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

被引：2

作者：

Soro-Arnaiz, Ines ^{[1
]}

Fitzgerald, Gillian ^{[1
,2
,3
,4
]}

Cherkaoui, Sarah ^{[2
,3
,4
]}

Zhang, Jing ^{[1
]}

Gilardoni, Paola ^{[1
]}

Ghosh, Adhideb ^{[5
,6
,7
]}

Bar-Nur, Ori ^{[5
]}

Masschelein, Evi ^{[1
]}

Maechler, Pierre ^{[8
]}

Zamboni, Nicola ^{[9
]}

Poms, Martin ^{[10
]}

Cremonesi, Alessio ^{[10
]}

Garcia-Canaveras, Juan Carlos ^{[11
]}

De Bock, Katrien ^{[1
]}

Morscher, Raphael Johannes ^{[2
,3
,4
,12
]}

机构：

[1] Swiss Fed Inst Technol, Dept Hlth Sci & Technol, Lab Exercise & Hlth, Schwerzenbach,Swiss Fed Inst Technol, CH-8603 Zurich, Switzerland

[2] Univ Zurich, Childrens Res Ctr, Pediat Canc Metab Lab, CH-8032 Zurich, Switzerland

[3] Univ Childrens Hosp Zurich, Div Oncol, CH-8032 Zurich, Switzerland

[4] Univ Zurich, Childrens Res Ctr, CH-8032 Zurich, Switzerland

[5] Swiss Fed Inst Technol, Dept Hlth Sci & Technol, Lab Regenerat & Movement Biol, Schwerzenbach, CH-8603 Zurich, Switzerland

[6] Swiss Fed Inst Technol, Funct Genom Ctr Zurich, CH-8032 Zurich, Switzerland

[7] Univ Zurich, CH-8032 Zurich, Switzerland

[8] Univ Geneva, Med Ctr, Dept Cell Physiol & Metab, CH-1211 Geneva, Switzerland

[9] Swiss Fed Inst Technol, Inst Mol Syst Biol, CH-8049 Zurich, Switzerland

[10] Univ Zurich, Univ Childrens Hosp Zurich, Div Clin Chem & Biochem, CH-8032 Zurich, Switzerland

[11] Hosp La Fe, Hlth Res Inst, Biomarkers & Precis Med Unit, Valencia 46026, Spain

[12] Med Univ Innsbruck, Div Human Genet, A-6020 Innsbruck, Austria

来源：

DEVELOPMENTAL CELL | 2024年 / 59卷 / 21期

关键词：

SKELETAL-MUSCLE; SATELLITE CELLS; SELF-RENEWAL; METABOLISM; EXPRESSION; HETEROGENEITY; REQUIREMENT; QUIESCENT; PROTEIN; ACID;

D O I：

10.1016/j.devcel.2024.07.015

中图分类号：

Q2 [细胞生物学];

学科分类号：

071009 ; 090102 ;

摘要：

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.

引用

页码：2850 / 2865.e8

页数：25

共 71 条

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