In the light, muscle stem cells reveal their secrets

They hibernate with age; reversing this might treat muscle loss someday

SAN ANTONIO (March 31, 2009) — UT Health Science Center San Antonio researchers are watching the activity of muscle stem cells — the cells that build our muscles — and are learning how to turn the activity level up or down. One day, it may be possible to selectively rev up these muscle stem cells to treat muscular dystrophy, regenerate muscle affected by cancer, and help the aging body regenerate lost or deficient muscle.

The San Antonio scientists are working with collaborators in Utah, California, Ohio and Pennsylvania on the project, which was described online March 30 by The FASEB Journal.

By altering a gene, the team was able to luminesce, or light up, muscle stem cells and watch the cells divide. “Until this time it has not been possible to tag muscle stem cells and observe their division with this level of specificity,” said lead author Charles Keller, M.D., of the Department of Cellular & Structural Biology at the UT Health Science Center. “By subtly altering a gene called Pax7, we can very readily turn other genes on or off in our experiments.” Dr. Keller is also a faculty investigator at the Health Science Center’s Greehey Children’s Cancer Research Institute.

The team quickly noticed a difference between younger and older mice.

“We were impressed with how quickly muscle stem cells divide in teenagers — teenage mice, that is, which are about 4-8 weeks old,” Dr. Keller said. “In the normal growth process, it appeared muscle stem cells and their progeny doubled monthly, but this slowed to nearly a complete halt when the mice reached middle adulthood, which we defined as 4 months of age or older. This result reflected that muscle stem cells significantly slow their natural activity with age.”

The next step will be to look at altering these stem cells’ potential to repair damaged muscle under normal and diseased conditions, such as later in life and for muscular dystrophy, Dr. Keller said.

Their team of scientists, including muscle biologist Tohru Hosoyama, Ph.D., are employing genetic engineering techniques to uncover factors that maintain quiescence (a quiet state or hibernation) of muscle stem cells. “In recent work that follows our FASEB Journal publication, we have been able to overcome this hibernation so that, theoretically, muscle stem cell activity can be switched on for therapeutic purposes,” Dr. Keller said.

Could waking up hibernating muscle stem cells actually lead to cancer? Dr. Keller said it is possible. He noted that, for any prospective future therapy to be successful, it must strike the proper balance between activating muscle stem cell activity and muscle regeneration and not activating cancerous changes. Muscle cancer, called rhabdomyosarcoma, is in fact a primary topic of study for Dr. Keller, a board-certified pediatrician and pediatric oncologist, and his team at the Greehey Children’s Cancer Research Institute.

If a therapeutic strategy could be developed to activate muscle stem cells on a limited, as-needed basis, it would have large implications for healthier aging.

“Getting older is natural to all of us; none of us are doing quite as well as our children,” Dr. Keller said. “If we could determine how to selectively turn on this muscle regeneration switch in mature mice, it could have implications in the near future not only for muscular dystrophy patients and muscle-related injuries, but also for aging adults. Sarcopenia, or age-related muscle wasting, is responsible for the majority of falls in the U.S., and costs the nation tens of billions annually in health care costs.”

Dr. Keller studied under Nobel laureate Mario Capecchi, Ph.D., at the University of Utah, and Dr. Capecchi is a co-author on the FASEB paper.

More information on the paper:
Biomarker system for studying muscle, stem cells, and cancer in vivo
Koichi Nishijo1, Tohru Hosoyama1, Christopher R.R. Byornson2, Beverly S. Schaffer1, Suresh I. Prajapati1, Ali N. Bahadur1, Mark S. Hansen3, Mary C. Blandford3, Amanda T. McCleish1, Brian P. Rubin4, Jonathan A. Epstein5, Thomas A. Rando2, Mario R. Capecchi3, and Charles Keller1
1Greehey Children’s Cancer Research Institute and Departments of Cellular & Structural Biology and Pediatrics, The University of Texas Health Science Center at San Antonio; 2Department of Neurology and Neurological Sciences, Stanford University; 3Department of Human Genetics, University of Utah; 4Departments of Anatomic Pathology and Molecular Genetics, Taussig Cancer Center and Lerner Research Institute, Cleveland Clinic; and 5Department of Cell and Developmental Biology, University of Pennsylvania

Photo legend:
The green area is an individual muscle fiber with its blue nucleus, while the pink area is a muscle stem cell and the dark is background. Remarkably, an entire muscle fiber can be generated from a single muscle stem cell. Muscle stem cells also are called ‘satellite’ cells because they are observed on the periphery of muscle fibers. The photo is courtesy of Koichi Nishijo, M.D., Ph.D., Greehey Children’s Cancer Research Institute.

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