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GLUD1 dictates muscle stem cell differentiation by controlling mitochondrial glutamate levels

par Inés Soro-Arnáiz, Sarah Cherkaoui, Gillian Fitzgerald, Jing Zhang, Paola Gilardoni, Adhideb Ghosh, Ori Bar-Nur, Evi Masschelein, Pierre Maechler, Nicola Zamboni, Martin Poms, Alessio Cremonesi, Juan Carlos García Cañaveras, Katrien De Bock et Raphael J. Morscher

Publié: 5 octobre 2023
Serveur de preprints: bioRxiv
DOI: 10.1101/2023.10.04.560525

Résumé

Summary

Muscle stem cells (MuSCs) enable muscle growth and regeneration after exercise or injury. Upon activation MuSCs metabolically rewire to meet the changing demands of proliferation. Here we describe that primary changes in metabolism itself can dictate MuSC fate decisions to control differentiation and fusion. We found that glutamine anaplerosis into the TCA cycle decreases during MuSC differentiation and coincides with decreased expression of the mitochondrial glutamate deaminase GLUD1. Genetic deletion of Glud1 in proliferating MuSCs resulted in precocious differentiation and imbalanced fusion combined with loss of self-renewal in vitro and in vivo . Mechanistically, deleting Glud1 caused mitochondrial glutamate accumulation in proliferating MuSCs and inhibited the malate-aspartate shuttle (MAS). Restoring MAS activity by supplementation of alanine normalized differentiation. In conclusion, high GLUD1 activity in proliferating MuSCs prevents deleterious mitochondrial glutamate accumulation and inactivation of the MAS. It thereby acts as a compartment specific metabolic brake on MuSC differentiation.

Highlights

Glutamine is the major TCA cycle substrate in MuSCs with decreasing contribution upon differentiation.
Loss of Glud1 impairs MuSC self-renewal capacity and causes imbalanced fusion in vitro and in vivo .
Glud1 deletion leads to mitochondrial glutamate trapping and malate-aspartate shuttle (MAS) dysfunction.
Restoration of MAS activity in Glud1 deficient MuSCs reverses precocious differentiation and imbalanced fusion.

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PREreview Pablo Ranea-Robles et al. du club ASAPbio Metabolism Crowd

Rédigé par Pablo Ranea-Robles et Marina Schernthanner du ASAPbio Metabolism Crowd

This review reflects comments and contributions from Marina Schernthanner and Pablo Ranea-Robles. Review synthesized by Pablo Ranea-Robles.

In this study, the authors studied the role of GLUD1 in satellite cells in the muscle. These cells are responsible for dynamic changes in muscular cells upon…

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