Penn Medicine Researchers Find TRF2 Protein Helps Prevent Muscle Scarring

Stripped of a protein typically known for protecting chromosome ends, muscle stem cells lose their identity and turn into fat and scar tissue, according to researchers at the Perelman School of Medicine at the University of Pennsylvania.

Published in Science Advances, the study shows that TRF2 plays a key role in keeping muscle stem cells functional and rebuilding injured tissue throughout life.

Scientists have long understood TRF2 as a guardian of telomeres at the tips of chromosomes. It shields them from deterioration or misidentification as broken DNA.

Laboratory experiments revealed that TRF2 levels shift in a precisely timed pattern as muscle stem cells move between rest, tissue repair, and self-renewal.

“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, 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.”

Researchers removed TRF2 from muscle stem cells in laboratory mice. The animals’ available supply of those cells gradually decreased.

The cells did not die. But they shed the molecular traits that allowed them to function properly.

“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.”

Without that cellular identity, injured muscle areas accumulated fat and scar tissue instead of rebuilding healthy muscle fibers. Further investigation showed that the protein attaches to regulatory regions across the genome containing G-quadruplex structures, which are also studied as cancer therapy targets.

The research team tested the loss of TRF2 in a mouse model of Duchenne muscular dystrophy. Removing the protein caused the disease to progress faster, which resulted in more severe muscle deterioration and shorter lifespans for the animals.

Grants from the National Institutes of Health supported the work. Funding also came from the National Institute of Arthritis and Musculoskeletal and Skin Diseases. Those supports included grants R01 DK123356, R01s CA174904, GM101149, and FDN-143330.