin mutants effectively recapitulates myofibrillar myopathy features, including aggregation, functional decline, and morphological alterations.
- The differential regenerative response between R406W and E413K mutants suggests distinct pathogenic mechanisms that may explain observed patient phenotypic heterogeneity.
- This model provides valuable insights into the heterogeneous mechanisms of desmin-related myofibrillar myopathies and opens avenues for future research.
