La Jolla scientists make ‘unexpected’ discovery in muscle-building protein – San Diego Union-Tribune

Scientists from the La Jolla-based Sanford Burnham Prebys medical research institute have made a discovery that they say “completely subverts” what scientists had known about certain proteins  by showcasing a new role for a critical protein in muscle cell development.

The findings could help improve treatment of muscle damage or disease, researchers say.

For 30 years, scientists have studied a protein known as MYOD and its role in turning on stem cells so they become muscle cells.

MYOD — myogenic determination gene 1 — also comes to the rescue when muscle tissue needs to be repaired after injury or to restore minor damage that occurs with athletic training or other physical activity. During this process, a protein that helps control when and how genes are turned on or off in a cell rallies nearby muscle stem cells to expand in number and become muscle cells capable of regenerating harmed muscle fibers.

While it has been known that this protein plugs into muscle stem cell DNA and reprograms the cells to build muscle and start the process, Sanford Burnham Prebys scientists and international colleagues recently published a paper indicating that MYOD also can repress the process for other genes.

“These [MYOD] proteins … are called transcriptional activators because historically, this class of protein [is used to] bind DNA … and activate gene expression,” said Dr. Pier Lorenzo Puri, a professor in the Center for Cardiovascular and Muscular Diseases at Sanford Burnham Prebys and the senior author of the study.

In the case of MYOD, they are all muscle cells. “So for over 30 years we learned that once MYOD or proteins like MYOD bind the DNA, they activate the expression of certain genes,” Puri said.

However, he said, researchers had “hypothesized that this is only half the job,” with the other half being to erase or repress any other gene expression.

Comparing the process to moving into a new home, he said “Let’s say you rent an apartment and you want to personalize the space with your furniture. So you bring your furniture in … but the apartment isn’t really yours until the old furniture is gone.”

Throughout life, he said, muscle cells regenerate but might not “perform perfectly because they are still retaining genes that should not have been expressed in muscle cells” — analogous to old furniture.

“That’s what MYOD does,” Puri said. “While it is activating gene expression for muscle cells, it represses the genes that were previously expressed.”

Discovering that MYOD proteins also do that job “completely subverts what we had been thinking about transcriptional activators until now,” he said. “This was completely unexpected.”

Puri and the team see their findings as an opportunity to expand ideas about how transcription factors operate.

The researchers now plan to explore what happens when MYOD’s repression of a cell’s previous identity is incomplete. This phenomenon may help explain why some athletes’ muscles recover better as they get older or why some people suffer from age-related muscle mass deterioration and frailty, known as sarcopenia, at a younger age.

“MYOD performance might make the difference,” Puri said.

The next step is to work on whether this information could be used in sports medicine.

“We are trying to understand more and more about why MYOD can bind these DNA sequences that were completely unexpected,” Puri said. “The idea is to understand the mechanism better and identify targets that can be pharmacologically modulated so that once we can identify a population … that might be subject to muscle impairment or muscle fitness or disease, we can try to correct that.

“We have the finding and the data that suggests the mechanism, but once that mechanism is clarified, we can find pharmacological targets and can start working on interventions that can correct defective MYOD.”

That plays into the “next generation” of medicine, he said. “That’s one of those approaches that we could make biomedicine personalized. … Based on what we learn, we can look at the level of what we can correct … in muscle health.”

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