����������

Can a professor’s stem cell research help regenerate muscle lost to aging and disease?

Like any 12-year-old girl, Maia Pinkelman serves up a complex combination of sweet and sass on any given day. She goes to school, reads and has a family who adores her. But her hurdles are anything but ordinary.

At eight months old, Maia was diagnosed with congenital muscular dystrophy, a disease caused by a genetic mutation that makes muscles break down faster than they can grow or repair. When her parents noticed their child wasn’t hitting milestones like being able to sit up, they embarked on a long diagnostic odyssey. The genes for congenital muscular dystrophy were not well-defined at the time.

Today, Maia is developmentally delayed and uses sign language and a talking computer to communicate. Her mother, Anne Rutkowski, an emergency room doctor in Los Angeles and founder of the nonprofit Cure CMD, says one of the greatest blessings is that her daughter still walks, thanks to being steroid responsive since she started to weaken at age 8 after intense physical therapy reached its limits. And while there is no cure for muscular dystrophy, ����������-Boulder molecular, cellular and developmental biology professor Bradley Olwin’s research on stem cell transplants and muscle repair may offer new hope for boosting Maia’s and thousands of others’ quality of life.

Olwin and his colleagues found that muscle stem cell transplants injected into injured mice restored mobility and added as much as 70 percent more girth to muscle mass. Ultimately this could signal some relief for those suffering from a range of degenerative muscular symptoms linked to aging and diseases like muscular dystrophy.

In muscular dystrophy, muscle fibers are missing a protein to keep them strong. The muscles are weak and contract, exerting a lot of force that literally rips the muscles apart. Continuous regeneration in the cells gets exhausted. While Olwin’s research wouldn’t fix the underlying genetic cause of muscular dystrophy, it may reduce symptoms and extend the operational life of muscles.

“What we were trying to do was boost the cells’ ability to regenerate and ask, ‘Does that keep the muscle functioning better?’ The answer was yes,” he says.

Muscle regeneration is thought to be done by a group of stem cells called satellite cells. They rest on top of the muscle fiber, sandwiched between connective tissue and muscle. What is unknown is how stem cells know that a muscle is injured and how they know how many cells to make to repair the injury.

“Normally these cells existing in your muscle are quiescent, which means they are not dividing,” Olwin says. “When your muscle gets damaged either through exercise or through an injury, these cells are activated and sense the damage. When the muscle is regenerated, you’ll find the same number of muscle stem cells or satellite cells present as there were prior to the damage.”

Olwin’s mice transplants utilize a relatively small number of cells, ranging from as few as eight to as many as 50. His lab expected muscle cells to expand to some extent but not as much as they did. Mice muscles grew 50 to 70 percent larger within the first month. Then they stopped, much like a bodybuilder’s large resistance muscles do as they approach their bulging limit and reduce functionality.

“The surprise is that the muscle size and the elevated number of stem cells stay that way for the life of the mouse,” Olwin says.

But he warns against imagining this as some kind of body building miracle or a Botox injection against aging’s normal muscular degeneration.

“To try to inject a large enough area to make that work would be a formidable obstacle to overcome,” he says.

The more immediate promise of Olwin’s research likely lies with a smaller range of issues, like someone’s diminished use of their hands after an injury or illness.

Approximately 35 million Americans are 65 or older, and this number is expected to double in the next 25 years. This is why the National Institute on Aging and the National Institute of Arthritis and Musculoskeletal and Skin Diseases has invested in Olwin’s research.

As people are living longer, the NIH aims to make later years as productive as possible, including minimizing disability. As elderly muscles lose their capacity to rebuild after injury or inactivity, it is possible that Olwin’s research may offer opportunities to bolster mobility or self-sufficiency for an aging population.

Specific localized treatments are where Olwin predicts muscle stem cell injections are likely to prove especially practical. This includes treatments for urinary incontinence or problems with esophageal muscles. Swallowing issues are a common hurdle created by some cancer treatments, and Olwin imagines a stem cell transplant in those isolated muscles could offer relief.

His lab, which had as many as 16 scientists during the mice transplants, is not using embryonic stem cells. Cells are taken from a grown mouse and injected into another mouse after a brief tissue culture treatment. In this case, Olwin injected healthy muscle stem cells from a donor mouse into another’s severely damaged leg muscles.

A leap to human applications, however, is not without hurdles.

“From a therapeutic standpoint, trying to inject stem cells into humans has a lot of problems,” Olwin says. “Cells could proliferate out of control and cause a tumor. There’s also the issue of perhaps not all the cells being delivered to the intended target, and if they go to another tissue these cells could cause problems.”

It’s a journey into the unknown. So far, no tumors have appeared in the mice.

Doing a transplant into a canine is the next step toward human applications. If it works without unexpected side effects, Phase I human safety clinical trials would be reasonable, Olwin says. But one key will be making an artificial environment for the muscle stem cells to remain viable.

“Right now we can’t grow them,” he says. “They won’t transplant. That’s a severe limitation,” he says.

Ultimately, he suggests it might be easier to find drugs or chemicals that induce existing host cells to mimic transplant cells.

Rutkowski says a potentially huge benefit of Olwin’s research might be keeping muscles healthier so people with muscular dystrophy can walk longer. Keeping patients walking has proven to delay the onset of many of muscular dystrophy’s other symptoms, she says.

“[Olwin’s] research is targeting one aspect but it’s one really important aspect,” she says. “A cure is a long way down the road. Treatment is something we can be hopeful for. His research falls in that realm — extending the quality of life.”