Groundbreaking Study Offers a Novel Approach to Enhance Neuromuscular Function in Patients with Duchenne Muscular Dystrophy

New research has identified the enzyme glutamate dehydrogenase 1 (GLUD1) as a new therapeutic target for Duchenne muscular dystrophy (DMD). In preclinical DMD mouse models, investigators demonstrated that inhibiting GLUD1 significantly enhances muscle strength and coordination, signaling a potential shift towards restoring muscle function rather than just managing symptoms. The groundbreaking study in The American Journal of Pathology, published by Elsevier, points towards a promising and feasible pathway to treat DMD based on muscle glutamate exploitation, addressing a clinically unmet need.

Muscular dystrophy comprises a group of genetic muscle degenerative disorders leading to progressive muscle wasting. DMD is the most common and severe form of muscular dystrophy, affecting 1 in 3,500–5,000 live male births globally. The underlying defects in the dystrophin gene cause muscle fiber disruption and chronic waves of muscle degeneration and regeneration. This results in the accumulation of inflammatory cells, fibrosis, and dysfunction of muscle precursors, ultimately leading to loss of muscle mass and function. The therapeutic approach for DMD is mainly focused on the relief of symptoms through treatment with glucocorticoids.

Lead investigator Prof. Massimiliano Mazzone, PhD, Laboratory of Tumor Inflammation and Angiogenesis, VIB-KU Leuven, Leuven, Belgium, says, “We previously demonstrated that both pharmacological and genetic inhibition of GLUD1 – an enzyme that converts L-glutamate into α-ketoglutarate and vice versa – in macrophages (a type of immune cells) significantly enhanced muscle regeneration and functional recovery in models of acute injury, ischemia, and aging. Given the lack of a definitive cure for DMD and the limited effectiveness of current therapies, which primarily aim to slow disease progression and improve quality of life, we were eager to investigate whether targeting GLUD1 could offer novel therapeutic insights specifically for this disease.”

Researchers investigated the therapeutic potential of targeting glutamate metabolism in DMD using the GLUD1 inhibitor R162. In a preclinical DMD mouse model (mdx mice), systemic R162 treatment significantly enhanced muscle strength and coordination.

Co-lead investigator Emanuele Berardi, PhD, Laboratory of Tumor Inflammation and Angiogenesis, VIB-KU Leuven, and Tissue Engineering Lab, KU Leuven, Leuven, Belgium, explains, “This functional recovery was linked to reduced muscle damage, enhanced myogenic potential of satellite cells, and restoration of neuromuscular junction (NMJ) structure and function. Interestingly, while GLUD1 inhibition in macrophages alone promoted satellite cell activation, it was not sufficient to restore muscle function, highlighting the essential but not standalone role of macrophages in muscle regeneration. We further demonstrated that macrophages are required to mediate the full therapeutic effect of R162, particularly in supporting NMJ remodeling.”

Co-investigator Andreia Pereira-Nunes, PhD, Laboratory of Tumor Inflammation and Angiogenesis, VIB-KU Leuven, Leuven, Belgium, and Life and Health Sciences Research Institute (ICVS), Braga, Portugal, adds, “Mechanistically, R162 treatment reprogrammed glutamate metabolism in dystrophic muscles, boosting local glutamate availability, which in turn enhanced NMJ morphological reorganization and restored acetylcholine levels. Importantly, the treatment was well tolerated and showed no adverse effects on body weight, food intake, or behavior.”

This study introduces a novel, non-steroidal therapeutic approach that does not target the genetic defect of DMD directly but instead enhances the neuromuscular function through metabolic reprogramming. The dual therapeutic action of R162 in enhancing both muscle precursor cell (satellite cell) function and neurotransmission offers a promising and potentially translatable approach to improving patient outcomes, particularly given its efficacy and safety in dystrophic mice used to study DMD.

Co-investigator Ummi Ammarah, PhD candidate, Laboratory of Tumor Inflammation and Angiogenesis, VIB-KU Leuven, Leuven, Belgium, and Molecular Biotechnology Center, University of Turin, Turin, Italy, concludes, “Our results provide the first proof-of-concept that metabolic drugs can be effectively used to treat muscular dystrophies, offering a novel strategy by bypassing the genetic defect and modifying a non-muscle–related function.”

Notes for editors

The article is “Pharmacologic Inhibition of Glutamate Dehydrogenase 1 Improves Functional Recovery of Neuromuscular Junctions and Muscle Function in Duchenne Muscular Dystrophy,” by Andreia Pereira-Nunes, Ummi Ammarah, Min Shang, Iris Charatsidou, Himal Sharma, Bruna Pereira Sorroche, Max Nobis, Thibaut Burg, Stijn Verschoren, Frédéric Relaix, Alessio Rotini, Ludo Van Den Bosch, Marcello Delfini, Emanuele Berardi, and Massimiliano Mazzone (https://doi.org/10.1016/j.ajpath.2025.05.003). It appears online ahead of The American Journal of Pathology, volume 195, issue 8 (August 2025), published by Elsevier.

The article is openly available at https://ajp.amjpathol.org/article/S0002-9440(25)00185-3/fulltext.

Full text of the article is also available to credentialed journalists upon request. Contact Eileen Leahy at +1 732 406 1313 or [email protected] to request a PDF of the article or more information. To reach the study’s authors, contact [email protected] or Joran Lauwers, Media Relations, VIB, at [email protected].

The study was supported by the ERC Consolidator Immunofit grant, FWO research grant G011124N, AFM-Téléthon grant 23117, the Patient Association "KanGO! Fund”, "Rondou fund for Duchenne Research" and Duchenne Parent Project Netherlands grant 22.002, FCT fellowship SFRH/BD/148476/2019, Key Research and Development Program of Zhejiang Province grant 2025C02163, FWO fellowships 11PRZ24N and 1SH4S24N, and FWO senior postdoctoral grant 12AIK24N.

About The American Journal of Pathology

The American Journal of Pathology, official journal of the American Society for Investigative Pathology, published by Elsevier, seeks high-quality original research reports, reviews, and commentaries related to the molecular and cellular basis of disease. The editors will consider basic, translational, and clinical investigations that directly address mechanisms of pathogenesis or provide a foundation for future mechanistic inquiries. Examples of such foundational investigations include data mining, identification of biomarkers, molecular pathology, and discovery research. High priority is given to studies of human disease and relevant experimental models using molecular, cellular, and organismal approaches. ajp.amjpathol.org

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