Researchers observe mesenchymal stem (or stromal) cells on a microscope. University of Ottawa researchers say that defective stem cells are the cause of a form of muscular dystrophy.Fred Lum/The Globe and Mail
Canadian researchers have made a discovery about muscle stem cells that may lead to more effective treatments for Duchenne muscular dystrophy, a degenerative disease that primarily affects boys.
The genetic disease causes muscles to deteriorate over time due to a lack of dystrophin, a protein involved in the repair of muscle fibres damaged by injury, exercise or just the tasks of everyday living.
Those affected by Duchenne muscular dystrophy, which occurs in about one in 3,600 births, typically die in their late 20s or early 30s, usually of respiratory failure or cardiac disease caused by weakened and scarred lung or heart muscles.
"For nearly 20 years, we've thought that the muscle weakness observed in patients with Duchenne muscular dystrophy is primarily due to problems in their muscle fibres, but our research shows that it is also due to intrinsic defects in the function of their muscle stem cells," said senior author Dr. Michael Rudnicki, director of the regenerative medicine program at the Ottawa Hospital Research Institute.
"This completely changes our understanding of Duchenne muscular dystrophy and could eventually lead to far more effective treatments."
Rudnicki's team determined that the protein dystrophin is present not only in muscle fibres, but also in muscle stem cells. Those stem cells give rise to precursor cells, which in turn generate new fibres to build and repair muscles throughout the body.
But in Duchenne muscular dystrophy, the stem cells are deficient in dystrophin, Rudnicki said.
"So the loss of dystrophin in the muscle fibres causes the muscle degeneration, and the loss of dystrophin in the stem cells means that they can't repair that damage," he said from Ottawa.
"And so the two together produce the full-blown disease."
Without the protein, stem cells produce ten-fold fewer muscle precursor cells, he said.
The study, published Monday in the journal Nature Medicine, was conducted in mouse cells, but the findings are expected to be the same in humans.
Rudnicki said the discovery should have profound implications for treating the disease.
"I think that down the road, it's possible we will be able to repair those deficiencies of the stem cells using drugs," he said. "If we can repair the stem cell deficit ... that may well significantly ameliorate the disorder."
That's the hope of Debra Chiabai, whose 15-year-old son Alex has Duchenne muscular dystrophy and now must use a wheelchair full time as his legs are too weak to allow him to walk.
Alex is able to attend school on a reduced schedule, but has to be helped onto the toilet and into the shower, although he is able to shower himself.
"Because it's progressive, those are things over the years that would be changing for him," Chiabai said from Ottawa.
Her son takes steroids, which help reduce inflammation and subsequent scarring in his muscles, but the drugs have side-effects that include stunted growth, cataract formation and bone loss.
"It doesn't stop things. It just hopefully gains a little bit more time," said Chiabai, conceding that her son's physical deterioration is "hard to watch."
With the new discovery, she hopes scientists will be able to zero in on drugs that target the lack of dystrophin in stem cells and prolong the lives of those affected.
"Frankly, we live, breathe and eat hope because if you had to just deal with it with no hope on the horizon, it would be pretty overwhelming."
Dr. Ronald Worton, who headed the Toronto Sick Kids Hospital team that isolated the mutated gene behind Duchenne muscular dystrophy in 1986, lauded the discovery that muscle stem cells are also involved in the disease.
Worton, now retired, said that even with the dystrophin gene identified, "it became clear to us and I guess to all scientists in the field that this was going to be really tough to fix."
"This discovery from Michael (Rudnicki) is a pretty big step in thinking about how do we stimulate the regeneration of muscle?" said Worton, suggesting that the feat might be accomplished in the future with cell therapy or the development of a drug treatment.
"And even if it doesn't totally block the disease or cure the disease, if you can keep the kids alive until they're 50 instead of 20 and let them have reasonable mobility, even if they're in a wheelchair but could feed themselves and breathe properly, that would be a big step forward."