GLUD1 dictates muscle stem cell differentiation by controlling mitochondrial glutamate levels

Abstract

SummaryMuscle stem cells (MuSCs) enable muscle growth and regeneration after exercise or injury. Upon activation MuSCs metabolically rewire to meet the changing demands of proliferation. Here we describe that primary changes in metabolism itself can dictate MuSC fate decisions to control differentiation and fusion. We found that glutamine anaplerosis into the TCA cycle decreases during MuSC differentiation and coincides with decreased expression of the mitochondrial glutamate deaminase GLUD1. Genetic deletion ofGlud1in proliferating MuSCs resulted in precocious differentiation and imbalanced fusion combined with loss of self-renewalin vitroandin vivo. Mechanistically, deletingGlud1caused mitochondrial glutamate accumulation in proliferating MuSCs and inhibited the malate-aspartate shuttle (MAS). Restoring MAS activity by supplementation of alanine normalized differentiation. In conclusion, high GLUD1 activity in proliferating MuSCs prevents deleterious mitochondrial glutamate accumulation and inactivation of the MAS. It thereby acts as a compartment specific metabolic brake on MuSC differentiation.Graphical AbstractHighlightsGlutamine is the major TCA cycle substrate in MuSCs with decreasing contribution upon differentiation.Loss ofGlud1impairs MuSC self-renewal capacity and causes imbalanced fusionin vitroandin vivo.Glud1deletion leads to mitochondrial glutamate trapping and malate-aspartate shuttle (MAS) dysfunction.Restoration of MAS activity inGlud1deficient MuSCs reverses precocious differentiation and imbalanced fusion.