Protein TRF2 Keeps Muscle Stem Cells Working, Mouse Study Finds

A protein best known for protecting the ends of chromosomes also keeps muscle stem cells in their working state, according to a study from the Perelman School of Medicine at the University of Pennsylvania. In mice whose muscle stem cells lacked the protein, called TRF2, injured muscle filled with fat and scar tissue instead of regrowing, and a mouse model of Duchenne muscular dystrophy got worse faster.

The work appeared in the journal Science Advances (DOI 10.1126/sciadv.aei7316). Foteini Mourkioti, an associate professor of orthopedic surgery at Penn Medicine, was the senior author. It is laboratory research in mice and has not produced a treatment for people.

What happened when TRF2 was removed from mice?

The team deleted TRF2 from muscle stem cells in laboratory mice. At first the animals’ muscles looked normal. Over time, the number of working muscle stem cells fell, and the mice became less able to mend damaged muscle.

The researchers had expected the cells to die, since losing TRF2 does that in other tissues. The cells stayed alive instead but lost the molecular identity that made them muscle stem cells. After an injury, the damaged muscle in these mice filled with fat and scar tissue, which cannot restore normal muscle function.

Other laboratory experiments showed that TRF2 activity changes as muscle stem cells shift between rest, repair and renewal. Normally, these cells stay mostly inactive, switch on after an injury to multiply and rebuild tissue, and some return to rest to serve as a reserve for the next injury.

How does TRF2 protect a stem cell’s identity?

TRF2 is known for shielding telomeres, the caps on chromosome ends. The researchers found it also attaches to regulatory stretches of DNA across the genome, which help decide which genes are switched on. Muscle stem cells rely on a particular pattern of gene activity to stay what they are.

Many of these TRF2 binding sites contain G-quadruplexes, folded DNA structures that form in guanine-rich sequences, where guanine is one of the building blocks described in the explainer on how DNA works. The team concluded that TRF2 works through these structures to preserve the stem cells’ identity. Mourkioti called that result “completely unexpected.”

What did the muscular dystrophy model show?

Duchenne muscular dystrophy is an inherited disorder that causes progressive muscle weakness and degeneration. The researchers removed TRF2 from muscle stem cells in a mouse model of the disease. Muscle degeneration moved faster and the mice survived for a shorter time, which suggests TRF2 helps preserve regeneration in muscle that is already struggling.

What is still unclear?

All of the findings come from mice and cell experiments. The study does not establish a treatment for muscular dystrophy. It identifies a mechanism that researchers may eventually be able to target, and Mourkioti’s group is now testing whether the way muscle stem cells use TRF2 could lead to strategies for the disease. More research is needed before anyone knows whether the results carry over to people.

The group also plans to look at cancer. Skeletal muscle regenerates well after injury, yet cancers that start in skeletal muscle are relatively rare, while some other tissues with heavy regeneration are more prone to cancer. By comparing how TRF2 controls genes in muscle and in other tissues, the researchers hope to learn how muscle keeps a strong repair system without frequent cancers.

Why it matters for muscle research

The result adds a second job to a protein that was studied mostly for chromosome protection, and it shows that muscle repair can fail without cell death. G-quadruplexes are already being examined as possible targets in cancer treatments, so the same structures now have a link to muscle stem cell function as well. Any therapy that strengthens muscle repair would also have to avoid encouraging uncontrolled cell growth, the authors note.

Source: ScienceDaily