A study recently published in the American Journal of Pathology found that R162, a novel enzyme inhibitor, improved muscle function in a mouse model of Duchenne muscular dystrophy (DMD).
Glutamate dehydrogenase (GLUD)-1 is an enzyme that plays a role in converting glutamate, an amino acid, into other compounds necessary for metabolism. Inhibition of GLUD-1 has been shown to promote muscle regeneration after injury by restoring function of the neuromuscular junctions, which are necessary for movement and muscle contraction.
In patients with DMD, the neuromuscular junctions become altered as a result of muscle fiber damage. Therefore, the authors hypothesized that targeting GLUD-1 may be a promising therapeutic avenue in DMD.
In their study, the authors treated a DMD mouse model with R162, a GLUD-1 inhibitor. They then carried out a variety of functional and biochemical tests to assess the effect of GLUD-1 inhibition on disease pathology.
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After four weeks of treatment, the mice exhibited significant improvements in their grip strength, ability to hang from a wire and ability to balance on a rod. Additionally, muscle quality was improved in treated mice.
The study also found that R162 improved the structure of neuromuscular junctions in the mice, with function approaching levels similar to healthy mice.
The authors identified macrophages, a type of cell that plays a role in repairing muscle injury, as a key player in the mechanism of R162, possibly by promoting cell signaling pathways necessary for the function of neuromuscular junctions.
Inhibiting GLUD-1 in macrophages alone, though, was not enough to fully restore muscle function, suggesting that several pathways may be responsible for the mode of action of R162.
“Taken together, these results are the first proof-of-concept that metabolic drugs can be used to treat muscular dystrophies, bypassing the genetic defect by modifying a non-muscle-related function,” the study’s authors concluded.
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