During her scientific training, Alessandra Sacco, Ph.D., watched enthralled as each muscle stem cell in a petri dish made a life-altering choice: to stay the same, or to transform into something new.
“At each cell division, a stem cell has to decide: Is it going to make more copies of itself, or is it going to mature into a committed cell type?” explains Sacco, associate professor in the Development, Aging and Regeneration Program at Sanford Burnham Prebys Medical Discovery Institute, and associate dean of Curriculum for the Graduate School. “That was fascinating to me. How does it choose what it wants to become?”
That fundamental question has been at the heart of her research ever since. As a postdoc at Stanford University, she found ways to isolate adult skeletal muscle stem cells and provided the first definitive evidence that they can self-renew in a living organism.
Today, her lab investigates exactly how muscle stem cells repair and regenerate skeletal muscle—something that has potential implications not only for devastating disorders like Duchenne muscular dystrophy, but also for a condition we all face: aging.
“During aging, our muscles become less strong, and we’re less efficient in regenerating muscle if there is an injury,” notes Sacco, who joined Sanford Burnham Prebys in 2010. “What we’re trying to understand is, how is that happening? And how can we improve the function of our muscle stem cells so we can maintain our strength and quality of life?”
Facts about sarcopenia
(Muscle loss with aging)
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The name sarcopenia is derived from the Greek sarx (flesh) and penia (loss)
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Most people begin losing modest amounts of muscle mass after age 30
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A sedentary lifestyle puts people at increased risk of developing sarcopenia
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A 10% reduction in sarcopenia would result in a savings of more than $1 billion per year in U.S. healthcare costs
Source: Journal of the American Geriatrics Society
nearly 25%
of 65+ year-olds are affected by sarcopenia
60%
of 80+ year-olds are affected by sarcopenia
Staving off decline
Throughout our lives, adult muscle stem cells have an important job: Maintain and repair our skeletal muscle tissue, such as leg, arm and back muscles.
The cells, which live on the outskirts of muscle fibers, do this in two ways. Some decide to differentiate into muscle cells, which then form new fibers to replace damaged ones. But other stem cells simply make copies of themselves, ensuring an adequate stem cell supply for the next injury.
The process works beautifully. But by our 40s, muscle mass begins a slow decline. Called sarcopenia, this age-related loss of muscle size and function accelerates in seniors and can lead to disability and loss of independence.
To find potential therapeutic targets that could prevent or reverse this decline, Sacco and her team are examining how muscle stem cells interact with an aging environment. For example, they found that a molecule called STAT3, which is more active in aging, inhibits skeletal muscle regeneration in older mice.
Another key aspect: the cells themselves. “Stem cells are not all identical; they each have different abilities,” she notes. “There’s a lot of diversity.”
Age vs. injury
Related to that diversity, her team has uncovered surprising findings about how stem cells respond to age versus injury. “It’s been thought that muscle regeneration during aging or during injury is essentially the same process and involves the same players,” Sacco says. “We found this is not the case at all.”
Using a genetic labeling tool called in vivo multi-lineage tracing, the team tracked the fate of individual stem cells in living mice. They found that, in an aging mouse, the diversity of the stem cell population stayed the same—but the cells did not function as well. With injury, the opposite happened: Stem cell diversity declined, but cell function improved.
The takeaway? Therapies for regenerating muscle will likely need to be different for seniors than for patients with injuries or chronic disease. “There probably isn’t a one-size-fits-all approach,” she says.
Choosing her path
Like the stem cells she studies, Sacco herself once faced a life- defining decision between two distinctly different paths.
Born and raised in Rome, she was the first in her family to go to college. But she soon found herself torn between staying in Italy, near her parents and two brothers, and pursuing greater scientific opportunities abroad.
She chose the latter path, taking a postdoc position at Stanford University. It was her first time living away from home. “It took a few months of adjustment!” she says, letting out a long, deep laugh. “But it made me grow.”
Today, she feels like “both an Italian and a Californian.” Most of all, she is a scientist and a dedicated mentor to other researchers at Sanford Burnham Prebys. (Two of her postdocs won the Institute’s prestigious Fishman Award last year.)
“The potential impact of what we discover is exciting, but day to day what attracts me is the process of working with the team to get there,” she says. “When you do research, you’re at the forefront of science. You’re trying to find answers that are not there yet. I really enjoy that challenge."
