GLUD1 determines murine muscle stem cell fate by controlling mitochondrial glutamate levels,Developmental Cell

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GLUD1 determines murine muscle stem cell fate by controlling mitochondrial glutamate levels
Developmental Cell ( IF 10.7 ) Pub Date : 2024-08-08 , DOI: 10.1016/j.devcel.2024.07.015
Inés Soro-Arnáiz ₁ , Gillian Fitzgerald ₂ , Sarah Cherkaoui ₃ , Jing Zhang ₁ , Paola Gilardoni ₁ , Adhideb Ghosh ₄ , Ori Bar-Nur ₅ , Evi Masschelein ₁ , Pierre Maechler ₆ , Nicola Zamboni ₇ , Martin Poms ₈ , Alessio Cremonesi ₈ , Juan Carlos Garcia-Cañaveras ₉ , Katrien De Bock ₁ , Raphael Johannes Morscher ₁₀

Affiliation

Laboratory of Exercise and Health, Department of Health Sciences and Technology, Swiss Federal Institute of Technology (ETH Zurich), Schwerzenbach, 8603 Zurich, Switzerland.
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.
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.
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.
Laboratory of Regenerative and Movement Biology, Department of Health Sciences and Technology, ETH Zurich, Schwerzenbach, 8603 Zurich, Switzerland.
Department of Cell Physiology and Metabolism, University of Geneva Medical Center, 1211 Geneva, Switzerland.
Institute of Molecular Systems Biology, ETH Zurich, 8049 Zurich, Switzerland.
Division of Clinical Chemistry and Biochemistry, University Children's Hospital Zurich, University of Zurich, 8032 Zurich, Switzerland.
Biomarkers and Precision Medicine Unit, Health Research Institute-Hospital La Fe, 46026 Valencia, Spain.
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.

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.

中文翻译：

GLUD1 通过控制线粒体谷氨酸水平来决定小鼠肌肉干细胞的命运

肌肉干细胞（MuSCs）能够在运动或受伤后促进肌肉生长和再生，但人们对新陈代谢如何控制其再生潜力知之甚少。我们描述了原发性代谢变化可以决定小鼠 MuSC 命运的决定。我们发现，在 MuSC 分化过程中，谷氨酰胺对三羧酸（TCA）循环的疏离减少，并且与线粒体谷氨酸脱氨酶 GLUD1 的表达降低相吻合。增殖的 MuSCs 中 Glud1 的缺失导致性早熟分化和融合，同时在体外和体内自我更新丧失。从机制上讲，删除 Glud1 导致线粒体谷氨酸积累并抑制苹果酸-天冬氨酸穿梭（MAS）。将 NADH 还原当量运输到线粒体中诱导的区室特异性 NAD+/NADH 比率的缺陷发生了变化。MAS 活性恢复或直接改变 NAD + / NADH 比率使肌生成正常化。总之，GLUD1 可防止有害的线粒体谷氨酸积累和增殖 MuSC 中 MAS 的失活。因此，它充当 MuSC 分化的区室特异性代谢制动器。

更新日期：2024-08-08

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