Telomere shortening is associated with muscular dystrophy


Muscular dystrophy (MD) refers to a group of muscle diseases characterized by progressive muscle weakening and wasting. The most common type of MD is Duchenne muscular dystrophy (DMD), which happens more frequently in boys.

According to a study published in Stem Cell Reports, the progressive muscle weakening and wasting seen in muscular dystrophy patients are associated with telomere shortening specifically in muscle stem cells. The finding supports that drugs that prevent telomere shortening and preserve muscle stem cell may be used to treat muscular dystrophy patients.

The corresponding author of the study is Dr. Foteini Mourkioti from the University of Pennsylvania, whose lab is aimed to uncover the fundamental aspects of skeletal muscle and cardiac function in health and disease.

A telomere is a structure at the end of a chromosome, composed of a repetitive DNA sequence (TTAGGG). Its main function is to stabilize the chromosome. Each time a cell divides, telomeres shorten. When telomeres get too short, the cell ceases to divide, a state known as senescence. So, telomere shortening is thought to be a biological clock that controls the number of self-renewing divisions within individual cells.

Muscle stem cells, present in skeletal muscle tissue, can self-renew and give rise to skeletal muscle cells. Many factors can cause muscle injury, such as weight bearing, exercise, trauma, and certain diseases. Muscle stem cells are responsible for muscle repair and regeneration when the muscle is injured. However, in severe illnesses like DMD, this regenerative capacity is exhausted.

It has been proposed that in MD, the continuous muscle damage requires muscle stem cells to divide rapidly, and this eventually exhausts the regeneration capacity of muscle stem cells by shortening their telomeres and inducing senescence.

However, no methods are available to accurately measure telomere length in muscle stem cells. To solve this, Dr. Mourkioti's team developed a novel detection method by optimizing the common technique FISH. The novel method, called MuQ-FISH, uses a fluorescent probe specific to the DNA sequence (TTAGGG) in telomeres. The longer the telomere is, the more fluorescent probes gather at it. By detecting the fluorescent signal, the researchers were enabled to measure the length of telomeres in cells.

With the help of MuQ-FISH, the researchers analyzed telomere length in muscle stem cells from uninjured wild-type mice as well as dystrophic mice. The results showed that there was no difference in telomere length between young and old wild-type mice, whereas young dystrophic mice had significantly shorter telomeres.

Next, the researchers examined muscle stem cells from 3 healthy people and 3 young DMD patients. They found that young DMD patients also had shorter telomeres in their muscle stem cells. Importantly, telomere length was normal in non-stem muscle cells.

These data demonstrate that telomere shortening specifically in muscle stem cells may help explain the regenerative failure in MD. So preventing telomeres from shortening and preserving muscle stem cells' regeneration capacity may be a treatment strategy for MD.
 
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