A muscle cell‐macrophage axis involving matrix metalloproteinase 14 facilitates extracellular matrix remodeling with mechanical loading

The extracellular matrix (ECM) in skeletal muscle plays an integral role in tissue development, structural support, and force transmission. For successful adaptation to mechanical loading, remodeling processes must occur. In a large cohort of older adults, transcriptomics revealed that genes involve...

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Bibliographic Details
Published in:The FASEB journal 2022-02, Vol.36 (2), p.e22155-n/a
Main Authors: Peck, Bailey D., Murach, Kevin A., Walton, R. Grace, Simmons, Alexander J., Long, Douglas E., Kosmac, Kate, Dungan, Cory M., Kern, Philip A., Bamman, Marcas M., Peterson, Charlotte A.
Format: Article
Language:English
Subjects:
Adult
Aged
Animals
Cells, Cultured
Collagen Type I - metabolism
Extracellular Matrix - metabolism
extracellular matrix remodeling
Female
Humans
Leukemia Inhibitory Factor - metabolism
Leukocytes, Mononuclear - metabolism
macrophage
Macrophages - metabolism
Male
Matrix Metalloproteinase 14 - metabolism
Mice
Muscle Contraction - physiology
Muscle Fibers, Skeletal - metabolism
muscle hypertrophy
Muscle, Skeletal - metabolism
Resistance Training - methods
scRNA‐seq
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Summary:The extracellular matrix (ECM) in skeletal muscle plays an integral role in tissue development, structural support, and force transmission. For successful adaptation to mechanical loading, remodeling processes must occur. In a large cohort of older adults, transcriptomics revealed that genes involved in ECM remodeling, including matrix metalloproteinase 14 (MMP14), were the most upregulated following 14 weeks of progressive resistance exercise training (PRT). Using single‐cell RNA‐seq, we identified macrophages as a source of Mmp14 in muscle following a hypertrophic exercise stimulus in mice. In vitro contractile activity in myotubes revealed that the gene encoding cytokine leukemia inhibitory factor (LIF) is robustly upregulated and can stimulate Mmp14 expression in macrophages. Functional experiments confirmed that modulation of this muscle cell‐macrophage axis facilitated Type I collagen turnover. Finally, changes in LIF expression were significantly correlated with MMP14 expression in humans following 14 weeks of PRT. Our experiments reveal a mechanism whereby muscle fibers influence macrophage behavior to promote ECM remodeling in response to mechanical loading.
ISSN:0892-6638
1530-6860
DOI:10.1096/fj.202100182RR