Credit: Sinhyu / iStock / Getty Images Plus
Researchers at the VIB-KU Leuven Center for Brain and Disease Research in Leuven, Belgium, have identified glutamate dehydrogenase 1 (GLUD1) as a novel therapeutic target for restoring muscle function in patients with Duchenne muscular dystrophy (DMD).
DMD is a progressive, X-linked recessive neuromuscular disorder caused by mutations in the DMD gene. As a result, the dystrophin protein, which is essential for maintaining muscle cell health and strength, is either dysfunctional or absent. This causes progressive muscle degeneration and weakness because the muscle cells become susceptible to injury.
Approximately one in 3,500 to 5,000 males born are affected by DMD, with symptoms usually occurring between the ages of two and three. DMD is the most severe and common form of muscular dystrophy. While there are therapies available, the majority of them focus on relieving symptoms or slowing down the progression of DMD.
In their study, published in The American Journal of Pathology under the title “Pharmacologic Inhibition of Glutamate Dehydrogenase 1 Improves Functional Recovery of Neuromuscular Junctions and Muscle Function in Duchenne Muscular Dystrophy,” the researchers wanted to find a way to restore muscle function rather than merely managing DMD symptoms.
“We previously demonstrated that both pharmacological and genetic inhibition of GLUD1 […] in macrophages (a type of immune cell) significantly enhanced muscle regeneration and functional recovery in models of acute injury, ischemia, and aging,” explained lead investigator Massimiliano Mazzone, PhD, of the Laboratory of Tumor Inflammation and Angiogenesis at VIB-KU Leuven.
“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.”
Using preclinical DMD mouse models, the researchers discovered that they could significantly increase muscle strength and coordination by systemically inhibiting the GLUD1 enzyme with the GLUD1 inhibitor R162.
R162 is a cell-permeable, bioavailable chemical compound that directly binds to GLUD1. The researchers used it as a non-steroidal therapeutic approach, using metabolic reprogramming to restore neuromuscular function instead of focusing on the genetic basis of the disease.
“Mechanistically, R162 treatment reprogrammed glutamate metabolism in dystrophic muscles, boosting local glutamate availability, which in turn enhanced neuromuscular junction morphological reorganization and restored acetylcholine levels,” said co-investigator Andreia Pereira-Nunes, PhD, of the Laboratory of Tumor Inflammation and Angiogenesis, VIB-KU Leuven, and Life and Health Sciences Research Institute, Braga in Portugal.
“Importantly, the treatment was well tolerated and showed no adverse effects on body weight, food intake, or behavior.”
“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,” added co-investigator Ummi Ammarah, PhD candidate at the Laboratory of Tumor Inflammation and Angiogenesis, VIB-KU Leuven, and the Molecular Biotechnology Center at the University of Turin in Italy.