Single nuclei transcriptomics of muscle reveals intra-muscular cell dynamics linked to dystrophin loss and rescue View Full Text


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Article Info

DATE

2022-09-19

AUTHORS

Deirdre D. Scripture-Adams, Kevin N. Chesmore, Florian Barthélémy, Richard T. Wang, Shirley Nieves-Rodriguez, Derek W. Wang, Ekaterina I. Mokhonova, Emilie D. Douine, Jijun Wan, Isaiah Little, Laura N. Rabichow, Stanley F. Nelson, M. Carrie Miceli

ABSTRACT

In Duchenne muscular dystrophy, dystrophin loss leads to chronic muscle damage, dysregulation of repair, fibro-fatty replacement, and weakness. We develop methodology to efficiently isolate individual nuclei from minute quantities of frozen skeletal muscle, allowing single nuclei sequencing of irreplaceable archival samples and from very small samples. We apply this method to identify cell and gene expression dynamics within human DMD and mdx mouse muscle, characterizing effects of dystrophin rescue by exon skipping therapy at single nuclei resolution. DMD exon 23 skipping events are directly observed and increased in myonuclei from treated mice. We describe partial rescue of type IIa and IIx myofibers, expansion of an MDSC-like myeloid population, recovery of repair/remodeling M2-macrophage, and repression of inflammatory POSTN1 + fibroblasts in response to exon skipping and partial dystrophin restoration. Use of this method enables exploration of cellular and transcriptomic mechanisms of dystrophin loss and repair within an intact muscle environment. Our initial findings will scaffold our future work to more directly examine muscular dystrophies and putative recovery pathways. More... »

PAGES

989

References to SciGraph publications

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  • Identifiers

    URI

    http://scigraph.springernature.com/pub.10.1038/s42003-022-03938-0

    DOI

    http://dx.doi.org/10.1038/s42003-022-03938-0

    DIMENSIONS

    https://app.dimensions.ai/details/publication/pub.1151119713

    PUBMED

    https://www.ncbi.nlm.nih.gov/pubmed/36123393


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