Macrophage-derived glutamine boosts satellite cells and muscle regeneration

Nature. 2020 Nov;587(7835):626-631. doi: 10.1038/s41586-020-2857-9. Epub 2020 Oct 28.

Abstract

Muscle regeneration is sustained by infiltrating macrophages and the consequent activation of satellite cells1-4. Macrophages and satellite cells communicate in different ways1-5, but their metabolic interplay has not been investigated. Here we show, in a mouse model, that muscle injuries and ageing are characterized by intra-tissue restrictions of glutamine. Low levels of glutamine endow macrophages with the metabolic ability to secrete glutamine via enhanced glutamine synthetase (GS) activity, at the expense of glutamine oxidation mediated by glutamate dehydrogenase 1 (GLUD1). Glud1-knockout macrophages display constitutively high GS activity, which prevents glutamine shortages. The uptake of macrophage-derived glutamine by satellite cells through the glutamine transporter SLC1A5 activates mTOR and promotes the proliferation and differentiation of satellite cells. Consequently, macrophage-specific deletion or pharmacological inhibition of GLUD1 improves muscle regeneration and functional recovery in response to acute injury, ischaemia or ageing. Conversely, SLC1A5 blockade in satellite cells or GS inactivation in macrophages negatively affects satellite cell functions and muscle regeneration. These results highlight the metabolic crosstalk between satellite cells and macrophages, in which macrophage-derived glutamine sustains the functions of satellite cells. Thus, the targeting of GLUD1 may offer therapeutic opportunities for the regeneration of injured or aged muscles.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Aging / metabolism
  • Amino Acid Transport System ASC / antagonists & inhibitors
  • Amino Acid Transport System ASC / metabolism
  • Animals
  • Cell Differentiation
  • Cell Proliferation
  • Female
  • Glutamate Dehydrogenase / deficiency
  • Glutamate Dehydrogenase / genetics
  • Glutamate Dehydrogenase / metabolism
  • Glutamate-Ammonia Ligase / antagonists & inhibitors
  • Glutamate-Ammonia Ligase / metabolism
  • Glutamine / metabolism*
  • Macrophages / enzymology
  • Macrophages / metabolism*
  • Male
  • Mice
  • Minor Histocompatibility Antigens / metabolism
  • Muscle, Skeletal / cytology
  • Muscle, Skeletal / injuries
  • Muscle, Skeletal / metabolism*
  • Muscle, Skeletal / pathology
  • Oxidation-Reduction
  • Regeneration*
  • Satellite Cells, Skeletal Muscle / cytology
  • Satellite Cells, Skeletal Muscle / metabolism*
  • TOR Serine-Threonine Kinases

Substances

  • Amino Acid Transport System ASC
  • Minor Histocompatibility Antigens
  • Slc1a5 protein, mouse
  • Glutamine
  • GluD1 protein, mouse
  • Glutamate Dehydrogenase
  • mTOR protein, mouse
  • TOR Serine-Threonine Kinases
  • Glutamate-Ammonia Ligase