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Elimination of myotonia improves myopathy in a muscleblind knockout model of myotonic dystrophy: longread sequencing of Clcn1 transcripts in muscle from Mbnl1 knockout, Exon 7a deletion, and ADR mice.

ABSTRACT: A cardinal sign of myotonic dystrophy type 1 (DM1) is myotonia, slow muscle relaxation after voluntary contraction. Myotonia results from mis-regulated splicing of chloride channel 1 (ClC-1), leading to loss of channel function and runs of involuntary action potentials in muscle fibers. Heralding the onset of weakness, myotonia is often the first symptom of DM1, and thus this raises the possibility that muscle hyperexcitability promotes the subsequent development of myopathy. We used genome editing to test this possibility by deleting the alternatively spliced and frameshift inducing ClC-1 exon 7a (E7a) in the Mbnl1 knockout model of DM1. Although several ClC-1 exons exhibit mis-regulated splicing in DM1, deletion of this single cryptic exon was sufficient to restore ClC-1 function and eliminate myotonia systemically and permanently. We utilized long-read sequencing to assess transcript isoform utilization in mice with Mbnl1 knockout, deletion of E7a reduced the frequency of other splicing defects in ClC-1 transcripts, likely as a passive consequence of restoring reading frame and nonsense surveillance.

ORGANISM(S): Mus musculus

PROVIDER: GSE311013 | GEO | 2026/04/27

REPOSITORIES: GEO

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Project description:Myotonic dystrophy type 1 (DM1) is an RNA dominant disease in which mutant transcripts containing an expanded CUG repeat (CUGexp) cause muscle dysfunction by interfering with biogenesis of other mRNAs. The toxic effects of mutant RNA are mediated partly through sequestration of splicing regulator Muscleblind-like 1 (Mbnl1), a protein that binds to CUGexp RNA. A gene that is prominently affected encodes chloride channel 1 (Clcn1), resulting in hyperexcitability of muscle (myotonia). To identify DM1-affected genes and study mechanisms for dysregulation, we performed global mRNA profiling in transgenic mice that express CUGexp RNA, as compared to Mbnl1 knockout and Clcn1 null mice. We found that the majority of changes induced by CUGexp RNA in skeletal muscle can be explained by reduced activity of Mbnl1, including many changes that are secondary to myotonia. The pathway most affected comprises genes involved in calcium signaling and homeostasis. Some effects of CUGexp RNA on gene expression are caused by abnormal alternative splicing or downregulation of Mbnl1-interacting mRNAs. However, several of the most highly dysregulated genes showed altered transcription, as indicated by parallel changes of the corresponding premRNAs. These results support the idea that trans-dominant effects of CUGexp RNA on gene expression in this transgenic model may occur at the level of transcription, RNA processing, and mRNA decay, and are mediated mainly but not entirely through sequestration of Mbnl1. Experiment Overall Design: All experiments involved generating expression profiles of quadriceps muscles taken from mice. Experiments 1 and 2: samples were hybridized to Moe430A and Moe430B arrays. Experiment 3: samples were hybridized to Mouse Genome 430 2.0 array. Experiment 1 compared expression profiles of wild-type mice (FVB strain) with two lines, designated 20b and 41, of CUGexp transgenic mice with FVB background. Experiment 2 compared expression profiles of Clcn1-null (myotonic) mice with the wild-type background strain (BALB). Experiment 3 compared expression profiles of Mbnl1-null mice with the wild-type background strain (FVB).

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Elimination of myotonia improves myopathy in a muscleblind knockout model of myotonic dystrophy: longread sequencing of Clcn1 transcripts in muscle from Mbnl1 knockout, Exon 7a deletion, and ADR mice.

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