Scientists uncover how muscles preserve their repair cells

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 relevant to better understanding 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, PhD, 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

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 lab 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 themselves 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," said Mourkioti "The loss of identity has severe implications for whether recovery from injury is even possible."

Identifying links to muscular dystrophy and cancer biology

When the researchers studied a mouse model of Duchenne muscular dystrophy, removing TRF2 from muscle stem cells dramatically accelerated disease progression, worsening muscle degeneration and shortening survival.

The researchers then uncovered why. Instead of acting only at chromosome ends, TRF2 also binds regulatory regions across the genome that control genes essential for muscle stem cell identity. Many of these regions contain secondary DNA structures called G-quadruplexes, which have emerged as promising targets in cancer research.

"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."

The discovery identifies a mechanism that helps muscle stem cells preserve their ability to regenerate damaged tissue and influences the progression of Duchenne muscular dystrophy in mice. The findings may also help researchers explore a longstanding biological question: why skeletal muscle is among the body’s most regenerative tissues, while cancers originating in muscle are rare. Understanding how skeletal muscle uses TRF2 differently from other tissues may reveal ways to promote regeneration without increasing cancer risk.

Mourkioti and her team are now investigating whether the unique way muscle stem cells use TRF2 could reveal new therapeutic strategies for muscular dystrophy and provide insights into cancer biology in tissues that are more susceptible 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).