Duchenne muscular dystrophy (DMD) is an X-linked disorder that affects one in every fifteen hundred boys born in the United States and currently has no known treatment. Researchers from the Perelman School of Medicine at the University of Pennsylvania have now found that shortened telomeres in muscle stem cells of people with muscular dystrophy may be limiting the muscle’s ability to regenerate, opening the door for potential new treatment targets. The findings were published online yesterday in Stem Cell Reports.
In muscular dystrophy disorders, gene mutations leave muscle fibers abnormally fragile, so that they are damaged even by ordinary physical activity. While muscle stem cells should be able to regenerate the lost muscle, slowing the disease, this is not the case. Some scientists have thus suspected that the constant cycles of muscle damage and repair erode the regenerative properties of these muscle stem cells by shortening their telomeres and inducing early senescence.
To enable their discovery, the research team developed a new stem cell telomere-measuring method, based on fluorescence in situ hybridization (FISH). The method (MuQ-FISH) uses a fluorescent probe designed to stick specifically to the repeating sequence that makes up telomeres. Using a microscope and electronic imaging equipment, the researchers were able to determine which telomeres were longer based on the intensity of the fluorescence.
Using this technique, the team first showed that the telomeres of muscle stem cells are about the same length in healthy lab mice, regardless of age. In contrast, young mice with a severe DMD-like disorder as well as in several teenage patients with DMD, the muscle stem cells on average had abnormally shortened telomeres.
"We found that in boys with DMD, the telomeres are so short that the muscle stem cells are probably exhausted," said the study's senior author, Foteini Mourkioti, Ph.D., an assistant professor of orthopaedic surgery and cell and developmental biology, and co-director of the Musculoskeletal Regeneration Program in the Penn Institute for Regenerative Medicine.
This discovery suggests that gene therapy and other treatments for muscular dystrophies may be administered most effectively early on, before muscle stem cells have weakened. It also points to telomeres as a potential target for future therapies. In the future, Mourkioti and the rest of the team plan to work on such treatments and learn more about the factors that shorten or maintain telomeres.
Image of stem cells courtesy of Penn Medicine.