Citation Information: JCI Insight. 2025;10(18):e195836. https://doi.org/10.1172/jci.insight.195836.
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.
Authors
Mackenzie L. Davenport, Amaya Fong, Gloria Montoya-Vazquez, Maria Fernanda Alves de Moura, Jodi L. Bubenik, Maurice S. Swanson
