Targeting GLUD1: A Promising Approach for Duchenne Muscular Dystrophy Treatment

Recent research led by Prof. Massimiliano Mazzone, PhD, from the Laboratory of Tumor Inflammation and Angiogenesis at VIB-KU Leuven, has identified glutamate dehydrogenase 1 (GLUD1) as a promising therapeutic target in the treatment of Duchenne muscular dystrophy (DMD). This study, published in the American Journal of Pathology on July 17, 2025, illustrates the potential of inhibiting GLUD1 to restore muscle function and strength in affected individuals.

Duchenne muscular dystrophy, a severe form of muscular dystrophy, affects approximately 1 in 3,500 to 5,000 live male births globally. It is characterized by genetic mutations that lead to the absence of dystrophin, a protein essential for muscle fiber integrity, resulting in progressive muscle degeneration. Current treatments predominantly focus on symptom management rather than addressing the underlying muscle degeneration.

In their preclinical studies using mdx mice, a model for DMD, researchers administered the GLUD1 inhibitor R162. The findings revealed that systemic treatment with R162 significantly enhanced muscle strength and coordination. According to Emanuele Berardi, PhD, a co-lead investigator, this functional recovery was associated with reduced muscle damage and improved myogenic potential of satellite cells, crucial for muscle regeneration. The restoration of neuromuscular junction (NMJ) structure and function was also noted, underscoring the multifaceted role of GLUD1 inhibition in muscle health.

The innovative approach of targeting glutamate metabolism offers a novel strategy for DMD treatment. Rather than directly addressing the genetic defect, the research suggests that enhancing neuromuscular function through metabolic reprogramming can yield significant benefits. As Andreia Pereira-Nunes, PhD, another co-investigator, highlights, the treatment resulted in the reprogramming of glutamate metabolism in dystrophic muscles, leading to improved NMJ morphology and neurotransmitter function.

This research presents a dual therapeutic action: improving satellite cell function while enhancing neurotransmission, which could translate into better patient outcomes. Ummi Ammarah, a PhD candidate involved in the study, emphasizes that the results serve as proof-of-concept for the efficacy of metabolic drugs in treating muscular dystrophies, providing an alternative pathway that bypasses the genetic defect.

Overall, the study posits that targeting GLUD1 may pave the way for new therapeutic strategies in DMD, addressing a critical unmet need in the management of this debilitating disease. The findings not only challenge the conventional treatment paradigms but also highlight the need for continued research into metabolic interventions as viable treatment options.

As the research community continues to explore these new avenues, the implications for DMD patient care could be profound, potentially enhancing quality of life and muscle function for those affected by this condition. Future studies will be essential to evaluate the long-term efficacy and safety of GLUD1 inhibition in human clinical trials, which may lead to regulatory approvals and clinical applications in the near future.