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Bulk RNA-sequencing of TA in MBNL1/2 KD muscle

ABSTRACT: Myotonic dystrophy type 1 (DM1) is a multisystemic disorder caused by expanded CTG repeats in DMPK transcripts and consequent loss of MBNL protein function. Skeletal muscle in DM1 displays abundant centrally located nuclei despite limited immune-cell–associated fibre necrosis, complicating interpretation of the underlying mechanisms of muscle damage and remodelling. Here, we combine single-nucleus RNA sequencing of human DM1 muscle biopsies with adult-onset, myofibre-specific Mbnl knockdown mouse models to investigate muscle stem cell (MuSC) behaviour in this context. We identify increased numbers of activated MuSCs and a distinct population of myonuclei exhibiting a transitional transcriptional state, including expression of MuSC-associated markers and elevated DMPK levels. In mice, myofibre-restricted MBNL knockdown induces myonuclear accretion in the absence of overt necrosis and promotes analogous transcriptionally distinct myonuclear states. MuSC lineage tracing and ablation demonstrate that MuSC fusion contributes to central nucleation. Together, these findings indicate that MuSC-mediated fusion drives myonuclear remodelling in DM1 muscle, giving rise to centrally located myonuclei with altered transcriptional states. Notably, MuSC ablation did not significantly alter key functional parameters, including myotonia and muscle force, indicating that MuSC-mediated fusion is not a major determinant of overt muscle dysfunction in this model.

ORGANISM(S): Mus musculus

PROVIDER: GSE335961 | GEO | 2026/07/15

REPOSITORIES: GEO

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