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

FASEB J. 2022 Feb;36(2):e22155. doi: 10.1096/fj.202100182RR.


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: extracellular matrix remodeling; macrophage; muscle hypertrophy; scRNA-seq.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Aged
  • Animals
  • Cells, Cultured
  • Collagen Type I / metabolism
  • Extracellular Matrix / metabolism*
  • Female
  • Humans
  • Leukemia Inhibitory Factor / metabolism
  • Leukocytes, Mononuclear / metabolism*
  • Macrophages / metabolism
  • Male
  • Matrix Metalloproteinase 14 / metabolism*
  • Mice
  • Muscle Contraction / physiology
  • Muscle Fibers, Skeletal / metabolism*
  • Muscle, Skeletal / metabolism
  • Resistance Training / methods


  • Collagen Type I
  • Leukemia Inhibitory Factor
  • MMP14 protein, human
  • Matrix Metalloproteinase 14