Researchers find shortened telomeres linked to dysfunction in Duchenne muscular dystrophy

September 7, 2017
Stem cells. Credit: Penn Medicine

Researchers from the Perelman School of Medicine at the University of Pennsylvania have made a discovery about muscular dystrophy disorders that suggest new possibilities for treatment. In a study published today online in Stem Cell Reports, researchers found that stem cells in the muscles of muscular dystrophy patients may, at an early age, lose their ability to regenerate new muscle, due to shortened telomeres.

Telomeres are tail-like chains of DNA at the ends of chromosomes that protect chromosomes during . In many cell types, telomeres also serve as biological countdown clocks, being shortened with every cell division until their reduced length triggers the death of the cell or an inactive, non-dividing state called senescence. The team found that telomeres specifically in stem are abnormally short in teenage boys with Duchenne Muscular Dystrophy (DMD), as well as in young mice with the same genetic disorder. The finding of shortened telomeres could help explain why prior research has found defects in the functions of muscle stem cells from patients.

"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, PhD, 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. "Due to the DMD, their muscle stem cells are constantly repairing themselves, which means the telomeres are getting shorter at an accelerated rate, much earlier in life. Future therapies that prevent telomere loss and keep muscle stem cells viable might be able to slow the progress of disease and boost muscle regeneration in the patients."

Muscles tend to degenerate in muscular dystrophy disorders because the gene mutations that cause these disorders leave muscle fibers abnormally fragile, so that they are damaged even by ordinary physical activity. In principle, muscle stem cells could regenerate this lost muscle, thereby slowing or even stopping the disease process. But some scientists, including Mourkioti, have suspected that in muscular dystrophy the continuous cycles of muscle damage and repair—requiring near-constant cell division for the muscle stem cells—soon erode the regenerative capacities of muscle stem cells, by shortening their telomeres and inducing early death or senescence.

"The problem with trying to identify what is happening in DMD muscle stem cells is that we've lacked sufficient tools for measuring telomere length in these stem cells," Mourkioti said.

To enable their discovery in DMD patients, Mourkioti and colleagues developed a new stem cell telomere-measuring method, based on an existing technique called fluorescence in situ hybridization (FISH). Telomeres are made of one short sequence of DNA building blocks (TTAGGG) repeated over and over, and the new FISH-based method (MuQ-FISH) uses a fluorescent probe designed to stick specifically to that sequence. Longer telomeres accumulate more probes and fluoresce more brightly. The technique can be used with a microscope and electronic imaging equipment to measure the lengths of telomeres within individual stem cells.

Mourkioti and her team initially used their new technique to show that the telomeres of muscle stem cells are about the same length in healthy lab mice, whether the mice are young or old. In contrast, the scientists found that in young mice with a severe DMD-like disorder as well as in several teenage patients with DMD, muscle stem cells on average had abnormally shortened telomeres. Other non-stem muscle cells in the DMD patients had normal telomere lengths.

The findings suggest that telomere-shortening specifically in muscle stem cells is a factor in the progressive muscle weakening and wasting seen in muscular dystrophy patients. That, in turn, suggests that gene therapy and other treatments now being developed for muscular dystrophies might be more beneficial if administered before muscle stem cells have lost their muscle-regenerating abilities. The findings also point to the possibility that future treatments to block the shortening of telomeres in muscle stem cells might be able to slow or even stop the disease. Mourkioti and colleagues now plan to employ their new method to help them find such a treatment, with an eye toward early intervention, when these stem cells are still capable of making new muscle.

"We are now looking for signaling pathways that affect telomere length in , so that in principle we can develop drugs to block those pathways and maintain length," Mourkioti said. "Currently very little is known about the factors that shorten or maintain telomeres."

There are about 30 distinct muscular dystrophy disorders, all caused by gene mutations that impair the integrity of muscle cells. The most common, DMD, is caused by mutations to a gene on the X-chromosome, and affects one of every fifteen hundred boys born in the United States. Milder muscular dystrophy disorders typically result in lifelong disability. More severe ones, such as DMD, eventually destroy the muscles needed for breathing, and reduce life expectancy to the mid-20s. At present, there is no specific treatment that can stop the progression of these diseases.

Explore further: Duchenne muscular dystrophy is a stem cell disease

Related Stories

Duchenne muscular dystrophy is a stem cell disease

November 16, 2015
A new study from The Ottawa Hospital and the University of Ottawa is poised to completely change our understanding of Duchenne muscular dystrophy and pave the way for far more effective treatments.

Stem cell foundation for muscular dystrophy treatment

July 14, 2011
Research at the Australian Regenerative Medicine Institute (ARMI) at Monash University could lay the groundwork for new muscular dystrophy treatments.

New muscular dystrophy drug target identified

June 1, 2016
Scientists at the University of Liverpool have discovered that muscle cells affected by muscular dystrophy contain high levels of an enzyme that impairs muscle repair. This finding provides a new target for potential drug ...

DNA damage response links short telomeres, heart disorder in Duchenne muscular dystrophy

October 31, 2016
Progressively shortening telomeres—the protective caps on the end of chromosomes—may be responsible for the weakened, enlarged hearts that kill many sufferers of Duchenne muscular dystrophy, according to a study by researchers ...

Promoting muscle regeneration in a mouse model of muscular dystrophy

April 1, 2013
Duchenne muscular dystrophy (DMD) is a degenerative skeletal muscle disease caused by mutations in the protein dystrophin. Dystrophin functions to protect muscle cells from injury and loss of functional dystrophin results ...

Recommended for you

Study finds immune system is critical to regeneration

September 20, 2017
The answer to regenerative medicine's most compelling question—why some organisms can regenerate major body parts such as hearts and limbs while others, such as humans, cannot—may lie with the body's innate immune system, ...

Thousands of new microbial communities identified in human body

September 20, 2017
A new study of the human microbiome—the trillions of microbial organisms that live on and within our bodies—has analyzed thousands of new measurements of microbial communities from the gut, skin, mouth, and vaginal microbiome, ...

Immune cells produce wound healing factor, could lead to new IBD treatment

September 20, 2017
Specific immune cells have the ability to produce a healing factor that can promote wound repair in the intestine, a finding that could lead to new, potential therapeutic treatments for inflammatory bowel disease (IBD), according ...

As men's weight rises, sperm health may fall

September 20, 2017
(HealthDay)—A widening waistline may make for shrinking numbers of sperm, new research suggests.

New model may help science overcome the brain's fortress-like barrier

September 19, 2017
Scientists have helped provide a way to better understand how to enable drugs to enter the brain and how cancer cells make it past the blood brain barrier.

Cell-based therapy success could be boosted by new antioxidant

September 19, 2017
Cell therapies being developed to treat a range of conditions could be improved by a chemical compound that aids their survival, research suggests.

0 comments

Please sign in to add a comment. Registration is free, and takes less than a minute. Read more

Click here to reset your password.
Sign in to get notified via email when new comments are made.