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

Fecha de publicación: 02/08/2024 Fecha Ahead of Print: 02/08/2024

Autores de IIS La Fe

Juan Carlos García Cañaveras

Autor

Participantes ajenos a IIS La Fe

Soro-Arnáiz I
Fitzgerald G
Cherkaoui S
Zhang J
Gilardoni P
Ghosh A
Bar-Nur O
Masschelein E
Maechler P
Zamboni N
Poms M
Cremonesi A
De Bock K
Morscher RJ

Grupos

Unidad de Biomarcadores y Medicina de Precisión (UBYMP)

Leader

Agustín Lahoz Rodríguez

Abstract

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.

Datos de la publicación

ISSN/ISSNe:: 1534-5807, 1878-1551
Tipo:: Article
Páginas:: -
DOI:: 10.1016/j.devcel.2024.07.015
Factor de Impacto:: 4,705 SCImago ℠
Cuartil:: Q1 SCImago ℠

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Filiaciones

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
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