A protein traditionally associated with protecting chromosome ends also plays an unexpected role in helping muscle stem cells remain functional and rebuild injured tissue, according to researchers at the Perelman School of Medicine at the University of Pennsylvania. The discovery could guide future research into muscular dystrophy treatments while also offering broader clues about cancer biology.
The study, published in Science Advances, found that TRF2 does much more than shield chromosomes. Within muscle stem cells, it helps preserve the genetic instructions that define the cells and allow them to regenerate muscle after damage.
“For years, TRF2 has been viewed as a protein whose primary job is protecting the ends of chromosomes from damage or corruption,” said senior author Foteini Mourkioti, PhD, an associate professor of Orthopedic Surgery at Penn Medicine. “But rather than simply protecting DNA, TRF2 seems to be key to regenerating muscle throughout life.”
TRF2 Has an Unexpected Role in Muscle Repair
Scientists have long known that TRF2 mainly operates at telomeres, the protective DNA caps located at the tips of chromosomes. Telomeres help keep chromosomes from deteriorating or being incorrectly identified by cells as broken pieces of DNA.
Muscle stem cells normally remain inactive until tissue is injured. They then become active, multiply, rebuild the damaged area, and produce replacement stem cells that return to a dormant state.
Laboratory experiments showed that TRF2 levels change in a carefully timed pattern as muscle stem cells move through these different stages. The amount of the protein rises and falls as the cells shift between rest, tissue repair, and self-renewal, suggesting that TRF2 helps organize the regeneration process.
Muscle Stem Cells Lost Their Identity
To determine what happens without the protein, the researchers removed TRF2 from muscle stem cells in laboratory mice. The animals’ muscles initially looked normal, but their supply of muscle stem cells gradually decreased.
The cells did not die, which was unexpected based on the effects of TRF2 loss in other tissues. Instead, they lost the molecular characteristics that allowed them to function as muscle stem cells.
This loss of identity had serious consequences after injury. Rather than rebuilding healthy muscle, the damaged areas accumulated fat and scar tissue.
“This completely changes how we think about TRF2’s role in these cells,” said Mourkioti. “The loss of identity has severe implications for whether recovery from injury is even possible.”
Duchenne Muscular Dystrophy Progressed Faster
The team also examined TRF2 in a mouse model of Duchenne muscular dystrophy. When the protein was removed from muscle stem cells, the disease advanced much more rapidly. Muscle deterioration became more severe, and the mice had shorter lifespans.
Further investigation revealed how TRF2 produces these effects. The protein does not operate exclusively at chromosome ends. It also attaches to regulatory regions throughout the genome that control genes needed to preserve muscle stem cell identity.
Many of those genomic regions contain secondary DNA formations known as G-quadruplexes, which are also being studied as potential targets for cancer therapies.
“We found that TRF2 works through these secondary DNA structures to preserve the identity of muscle stem cells and keep them capable of repairing damaged muscle,” Mourkioti said. “That was completely unexpected.”
A Possible Connection Between Regeneration and Cancer
The findings reveal a biological mechanism that allows muscle stem cells to retain their regenerative abilities. They also show that this mechanism can affect the progression of Duchenne muscular dystrophy in mice.
The discovery may help scientists investigate a longstanding puzzle. Skeletal muscle has an exceptional ability to regenerate, yet cancers that begin in muscle tissue are relatively uncommon.
Determining how muscle stem cells use TRF2 differently from cells in other tissues could eventually help researchers stimulate tissue repair without also raising the risk of cancer.
Mourkioti and her colleagues are now studying whether this unusual use of TRF2 could lead to new therapeutic approaches for muscular dystrophy. They also hope it will provide insight into cancer biology in tissues that are more vulnerable to the disease.
The research was supported by grants from the National Institutes of Health/ National Institute of Arthritis and Musculoskeletal and Skin Diseases (R01 DK123356, R01s CA174904, GM101149, and FDN-143330).
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