A muscle cell‐macrophage axis involving matrix metalloproteinase 14 facilitates extracellular matrix remodeling with mechanical loading
Open Access
- 19 January 2022
- journal article
- research article
- Published by Wiley in The FASEB Journal
- Vol. 36 (2), e22155
- https://doi.org/10.1096/fj.202100182rr
Abstract
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.Keywords
Funding Information
- National Institute on Aging (AG046920, AG049086, AG063994)
- National Institute of Diabetes and Digestive and Kidney Diseases (DK119619)
- University of Kentucky (UL1TR001998)
This publication has 31 references indexed in Scilit:
- Matrix metalloproteinase-2 plays a critical role in overload induced skeletal muscle hypertrophyMuscles, Ligaments and Tendons Journal, 2019
- Highly Dynamic Transcriptional Signature of Distinct Macrophage Subsets during Sterile Inflammation, Resolution, and Tissue RepairThe Journal of Immunology, 2016
- Isolation of skeletal muscle stem cells by fluorescence-activated cell sortingNature Protocols, 2015
- Monocyte/Macrophage-derived IGF-1 Orchestrates Murine Skeletal Muscle Regeneration and Modulates Autocrine PolarizationMolecular Therapy, 2015
- MMP-14 in skeletal muscle repairJournal of Muscle Research and Cell Motility, 2015
- LIF negatively regulates tumour-suppressor p53 through Stat3/ID1/MDM2 in colorectal cancersNature Communications, 2014
- Exercise induces expression of leukaemia inhibitory factor in human skeletal muscleJournal Of Physiology-London, 2008
- Urokinase-type plasminogen activator and macrophages are required for skeletal muscle hypertrophy in miceAmerican Journal of Physiology-Cell Physiology, 2007
- Inflammatory monocytes recruited after skeletal muscle injury switch into antiinflammatory macrophages to support myogenesisThe Journal of Experimental Medicine, 2007
- Leukemia inhibitory factor restores the hypertrophic response to increased loading in the LIF(−/−) mouseCytokine, 2006