Protein TRF2 is essential for muscle stem cells: without it, injured muscle fills with fat and scar tissue
University of Pennsylvania researchers found in mice that the protein TRF2 helps muscle stem cells keep their identity and repair damaged tissue. The discovery could open new directions in muscular dystrophy research.
Researchers at the Perelman School of Medicine at the University of Pennsylvania have found in laboratory mice that the protein TRF2 is needed for muscle stem cells to work properly. Without it, injured muscle is not rebuilt and instead fills with fat and scar tissue. The study, published in the journal Science Advances, could inform future research into treatments for muscular dystrophy.
TRF2 was previously known mainly for protecting telomeres, the protective structures at the ends of chromosomes. The new results show it also helps muscle stem cells retain the genetic instructions that define them. These cells are the body's reserve for repairing damaged muscle: usually dormant, they activate and multiply after an injury, and some then return to rest to respond to later damage. In the experiments, TRF2 levels shifted as the cells moved between these stages.
What happened in mice lacking TRF2
The scientists removed the protein from muscle stem cells in mice. At first the muscles looked normal, but over time the number of functional stem cells declined and the animals became less able to repair damage. The cells did not die, as the team had expected, but lost their molecular identity. After injury, fat and scar tissue formed in place of healthy muscle.
In a mouse model of Duchenne muscular dystrophy, an inherited disease causing progressive muscle weakness, removing TRF2 markedly worsened the condition: muscle degeneration progressed faster and survival was shorter.
How the protein works
TRF2 also attaches to regulatory regions of DNA across the genome that control gene activity. Many contain G-quadruplexes, unusual DNA structures formed by guanine-rich sections. The researchers say the protein interacts with them to maintain the gene program of muscle stem cells.
Senior author Foteini Mourkioti, an associate professor of orthopedic surgery at Penn Medicine, said the finding changes how the protein's role is understood. The team is now examining whether this mechanism could lead to new muscular dystrophy treatments, and what it may reveal about cancer, given that skeletal muscle regenerates very well yet cancers arising from it are relatively uncommon.
The results do not yet establish a new treatment, and further research is needed to determine whether they apply to people. The work was supported by the US National Institutes of Health.
