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.

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Published in The FASEB Journal, v. 36, issue 2, e22155.

© 2022 The Authors

This is an open access article under the terms of the Creative Commons Attribution-NonCommercial-NoDerivs License, which permits use and distribution in any medium, provided the original work is properly cited, the use is non-commercial and no modifications or adaptations are made.

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This work was supported by funding from the NIH National Institutes of Arthritis and Musculoskeletal and Skin Diseases (AR060701 to C.A.P and AR071753 to K.A.M), National Institute on Aging (AG046920 to C.A.P, M.M.B, and P.A.K, AG049086 to C.A.P, and AG063994 to K.A.M), National Institute of Diabetes and Digestive and Kidney Diseases (DK119619 to C.A.P), a Paul Glenn Investigator Award (C.A.P) and the University of Kentucky CTSA award (UL1TR001998).

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