By Gail Balfour, Muscular Dystrophy Canada
Late last year, a breakthrough study out of Ottawa made headlines around the globe as the first to show that Duchenne muscular dystrophy (DMD) directly affects muscle stem cells – findings that are already changing long-held beliefs around the causes of the disease.
The study, entitled “Dystrophin expression in muscle stem cells regulates their polarity and asymmetric division” was published in Nature Medicine on November 16, 2015. The research concluded that muscle wasting in DMD not only is caused by myofiber fragility, but also is made worse by impaired regeneration due to satellite cell dysfunction.
“For nearly 20 years, we’ve thought that the muscle weakness observed in patients with Duchenne muscular dystrophy was primarily due to problems in their muscle fibres,” said Dr. Michael Rudnicki, senior author of the study, and director of the Regenerative Medicine Program at The Ottawa Hospital. “But our research shows that it is also due to intrinsic defects in the function of their muscle stem cells.”
According to Dr. Rudnicki, who is also a professor at the University of Ottawa, these research findings “completely change our understanding of Duchenne muscular dystrophy, and could eventually lead to far more effective treatments.”
DMD is caused by genetic mutations that result in the loss of the dystrophin protein, leading to progressive muscle weakness, and death by the second or third decade of life.
For many years, dystrophin was thought to be a simple structural protein only found in muscle fibres. But in this study, Dr. Rudnicki and his team discovered that muscle stem cells also express the dystrophin protein, and without this protein, they produce ten-fold fewer muscle precursor cells – which in turn generate fewer functional muscle fibres. They also discovered that dystrophin is a key piece of the molecular machinery that enables muscle stem cells to sense their orientation in surrounding tissue.
“Muscle stem cells that lack dystrophin cannot tell which way is up and which way is down,” said Dr. Rudnicki. “This is crucial because muscle stem cells need to sense their environment to decide whether to produce more stem cells or to form new muscle fibres. Without this information, muscle stem cells cannot divide properly and cannot properly repair damaged muscle.”
This research was conducted in mouse cells, but it is expected that the findings will hold in humans, as the dystrophin protein is very similar in all mammals.
Current treatments for Duchenne muscular dystrophy are limited to steroids and physical therapy that slow disease progression and lessen symptoms. Experimental approaches such as gene therapy are also being investigated, but Dr. Rudnicki’s research suggests that these approaches will need to be modified so that they target muscle stem cells as well as muscle fibres.
“We’re already looking at approaches to correct this problem in muscle stem cells,” said Dr. Rudnicki. “I’m not sure if we will ever cure Duchenne muscular dystrophy, but I’m very hopeful that someday in the future, we will have new therapies that correct the ability of muscle stem cells to repair the muscles of afflicted patients and turn this devastating, lethal disease into a chronic but manageable condition.”
The study was funded by the U.S. National Institutes of Health, the Canadian Institutes of Health Research, Muscular Dystrophy Canada, the Muscular Dystrophy Association (U.S.), the Stem Cell Network, the Canada Research Chairs program, the Ontario Ministry of Research and Innovation, Deutsche Forschungsgemeinschaft, the Swiss National Science Foundation and The Ottawa Hospital Foundation.
Note, the above article was republished and is copyrighted from Research in the Works, a Muscular Dystrophy Canada annual publication. For more information, visit www.muscle.ca/respiratory.
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