Macrophage-derived glutamine boosts satellite cells and muscle regeneration

Min Shang, Federica Cappellesso, Ricardo Amorim, Jens Serneels, Federico Virga, Guy Eelen, Stefania Carobbio, Melvin Y. Rincon, Pierre Maechler, Katrien Bock, Ping-Chih Ho, Marco Sandri, Bart Ghesquière, Peter Carmeliet, Mario Di Matteo, Emanuele Berardi () and Massimiliano Mazzone ()
Additional contact information
Min Shang: Center for Cancer Biology, VIB
Federica Cappellesso: Center for Cancer Biology, VIB
Ricardo Amorim: Center for Cancer Biology, VIB
Jens Serneels: Center for Cancer Biology, VIB
Federico Virga: Center for Cancer Biology, VIB
Guy Eelen: Center for Cancer Biology, VIB
Stefania Carobbio: University of Geneva Medical Center
Melvin Y. Rincon: VIB–KU Leuven Center for Brain and Disease Research
Pierre Maechler: University of Geneva Medical Center
Katrien Bock: ETH
Ping-Chih Ho: Ludwig Cancer Research, University of Lausanne
Marco Sandri: Venetian Institute of Molecular Medicine
Bart Ghesquière: Center for Cancer Biology, VIB
Peter Carmeliet: Center for Cancer Biology, VIB
Mario Di Matteo: Center for Cancer Biology, VIB
Emanuele Berardi: Center for Cancer Biology, VIB
Massimiliano Mazzone: Center for Cancer Biology, VIB

Nature, 2020, vol. 587, issue 7835, 626-631

Abstract: 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.

Date: 2020
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DOI: 10.1038/s41586-020-2857-9

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