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Updated: Sep 11, 2025
Isometric and Eccentric Force Generation Assessment of Skeletal Muscles Isolated from Murine Models of Muscular Dystrophies
Published on: January 31, 2013
Differential pathology and susceptibility to MBNL loss across muscles in myotonic dystrophy mouse models
Mackenzie L Davenport1,2,3,4, Amaya Fong1,2,3, Gloria Montoya-Vazquez1,2,3
1Department of Molecular Genetics and Microbiology.
Abstract:
There are 2 subtypes of myotonic dystrophy, DM1 and DM2, each caused by repeat expansion mutations. The leading pathogenic mechanism is RNA-mediated toxicity, whereby (C)CUG expansions sequester the muscleblind-like (MBNL) family of RNA binding proteins. However, key differences exist in muscle involvement patterns and histopathology between DM1 and DM2. The cause of these disparities both in how the muscles are affected within each disease and between the 2 diseases is unknown, and it is unclear if current DM mouse models recapitulate these differences or develop differential muscle susceptibility. Here, we examined the expression of disease-relevant genes across healthy human muscles from a transcriptomic atlas and collected a series of muscles from Mbnl-KO mice to evaluate characteristic histologic and molecular features of DM pathology. Our results indicate that MBNL loss discordantly affects muscles, likely through a splicing-independent mechanism, and results in a fiber atrophy profile more like DM1 than DM2. These findings point to a predominant role for MBNL loss in muscle pattern involvement in DM1, provide further evidence for additional DM2 pathomechanisms, and have important implications for muscle choice when performing analyses in new mouse models and evaluating therapeutic modalities and biomarkers.
Insights
Myotonic dystrophy subtypes DM1 and DM2 involve muscles differently. MBNL protein loss in mice models shows fiber atrophy similar to DM1, suggesting MBNL loss is key in DM1 muscle effects.
Area of Science:
- Molecular Biology
- Genetics
- Neuromuscular Disorders
Background:
- Myotonic dystrophy (DM) comprises DM1 and DM2, caused by repeat expansion mutations.
- A primary mechanism involves RNA toxicity, sequestering muscleblind-like (MBNL) proteins.
- Distinct muscle involvement and histopathology patterns exist between DM1 and DM2, with underlying causes unknown.
Purpose of the Study:
- To investigate the differential impact of MBNL loss on muscle pathology.
- To determine if MBNL loss explains muscle susceptibility patterns in DM1 and DM2.
- To assess the utility of Mbnl knockout mouse models in recapitulating DM-specific muscle features.
Main Methods:
- Analysis of a human muscle transcriptomic atlas to examine disease-relevant gene expression.
- Histological and molecular evaluation of muscles from Mbnl knockout mice.
- Comparison of observed pathology with known DM1 and DM2 muscle characteristics.
Main Results:
- MBNL loss leads to discordant muscle effects, suggesting a splicing-independent mechanism.
- The resulting fiber atrophy profile in Mbnl knockout mice more closely resembles DM1 than DM2.
- Human muscle data revealed differential gene expression patterns relevant to DM pathology.
Conclusions:
- MBNL loss plays a significant role in the muscle involvement patterns observed in DM1.
- Additional pathogenic mechanisms beyond MBNL sequestration likely contribute to DM2.
- Findings impact the selection of muscles for analysis in DM mouse models and the evaluation of therapies.
