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Updated: Jul 23, 2025
Modeling Myotonic Dystrophy 1 in C2C12 Myoblast Cells
Published on: July 29, 2016
Therapeutic Targeting of the GSK3β-CUGBP1 Pathway in Myotonic Dystrophy
Maggie Lutz1, Miranda Levanti1, Rebekah Karns2
1Division of Neurology, Cincinnati Children's Hospital, Cincinnati, OH 45229, USA.
Abstract:
Myotonic Dystrophy type 1 (DM1) is a neuromuscular disease associated with toxic RNA containing expanded CUG repeats. The developing therapeutic approaches to DM1 target mutant RNA or correct early toxic events downstream of the mutant RNA. We have previously described the benefits of the correction of the GSK3β-CUGBP1 pathway in DM1 mice (HSA model) expressing 250 CUG repeats using the GSK3 inhibitor tideglusib (TG). Here, we show that TG treatments corrected the expression of ~17% of genes misregulated in DM1 mice, including genes involved in cell transport, development and differentiation. The expression of chloride channel 1 (Clcn1), the key trigger of myotonia in DM1, was also corrected by TG. We found that correction of the GSK3β-CUGBP1 pathway in mice expressing long CUG repeats (DMSXL model) is beneficial not only at the prenatal and postnatal stages, but also during adulthood. Using a mouse model with dysregulated CUGBP1, which mimics alterations in DM1, we showed that the dysregulated CUGBP1 contributes to the toxicity of expanded CUG repeats by changing gene expression and causing CNS abnormalities. These data show the critical role of the GSK3β-CUGBP1 pathway in DM1 muscle and in CNS pathologies, suggesting the benefits of GSK3 inhibitors in patients with different forms of DM1.
Insights
GSK3 inhibitor tideglusib corrects toxic RNA in myotonic dystrophy type 1 (DM1) mice by regulating the GSK3β-CUGBP1 pathway. This approach benefits muscle and CNS pathologies, suggesting therapeutic potential for DM1 patients.
Area of Science:
- Neuroscience
- Genetics
- Pharmacology
Background:
- Myotonic Dystrophy type 1 (DM1) is a neuromuscular disorder caused by toxic RNA with expanded CUG repeats.
- Current therapies aim to target mutant RNA or downstream toxic events.
- The GSK3β-CUGBP1 pathway is a potential therapeutic target in DM1.
Purpose of the Study:
- To evaluate the efficacy of the GSK3 inhibitor tideglusib (TG) in correcting DM1-associated pathologies.
- To investigate the role of the GSK3β-CUGBP1 pathway in DM1 pathogenesis in both muscle and the central nervous system (CNS).
Main Methods:
- Treatment of DM1 mouse models (HSA and DMSXL) with tideglusib.
- Gene expression analysis to identify corrected genes.
- Assessment of chloride channel 1 (Clcn1) expression.
- Utilizing a mouse model with dysregulated CUGBP1 to mimic DM1 alterations.
Main Results:
- Tideglusib treatment corrected the expression of approximately 17% of misregulated genes in DM1 mice, including those involved in cell transport, development, and differentiation.
- TG normalized the expression of Clcn1, a key factor in DM1 myotonia.
- Correction of the GSK3β-CUGBP1 pathway was beneficial across prenatal, postnatal, and adult stages in DM1 mice.
- Dysregulated CUGBP1 was shown to contribute to expanded CUG repeat toxicity and CNS abnormalities.
Conclusions:
- The GSK3β-CUGBP1 pathway plays a critical role in DM1-related muscle and CNS pathologies.
- GSK3 inhibitors like tideglusib show promise for treating various forms of DM1.
- Targeting this pathway offers a potential therapeutic strategy for DM1 patients.
