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

Year: 2024

Type: article

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.

Source: Repository for Publications and Research Data (ETH Zurich)

DOI: 10.3929/ethz-b-000703982

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

Language: English

Topic: Muscle Physiology and Disorders

Subfield: Molecular Biology

Field: Biochemistry, Genetics and Molecular Biology

Domain: Life Sciences

SDG: Good health and well-being

Open Access status: green

OpenAlex ID: W6910038056

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