Myotonic dystrophy type 1 is caused by the expression of expanded CTG repeats in the DMPK gene and the resulting loss of function of MBNL protein. Affected skeletal muscle displays abundant centrally located nuclei despite limited immune-cell–associated fibre necrosis, complicating interpretation of muscle damage and remodelling mechanisms. Here we show that muscle stem cells are activated and fuse with existing muscle fibres in myotonic dystrophy type 1. Single-nucleus transcriptomics in patient’s muscle identifies increased activated muscle stem cells and distinct myonuclear populations exhibiting transitional transcriptional states, including muscle stem cell associated markers and elevated DMPK expression. Myofibre-specific MBNL knockdown mouse models demonstrate that muscle stem cell fusion contributes to central nucleation, whereas their deletion does not improve myotonia or muscle strength. Together, these findings indicate that loss of MBNL function in muscle drives myonuclear accretion through stem cell-mediated fusion, giving rise to myonuclei with immature states in myotonic dystrophy type 1. This study shows that muscle stem cells fuse with existing muscle fibres in myotonic dystrophy type 1, producing centrally located nuclei with altered gene-expression states and reshaping diseased muscle.
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. Preceding the onset of weakness, myotonia is often the first symptom of DM1, and thus this raises the possibility that muscle hyperexcitability contributes to the subsequent weakness and myopathy. Here, we show that genomic deletion of ClC-1 exon 7a (E7a), a cryptic exon abnormally regulated in DM1, completely rescues of ClC-1 function and yields permanent elimination of myotonia in the muscleblind-like 1 (Mbnl1) knockout mouse model of DM1. The restoration of normal excitability results in normalization of muscle force generation, correction of fiber-type distribution, and improvement of muscle histology. E7a deletion also partially corrects the muscle transcriptome, including changes of differential gene expression and alternative splicing. These results indicate that E7a inclusion is a lynchpin splice event that contributes to myotonic myopathy, and support myotonia reduction as a therapeutic objective in DM1. Myotonia is a hallmark symptom of myotonic dystrophy (DM1). Eliminating myotonia in a DM1 mouse model improved muscle function and corrected transcriptome dysregulation, supporting myotonia as a driver of myopathy and a potential therapeutic target.
Matthew T. Sipple, S. Hamazaki, Vanessa Todorow et al.· Nature Communications· 0 citations
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