“A protein best known for protecting the ends of chromosomes also helps muscle stem cells preserve their identity and repair damaged tissue, according to a new study from researchers at the Perelman School of Medicine at the University of Pennsylvania. The findings offer new clues for treating muscular dystrophy and provide new insights into the mechanisms of cancer.
The study, published in Science Advances, showed that the protein TRF2 goes far beyond its known role in protecting chromosomes. In muscle stem cells, the protein helps maintain the genetic program that allows these cells to preserve their identity, enabling muscles to regenerate after injury.
“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, Ph.D., an associate professor of Orthopaedic Surgery at Penn Medicine. “But rather than simply protecting DNA, TRF2 seems to be key to regenerating muscle throughout life.””
Uncovering a surprising new role for TRF2 – Muscle Repair
“TRF2 is a protein long known to function primarily at the tips of chromosomes, the telomeres. Telomeres are protective DNA caps that help prevent chromosomes from becoming damaged or mistakenly recognized as broken DNA.
When muscles are injured, muscle stem cells awaken from a resting state, multiply, repair damaged tissue and then replenish themselves by returning to a dormant state. The researchers discovered through laboratory tests that TRF2 levels rise and fall precisely during these transitions, showing that the protein is dynamically regulated as muscle stem cells switch between resting, repair and self-renewing states. This suggests that TRF2 helps coordinate the regenerative process.
When the team removed TRF2 from the muscle stem cells of lab mice, the muscles initially appeared normal, but the population of muscle stem cells gradually declined. Surprisingly, the cells did not die, as scientists would have expected based on TRF2’s role in other tissues. Instead, they lost the molecular identity required to function as muscle stem cells. As a result, injured muscles failed to regenerate properly, accumulating scar tissue and fat instead of healthy muscle tissue.
“This completely changes how we think about TRF2’s role in these cells,” Mourkioti said. “The loss of identity has severe implications for whether recovery from injury is even possible.””