Using in vivo muscle stem cell (satellite cell)-specific extracellular vesicle (EV) tracking, satellite cell depletion, in vitro cell culture, and single-cell RNA sequencing, we show satellite cells communicate with other cells in skeletal muscle during mechanical overload. Early satellite cell EV communication primes the muscle milieu for proper long-term extracellular matrix (ECM) deposition and is sufficient to support sustained hypertrophy in adult mice, even in the absence of fusion to muscle fibers. Satellite cells modulate chemokine gene expression across cell types within the first few days of loading, and EV delivery of miR-206 to fibrogenic cells represses Wisp1 expression required for appropriate ECM remodeling. Late-stage communication from myogenic cells during loading is widespread but may be targeted toward endothelial cells. Satellite cells coordinate adaptation by influencing the phenotype of recipient cells, which extends our understanding of their role in muscle adaptation beyond regeneration and myonuclear donation.

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Published in iScience, v. 24, issue 4, 102372.

© 2021 The Authors

This is an open access article under the CC BY-NC-ND license (https://creativecommons.org/licenses/by-nc-nd/4.0/).

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Funding Information

This work was supported by funding from the NIH National Institutes of Arthritis and Musculoskeletal and Skin Diseases (AR060701to C.A.P. and J.J.M. and AR071753 to K.A.M), National Institute on Aging (AG049086 to C.A.P. and J.J.M.and AG063994 to K.A.M), National Institute of Diabetes and Digestive and Kidney Diseases (DK119619 to C.A.P. and J.J.M), and National Institute of General Medical Sciences (GM130349 to J.J.S.).

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The accession number for the scRNA-seq data reported in this paper is GEO: GSE168872. The code to find the proportional difference in cell populations between two samples is available as an R library on GitHub: https://github.com/rpolicastro/scProportionTest/releases/tag/v1.0.0.

Supplemental information can be found online at https://doi.org/10.1016/j.isci.2021.102372. It is attached to the end of the downloaded article, and is also available for download as an additional file listed at the end of this record.

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Graphical abstract

mmc2.mp4 (1047 kB)
Video S1. High-magnification movie of tdTomato-containing EVs from tamoxifen-treated Pax7-tdT myogenic progenitor cells moving in and out of focus in solution, related to figure 1

mmc1.pdf (3471 kB)
Supplemental information