“Muscle-wasting disorders represent a huge unmet clinical need. There is really no good pharmacological method, either with a drug or a biologic, for enhancing muscle repair.”
– Michael Rudnicki
Many of us take our muscles for granted, particularly when it comes to the simple things they help us do, such as standing, walking, catching a baseball or breathing. But have you ever stopped to wonder what life would be like if they failed and wasted away?
This is the daily reality for young men suffering from Duchenne muscular dystrophy (DMD). Triggered by a mutation in the dystrophin gene, this X-linked genetic disorder affects one in every 3,500 live male births. Normally, the gene’s coded protein, dystrophin, acts as an anchor between the contracting muscle and its surrounding environment, stabilizing the muscle. In DMD patients, however, the lack of dystrophin creates a fragile muscle that tears at every contraction. The ongoing damage culminates in crippling muscle degeneration, leaving the muscle weak and wasted. Beginning in the legs, this insidious disease makes its slow and relentless way up the body, eventually leading to near-total muscle paralysis. There is no cure, only treatment to ease symptoms, improve quality of life and slow disease progress. Most patients do not live to see their 30th birthday. Still, there is hope.
In December 2012, a team led by Michael Rudnicki, a senior scientist at the Ottawa Hospital Research Institute and a pioneer in muscle stem cell biology, published its findings on a new candidate for therapy, a protein secreted by muscle. Rudnicki’s laboratory had previously established that the protein, called Wnt7a, plays a role in expanding muscle stem cell numbers—the same cells responsible for the muscle’s regenerative capabilities—while simultaneously enlarging pre-existing and newly generated muscle tissue.
“We had already documented the effect of Wnt7a in healthy mice,” says Rudnicki, a professor in the Faculty of Medicine at the University of Ottawa who holds the Canada Research Chair in Molecular Genetics. “But we were very interested in learning whether or not it would also function in mice with muscular dystrophy.”
To test this theory, purified Wnt7a protein was injected directly into the muscles of mice carrying the mutant dystrophin gene. As with fit mice, the researchers noted an increase in total muscle mass and muscle strength in the mutant animals. Amazingly, the number of muscle stem cells nearly doubled.
“Wnt7a augments and accelerates repair in a very striking manner,” says Rudnicki. “And because it is a mechanism normally used by the body, there appears to be no downside at this point.”
But that’s not all this protein can do. The team also discovered a shift in the muscle cell composition of treated mutant mice, from fast twitch muscle fibre, used for bursts of speed and power, to more slow twitch fibre, required for sustained low-force contractions. Most notably, slow twitch cells are less susceptible to contraction-induced tearing, the same tearing at the heart of DMD.
“We are not curing the genetic basis for the disease,” says Rudnicki. “What we are doing is stimulating repair. If one can stimulate repair to a high enough degree you don’t need to cure the genetic basis, you just have ongoing repair.”
The team further validated its findings in human cells. When treated with Wnt7a, healthy cultured human muscle cells responded in exactly the same way as in mice.
So what does the future hold for Wnt7a? While it may be too early to tell, Rudnicki envisions the protein as a regenerative treatment, used solely or in conjunction with other therapeutics. This could dramatically affect treatment not only of DMD, but of a whole spectrum of muscle injury and disease.
“Muscle-wasting disorders represent a huge unmet clinical need,” he says. “Everything from knee replacement to ICU (intensive care unit)- induced weakness to sarcopenia in the elderly, as well as muscular dystrophies. There is really no good pharmacological method, either with a drug or a biologic, for enhancing muscle repair.”
But that may soon change. “Many of us think that in our lifetime, a real revolution will occur in how treatments are delivered to patients,” considers Rudnicki. “We are going to be able to treat diseases that we couldn’t treat before. And those treatments might approach a cure. I think regenerative medicine is going to have a great impact.” In his words, “this is disruptive technology”—technology that will displace existing medical practices. It’s a critical development that may give new hope to a generation of young men living with Duchenne muscular dystrophy.
by John-Paul Michalski
Winner of the 2013 student science journalism competition
The Institute for Science, Society and Policy held a science journalism competition in 2013, inviting all students to report on a recent University of Ottawa discovery or invention. John-Paul Michalsk, a doctoral student in neuroscience, won the competition with this story on leading research by Michael Rudnicki of the Faculty of Medicine.