New approach prevents muscular dystrophy damage in mice

Using drug compounds to target specific molecules within muscle cells can ameliorate Duchenne muscular dystrophy in mice, researchers report.

People who have Duchenne muscular dystrophy have a genetic flaw that causes muscle membrane damage, preventing muscle cells from repairing themselves, according to recent research.

Now, researchers have found that targeting a string of molecules called a calcium ion channel in the lysosomes of muscle cells can increase membrane repair, ameliorating muscular dystrophy in mice afflicted with the disease.

“Potentially, all of these forms of muscular dystrophy can be treated in this way.”

Lysosomes are the “recycling bins” of cells. Broken bits of proteins and other damaged organelles go into lysosomes go, and out come recycled amino acids and sugars for the cell to reuse. Within lysosomes, a calcium ion channel called called mucolipin 1, or TRPML1, helps facilitate muscle membrane repair.

In an earlier study, lead author of the new research Haoxing Xu, a professor in the molecular, cellular, and developmental biology department at the University of Michigan, found that mice that lacked this channel in their lysosomes displayed symptoms similar to muscular dystrophy.

In the new study, the researchers found that upregulating TRPML1 using a small molecule drug boosted lysosome function and lessened muscle damage in mice with muscular dystrophy.

“The idea is that if a loss-of-function mutation on this channel causes muscular dystrophy, then increasing channel activity or expression with a small molecule drug may be a way to reduce muscle damage in muscular dystrophy,” says Xu.

Researchers from the National Institutes of Health’s National Center for Advancing Translational Sciences (NCATS) carried out high-throughput screening and medicinal chemistry studies to produce the first-in-class TRPML1 activator that they tested in cell and animal models. The researchers report that activating TRPML1 either genetically or using pharmaceutical compounds protected muscle cells in mice with muscular dystrophy.

They found that both skeletal and heart muscle tissues were protected in the mice. The team then applied the same small molecule compounds to human muscle cells from patients with Duchenne muscular dystrophy. They found similar protective effects.

In recent years, researchers have tested gene therapy and genome editing approaches to treating muscular dystrophy, but because there are thousands of gene mutations that could prompt the disease, that approach is challenging, Xu says. Targeting the ion channel, present in all muscle cells, could provide a broader reach to treating the disease.

“Potentially, all of these forms of muscular dystrophy can be treated in this way,” Xu says. “This drug approach can target all muscle cells.”

“We believe that TRPML1 activators can be useful for the treatment of multiple neurodegenerative disorders as well,” says Juan Marugan of NCATS.

These researchers have patented the TRPML1 compounds and are ready for licensing to the pharmaceutical industry.

The research appears in Science Advances.

Source: University of Michigan

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