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Metabolite Compound Delays Progression of Duchenne Muscular Dystrophy in Mice

Duchenne muscular dystrophy (DMD) is a genetic disorder characterized by progressive muscle degeneration and weakness due to the alterations of a protein called dystrophin that helps keep muscle cells intact. Until recently, boys with DMD usually did not survive much beyond their teen years. Advances in cardiac and respiratory care have increased life expectancy and have increased survival into the early 30s.

There are strategies in DMD, such as gene therapy, exon skipping, stop codon read-through, and gene repair. A new study reports a promising treatment that may one day be developed for DMD. Researchers from the Swiss Federal Institute of Technology EPFL and the University of Lausanne in collaboration with scientists at the Swiss life science company Amazentis have demonstrated how progression of DMD can be delayed in mouse models by supplementing their diets with a metabolite compound, Urolithin A.

Their findings are published in the journal Science Translational Medicine, in a paper titled, “Urolithin A improves muscle function by inducing mitophagy in muscular dystrophy.”

The mitochondria, often labeled the powerhouse of the cell, are the organelle responsible for energy production within the cell. Mitochondrial dysfunction has been implicated in DMD. The researchers studied the role of mitochondrial autophagy in muscle stem cells and DMD.

“Mitochondrial dysfunction contributes to DMD, yet the mechanisms by which this occurs remain elusive,” wrote the researchers. “Our data in experimental models and patients with DMD show that reduced expression of genes involved in mitochondrial autophagy, or mitophagy, contributes to mitochondrial dysfunction.”

“Duchenne muscular dystrophy is the most common fatal genetic disease diagnosed in childhood with still no cure available,” explained Johan Auwerx, MD, PhD, lead author and professor at the EPFL. “Our work represents a significant breakthrough in the search for new therapeutic approaches for muscular dystrophies.”

When the scientists fed the compound to DMD mice for just 10 weeks, they saw mitophagy levels rise effectively restoring them to normal. The natural compound Urolithin A is known to activate mitophagy and improve mitochondrial health in both mice and humans.

The scientists observed a reduction of muscle damage and improvement in muscle health and performance. The DMD mice administered Urolithin A saw grip strength increase by 31%, running performance increase by 45%, and survival increased by 40% compared to the control group.

An important observation was that Urolithin A reduced fibrosis in muscles of the DMD mouse heart and diaphragm by 36% and 39%, and enhance regeneration of mouse muscle stem cells.

“Prior to this study, it was understood that the dramatic loss of muscle function in DMD patients was associated with mitochondrial dysfunctions. Here we discovered that defective mitophagy, the removal and recycling of dysfunctional mitochondria, plays a key role in the progression of DMD,” noted Davide D’Amico, PhD, project leader at Amazentis and first author of the study.

These findings show that Urolithin A can support not only healthy muscle, but also provide hope for a potential treatment for DMD and progressive muscle diseases.

“These data indicate that restoration of mitophagy alleviates symptoms of DMD and suggest that UA may have potential therapeutic applications for muscular dystrophies,” concluded the researchers.

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