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Updated: Sep 25, 2025
Direct Reprogramming of Human Fibroblasts into Myoblasts to Investigate Therapies for Neuromuscular Disorders
Published on: April 3, 2021
Molecular characterization of myotonic dystrophy fibroblast cell lines for use in small molecule screening
Jana R Jenquin1,2, Alana P O'Brien3, Kiril Poukalov3
1Department of Biochemistry and Molecular Biology, Center for NeuroGenetics, College of Medicine, University of Florida, Gainesville, FL 32610, USA.
Abstract:
Myotonic dystrophy type 1 (DM1) and type 2 (DM2) are common forms of adult onset muscular dystrophy. Pathogenesis in both diseases is largely driven by production of toxic-expanded repeat RNAs that sequester MBNL RNA-binding proteins, causing mis-splicing. Given this shared pathogenesis, we hypothesized that diamidines, small molecules that rescue mis-splicing in DM1 models, could also rescue mis-splicing in DM2 models. While several DM1 cell models exist, few are available for DM2 limiting research and therapeutic development. Here, we characterize DM1 and DM2 patient-derived fibroblasts for use in small molecule screens and therapeutic studies. We identify mis-splicing events unique to DM2 fibroblasts and common events shared with DM1 fibroblasts. We show that diamidines can partially rescue molecular phenotypes in both DM1 and DM2 fibroblasts. This study demonstrates the potential of fibroblasts as models for DM1 and DM2, which will help meet an important need for well-characterized DM2 cell models.
Insights
This study shows that patient-derived fibroblasts can model both myotonic dystrophy type 1 (DM1) and type 2 (DM2). Diamidines partially rescued molecular issues in these DM1 and DM2 models, aiding therapeutic development.
Area of Science:
- Biochemistry
- Genetics
- Molecular Biology
Background:
- Myotonic dystrophy type 1 (DM1) and type 2 (DM2) are adult-onset muscular dystrophies.
- Both diseases share a pathogenic mechanism involving toxic-expanded repeat RNAs sequestering MBNL proteins, leading to RNA mis-splicing.
- Existing DM2 cell models are limited, hindering research and therapeutic development.
Purpose of the Study:
- To characterize DM1 and DM2 patient-derived fibroblasts for use in small molecule screens.
- To identify DM2-specific and shared mis-splicing events in DM1 and DM2 fibroblasts.
- To evaluate the potential of diamidines in rescuing molecular phenotypes in DM1 and DM2 models.
Main Methods:
- Utilized patient-derived fibroblasts for DM1 and DM2.
- Analyzed RNA mis-splicing events unique to DM2 and common to DM1.
- Tested the efficacy of diamidines in partially rescuing molecular phenotypes.
Main Results:
- Identified distinct and shared mis-splicing events in DM1 and DM2 fibroblasts.
- Demonstrated that diamidines can partially rescue molecular phenotypes in both DM1 and DM2 fibroblast models.
- Established fibroblasts as valuable models for DM1 and DM2 research.
Conclusions:
- Patient-derived fibroblasts are effective models for studying DM1 and DM2.
- Diamidines show potential for rescuing molecular defects in both DM1 and DM2.
- This work addresses the need for robust DM2 cell models, facilitating future therapeutic strategies.
