Pharmacologic Inhibition of Glutamate Dehydrogenase 1 Improves Functional Recovery of Neuromuscular Junctions and Muscle Function in Duchenne Muscular Dystrophy

Presynaptic terminals of neuromuscular junctions (NMJs) are sensitive to glutamate, which contributes to NMJ plasticity and synaptic neurotransmission. However, the effect of glutamate on neurotransmission and its pharmacologic modulation in muscle pathologies are understudied. In this study, the ef...

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Vydáno v:	The American journal of pathology Ročník 195; číslo 8; s. 1537
Hlavní autoři:	Pereira-Nunes, Andreia, Ammarah, Ummi, Shang, Min, Charatsidou, Iris, Sharma, Himal, Pereira Sorroche, Bruna, Nobis, Max, Burg, Thibaut, Verschoren, Stijn, Relaix, Frédéric, Rotini, Alessio, Van Den Bosch, Ludo, Delfini, Marcello, Berardi, Emanuele, Mazzone, Massimiliano
Médium:	Journal Article
Jazyk:	angličtina
Vydáno:	United States 01.08.2025
Témata:	Animals Disease Models, Animal Enzyme Inhibitors - pharmacology Glutamate Dehydrogenase - antagonists & inhibitors Glutamate Dehydrogenase - metabolism Glutamic Acid - metabolism Male Mice Mice, Inbred C57BL Mice, Inbred mdx Muscle Contraction - drug effects Muscle, Skeletal - drug effects Muscle, Skeletal - physiopathology Muscular Dystrophy, Duchenne - drug therapy Muscular Dystrophy, Duchenne - enzymology Muscular Dystrophy, Duchenne - pathology Muscular Dystrophy, Duchenne - physiopathology Neuromuscular Junction - drug effects Recovery of Function - drug effects Synaptic Transmission - drug effects
ISSN:	1525-2191, 1525-2191
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Popis
Shrnutí:	Presynaptic terminals of neuromuscular junctions (NMJs) are sensitive to glutamate, which contributes to NMJ plasticity and synaptic neurotransmission. However, the effect of glutamate on neurotransmission and its pharmacologic modulation in muscle pathologies are understudied. In this study, the efficacy of pharmacologic blockade of glutamate dehydrogenase (GLUD)-1 was investigated in mdx mice, a model of Duchenne muscular dystrophy. The GLUD1 inhibitor R162 mitigated the malfunctioning of NMJs by enhancing glutamate release from muscle fibers and increasing its availability in the muscle interstitium. Glutamate binding to its N-methyl-d-aspartate receptor on the presynaptic bottom of NMJs resulted in the increased release of acetylcholine and functional recovery of the action potential and muscle contraction, ultimately improving muscle performance. Finally, the GLUD1 inhibitor did not affect the homeostatic control of NMJs and the behavior of either healthy or dystrophic mice. This study suggests a promising and feasible therapeutic approach, based on muscle glutamate exploitation, to treating Duchenne muscular dystrophy, an unmet need in the clinic.
Bibliografie:	ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23
ISSN:	1525-2191 1525-2191
DOI:	10.1016/j.ajpath.2025.05.003