Single-cell analysis of skeletal muscle macrophages reveals age-associated functional subpopulations
- National Institute on Aging, United States
Abstract
Tissue-resident macrophages represent a group of highly responsive innate immune cells that acquire diverse functions by polarizing towards distinct subpopulations. The subpopulations of macrophages that reside in skeletal muscle (SKM) and their changes during aging are poorly characterized. By single-cell transcriptomic analysis with unsupervised clustering, we found eleven distinct macrophage clusters in male mouse SKM with enriched gene expression programs linked to reparative, proinflammatory, phagocytotic, proliferative, and senescence-associated functions. Using a complementary classification, membrane markers LYVE1 and MHCII identified four macrophage subgroups: LYVE1-/MHCIIhi (M1-like, classically activated), LYVE1+/MHCIIlo (M2-like, alternatively activated), and two new subgroups, LYVE1+/MHCIIhi and LYVE1-/MHCIIlo. Notably, one new subgroup, LYVE1+/MHCIIhi, had traits of both M2 and M1 macrophages, while the other new subgroup, LYVE1-/MHCIIlo, displayed strong phagocytotic capacity. Flow cytometric analysis validated the presence of the four macrophage subgroups in SKM, and found that LYVE1- macrophages were more abundant than LYVE1+ macrophages in old SKM. A striking increase in proinflammatory markers (S100a8 and S100a9 mRNAs) and senescence-related markers (Gpnmb and Spp1 mRNAs) was evident in macrophage clusters from older mice. In sum, we have identified dynamically polarized SKM macrophages and propose that specific macrophage subpopulations contribute to the proinflammatory and senescent traits of old SKM.
Data availability
The single-cell RNA-seq analysis was uploaded to GEO with identifier GSE195507.
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Single-cell analysis of skeletal muscle macrophages reveals age-associated functional subpopulationsNCBI Gene Expression Omnibus, GSE195507.
Article and author information
Author details
Funding
National Institutes of Health (Z01-AG000511)
- Linda K Krasniewski
- Papiya Chakraborty
- Chang-Yi Cui
- Krystyna Mazan-Mamczarz
- Christopher Dunn
- Yulan Piao
- Jinshui Fan
- Changyou Shi
- Tonya Wallace
- Cuong Nguyen
- Isabelle A Rathbun
- Rachel Munk
- Dimitrios Tsitsipatis
- Supriyo De
- Payel Sen
- Luigi Ferrucci
- Myriam M Gorospe
The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.
Reviewing Editor
- Bérénice A Benayoun, University of Southern California, United States
Ethics
Animal experimentation: All animal study protocols were approved by the NIA Institutional Review Board (Animal Care and Use Committee). (ASP #476-LGG-2023)
Version history
- Received: February 17, 2022
- Preprint posted: February 24, 2022 (view preprint)
- Accepted: October 10, 2022
- Accepted Manuscript published: October 19, 2022 (version 1)
- Version of Record published: November 2, 2022 (version 2)
Copyright
This is an open-access article, free of all copyright, and may be freely reproduced, distributed, transmitted, modified, built upon, or otherwise used by anyone for any lawful purpose. The work is made available under the Creative Commons CC0 public domain dedication.
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Single-cell analysis of skeletal muscle macrophages reveals age-associated functional subpopulations
eLife 11:e77974.
https://doi.org/10.7554/eLife.77974
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