When muscles are injured, the body normally activates specialized stem cells that help rebuild damaged tissue. But scientists have discovered that without one critical protein, this repair system can break down, leaving injured muscles filled with fat and scar tissue instead of healthy muscle.
Researchers at the Perelman School of Medicine at the University of Pennsylvania have identified an unexpected role for a protein called TRF2, which was previously known primarily for protecting chromosomes. Their findings suggest that TRF2 is also essential for maintaining the identity of muscle stem cells, allowing them to continue repairing and regenerating muscle throughout life.
The discovery, published in Science Advances, could provide new directions for muscular dystrophy treatments. It may also help scientists understand important differences between muscle regeneration and cancer, including why skeletal muscle can repair itself so effectively while cancers originating in muscle are relatively uncommon.
“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.”
A Hidden Protein With an Unexpected Role in Muscle Repair
For years, scientists have studied TRF2 because of its role in safeguarding telomeres, the protective structures found at the ends of chromosomes. Chromosomes carry our genetic information, and telomeres help keep their ends from deteriorating or being mistaken for damaged DNA.
The new research shows that TRF2 has another important responsibility. It helps muscle stem cells retain the genetic instructions that make them muscle stem cells in the first place. Maintaining that identity is essential because these specialized cells serve as the body’s reserve supply for repairing injured muscle.
Under normal conditions, muscle stem cells spend much of their time inactive. When an injury occurs, they become active, multiply, and help replace damaged muscle tissue. Some then return to a resting state, preserving a population of stem cells that can respond to future injuries.
Through laboratory experiments, the researchers found that TRF2 levels change as muscle stem cells move between these different stages. The protein’s activity rises and falls as the cells transition from dormancy to repair and then replenish themselves, suggesting that TRF2 helps regulate the entire regeneration process.
Without TRF2, Damaged Muscles Accumulate Fat and Scar Tissue
To understand how important TRF2 is, the scientists removed the protein from muscle stem cells in laboratory mice. At first, the animals’ muscles appeared normal, suggesting that the loss of TRF2 did not immediately damage existing muscle tissue.
Over time, however, a serious problem emerged. The population of functional muscle stem cells began to decline, leaving the animals increasingly unable to repair damaged muscle.
The researchers initially expected the cells to die, since losing TRF2 can produce that outcome in other tissues. Instead, they discovered something more surprising: the cells remained alive but lost the molecular identity that allowed them to function as muscle stem cells.
In effect, the cells no longer maintained the biological program needed to perform their specialized repair duties.
The consequences became clear when the muscles were injured. Rather than rebuilding healthy muscle, the damaged tissue accumulated fat and scar tissue, a form of tissue replacement that cannot restore normal muscle function.
“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.”
A Potential Breakthrough for Muscular Dystrophy Research
The team also investigated whether TRF2 plays a role in Duchenne muscular dystrophy, a serious inherited disorder that causes progressive muscle weakness and degeneration. The disease interferes with the body’s ability to maintain healthy muscles, making effective repair especially important.
Using a mouse model of Duchenne muscular dystrophy, the researchers removed TRF2 from muscle stem cells and observed a dramatic worsening of the disease.
Muscle degeneration progressed much faster, and the affected mice had shorter survival times. These findings indicate that TRF2 plays an important role in preserving the regenerative capacity of muscles already struggling with a serious genetic disease.
The results do not yet establish a new treatment for muscular dystrophy. However, they identify a biological mechanism that researchers may eventually be able to target to help preserve muscle stem cell function and improve tissue repair.
How TRF2 Protects the Identity of Muscle Stem Cells
Further experiments revealed how TRF2 performs this unexpected function.
Although the protein is best known for working at the ends of chromosomes, the researchers found that it also attaches to regulatory regions throughout the genome. These regions help control which genes are active or inactive, determining how cells behave and what specialized functions they perform.
For muscle stem cells, this regulation is particularly important. Their ability to repair muscle depends on maintaining a specific pattern of gene activity that preserves their identity and regenerative potential.
The scientists discovered that many of the DNA regions associated with TRF2 contain unusual structures known as G-quadruplexes. These structures form when sections of DNA rich in the building block guanine fold into distinctive arrangements involving four interacting strands or segments.
G-quadruplexes have attracted considerable scientific interest because they can influence how genes function. They are also being investigated as possible targets for cancer treatments.
The Penn researchers found that TRF2 interacts with these specialized DNA structures to help maintain the genetic program that keeps muscle stem cells functioning properly.
“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.”
What Muscle Regeneration Could Reveal About Cancer
Beyond muscular dystrophy, the discovery may help researchers investigate a longstanding mystery about muscle biology.
Skeletal muscle, the type of muscle that allows the body to move, has an impressive ability to regenerate after injury. Yet cancers that originate in skeletal muscle are relatively rare, even though other tissues with substantial regenerative activity can be more vulnerable to cancer.
This raises an important question: how can muscle maintain such a powerful repair system without frequently developing cancer?
The researchers believe that TRF2’s unusual role in muscle stem cells could offer clues. By examining how the protein regulates gene activity in muscle compared with other tissues, scientists may gain a better understanding of the mechanisms that support regeneration while limiting the risk of uncontrolled cell growth.
That distinction matters because cancer develops when cells acquire changes that allow them to grow and divide without the normal biological restraints. Finding ways to strengthen muscle repair without encouraging abnormal growth would be an important goal for future therapies.
Mourkioti and her colleagues are now investigating whether the way muscle stem cells use TRF2 could lead to new treatment strategies for muscular dystrophy. They also hope to determine what this mechanism can reveal about cancer biology in tissues that are more susceptible to the disease.
Although additional research is needed to determine whether these findings can be translated into treatments for people, the discovery reveals an important part of the body’s muscle repair system. It also demonstrates that a protein long associated with protecting DNA has a much broader role in keeping muscles capable of healing.
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).