GLUD1 determines murine muscle stem cell fate by controlling mitochondrial glutamate levels.

Autor:	Soro-Arnáiz I; Laboratory of Exercise and Health, Department of Health Sciences and Technology, Swiss Federal Institute of Technology (ETH Zurich), Schwerzenbach, 8603 Zurich, Switzerland., Fitzgerald G; Laboratory of Exercise and Health, Department of Health Sciences and Technology, Swiss Federal Institute of Technology (ETH Zurich), Schwerzenbach, 8603 Zurich, Switzerland; Pediatric Cancer Metabolism Laboratory, Children's Research Center, University of Zurich, 8032 Zurich, Switzerland; Division of Oncology, University Children's Hospital Zurich and Children's Research Center, University of Zurich, 8032 Zurich, Switzerland., Cherkaoui S; Pediatric Cancer Metabolism Laboratory, Children's Research Center, University of Zurich, 8032 Zurich, Switzerland; Division of Oncology, University Children's Hospital Zurich and Children's Research Center, University of Zurich, 8032 Zurich, Switzerland., Zhang J; Laboratory of Exercise and Health, Department of Health Sciences and Technology, Swiss Federal Institute of Technology (ETH Zurich), Schwerzenbach, 8603 Zurich, Switzerland., Gilardoni P; Laboratory of Exercise and Health, Department of Health Sciences and Technology, Swiss Federal Institute of Technology (ETH Zurich), Schwerzenbach, 8603 Zurich, Switzerland., Ghosh A; Laboratory of Regenerative and Movement Biology, Department of Health Sciences and Technology, ETH Zurich, Schwerzenbach, 8603 Zurich, Switzerland; Functional Genomics Center Zurich, ETH Zurich and University of Zurich, 8032 Zurich, Switzerland., Bar-Nur O; Laboratory of Regenerative and Movement Biology, Department of Health Sciences and Technology, ETH Zurich, Schwerzenbach, 8603 Zurich, Switzerland., Masschelein E; Laboratory of Exercise and Health, Department of Health Sciences and Technology, Swiss Federal Institute of Technology (ETH Zurich), Schwerzenbach, 8603 Zurich, Switzerland., Maechler P; Department of Cell Physiology and Metabolism, University of Geneva Medical Center, 1211 Geneva, Switzerland., Zamboni N; Institute of Molecular Systems Biology, ETH Zurich, 8049 Zurich, Switzerland., Poms M; Division of Clinical Chemistry and Biochemistry, University Children's Hospital Zurich, University of Zurich, 8032 Zurich, Switzerland., Cremonesi A; Division of Clinical Chemistry and Biochemistry, University Children's Hospital Zurich, University of Zurich, 8032 Zurich, Switzerland., Garcia-Cañaveras JC; Biomarkers and Precision Medicine Unit, Health Research Institute-Hospital La Fe, 46026 Valencia, Spain., De Bock K; Laboratory of Exercise and Health, Department of Health Sciences and Technology, Swiss Federal Institute of Technology (ETH Zurich), Schwerzenbach, 8603 Zurich, Switzerland. Electronic address: katrien-debock@ethz.ch., Morscher RJ; Pediatric Cancer Metabolism Laboratory, Children's Research Center, University of Zurich, 8032 Zurich, Switzerland; Division of Oncology, University Children's Hospital Zurich and Children's Research Center, University of Zurich, 8032 Zurich, Switzerland; Division of Human Genetics, Medical University Innsbruck, 6020 Innsbruck, Austria. Electronic address: raphael.morscher@kispi.uzh.ch.
Jazyk:	angličtina
Zdroj:	Developmental cell [Dev Cell] 2024 Aug 02. Date of Electronic Publication: 2024 Aug 02.
DOI:	10.1016/j.devcel.2024.07.015
Abstrakt:	Muscle stem cells (MuSCs) enable muscle growth and regeneration after exercise or injury, but how metabolism controls their regenerative potential is poorly understood. We describe that primary metabolic changes can determine murine MuSC fate decisions. We found that glutamine anaplerosis into the tricarboxylic acid (TCA) cycle decreases during MuSC differentiation and coincides with decreased expression of the mitochondrial glutamate deaminase GLUD1. Deletion of Glud1 in proliferating MuSCs resulted in precocious differentiation and fusion, combined with loss of self-renewal in vitro and in vivo. Mechanistically, deleting Glud1 caused mitochondrial glutamate accumulation and inhibited the malate-aspartate shuttle (MAS). The resulting defect in transporting NADH-reducing equivalents into the mitochondria induced compartment-specific NAD + /NADH ratio shifts. MAS activity restoration or directly altering NAD + /NADH ratios normalized myogenesis. In conclusion, GLUD1 prevents deleterious mitochondrial glutamate accumulation and inactivation of the MAS in proliferating MuSCs. It thereby acts as a compartment-specific metabolic brake on MuSC differentiation. Competing Interests: Declaration of interests The authors declare no competing interests. (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)
Databáze:	MEDLINE
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