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Duchenne muscular dystrophy (DMD) is an X-linked recessive disorder caused by the loss of full-length dystrophin at the sarcolemma, resulting in myofiber fragility, degeneration, and impaired regeneration. Beyond this classical view, dysfunction of muscle stem cells (mSCs) has been proposed to contribute to disease progression, with studies suggesting that polarized dystrophin within mSCs regulates asymmetric division and self-renewal. My study aimed to elucidate the dynamic processes governing the establishment of dystrophin compartmentalization within muscle satellite cells. In this study, we reassessed the presence and distribution of dystrophin in mSCs using a mouse model expressing a dystrophin-EGFP fusion and tdTomato protein specifically in mSCs. Despite high Dmd transcription, no dystrophin protein was detected in mSCs at any activation state, as confirmed by in vivo imaging, histology, FACS, and capillary electrophoresis.Dystrophin accumulation observed near mSCs originated from the sarcolemma, rather than from the mSCs themselves, and showed no consistent polarity. These findings challenge the prevailing hypothesis that dystrophin plays a direct role in establishing muscle stem cell polarity, and question the requirement for mSC-intrinsic dystrophin expression as a prerequisite for effective muscle regeneration. While our results do not question the importance of polarized division in mSC biology or the existence of stem cell dysfunction in DMD, they argue against dystrophin as a regulator of these processes. Alternative mechanisms may underlie mSC impairment. This work refines our understanding of DMD pathophysiology and suggests that therapeutic restoration of dystrophin in mSCs may not be necessary for effective muscle regeneration.

Dystrophin is essential for muscle health: its sarcolemmal absence causes the fatal, X-linked condition, Duchenne muscular dystrophy (DMD). However, its normal, spatial organization remains poorly understood, which hinders the interpretation of efficacy of its therapeutic restoration. Using female reporter mice heterozygous for fluorescently tagged dystrophin (DmdEGFP ), we here reveal that dystrophin distribution is unexpectedly compartmentalized, being restricted to myonuclear-defined sarcolemmal territories extending ~80 μm, which we called “basal sarcolemmal dystrophin units (BSDUs).” These territories were further specialized at myotendinous junctions, where both Dmd transcripts and dystrophin protein were enriched. Genome-level correction in X-linked muscular dystrophy mice via CRISPR/Cas9 gene editing restored a mosaic of separated dystrophin domains, whereas transcript-level Dmd correction, following treatment with tricyclo-DNA antisense oligonucleotides, restored dystrophin initially at junctions before extending along the entire fiber—with levels ~2% sufficient to moderate the dystrophic process. We conclude that widespread restoration of fiber dystrophin is likely critical for therapeutic success in DMD, perhaps most importantly, at muscle–tendon junctions.