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Manipulating the muscles
LA JOLLA, Calif.—A team of scientists at Sanford-Burnham Medical Research Institute, led by Pier Lorenzo Puri, recently unlocked the molecular messengers that translate inflammatory signals into the genetic changes that tell muscle stem cells to differentiate.
By discovering the fundamental mechanisms that could be manipulated to enhance how muscle stem cells regenerate injured or diseased muscles, the researchers say these findings could lead to new treatments for diseases like muscular dystrophy.
"This study helps us understand how muscle stem cells decipher external signals and elaborate them to turn genes on and off," explains Puri, who is also an associate faculty member at the Dulbecco Telethon Institute in Rome.
Puri tells ddn that the team has been working for three years on this specific work, but "it is at least eight years we have been working on the broader concept of deciphering the signaling by which external signals influence the epigenetic status of adult muscle stem cells."
According to Puri, there can be several applications for the findings of the research, including the treatment of neuromuscular diseases—specifically, extending muscle stem cell capability to regenerate diseased muscles.
Under normal circumstances, adult stem cells reside in muscle tissue, where they can differentiate into a number of different cell types. Puri explains that after an injury (or even a strenuous workout), muscles are inflamed as cells and molecules flood the area to control damage and begin repairs.
"Some muscle stem cells differentiate when called upon to replace muscle tissue damaged by injury or genetic disease, becoming new muscle cells, while others make more stem cells," he says.
Moreover, Puri notes that the researchers recently uncovered the molecular messengers that translate inflammatory signals into the genetic changes that tell muscle stem cells to differentiate.
"Now we're applying this information to help patients with muscular dystrophies, a group of genetic diseases characterized by progressive muscle loss," he explains.
As the research began, Puri says the team believed the end result was thought to be possible because of the in vivo data (response of mice to treatment) and Chromatin immunoprecipitation experiments showing the same pattern of response to inhibitors of distinct effectors of the TNF-p38- Polycomb pathway.
Puri's findings begin with an inflammatory molecule called tumor necrosis factor (TNF), which initiates a chain reaction of molecular events when it wakes up a protein called p38 alpha MAPK.
This protein is known to play a role in many processes, but here Puri and his colleagues show that TNF tells p38 alpha MAPK to enter the nucleus, where it keeps a damper on the part of the genome that defines the identity of muscle cells.
"Essentially, p38 alpha MAPK determines whether stem cells loitering in adult muscle tissue keep refreshing the pool of stem cells or differentiate into functioning muscle cells," Puri says.
According to Puri, this information on p38 alpha MAPK's role in muscle is important because it gives researchers a target to artificially dial the stem cell population up or down. In this study they used a chemical inhibitor and antibodies directed against TNF to block the p38 alpha MAPK activity specifically in stem cells, thus producing more stem cells.
Puri points out that anti-TNF antibodies provide a potential mechanism to generate more muscle stem cells in muscular dystrophy patients, especially since they are already FDA-approved to treat septic shock and arthritis. The team verified their discoveries in a mouse model of Duchenne muscular dystrophy.
"In muscular dystrophy patients, the pool of stem cells capable of regenerating new muscle becomes exhausted," says Puri. "Here we've found a strategy to refresh the pool by modulating p38 alpha MAPK. Since the effect of this treatment is reversible, withdrawing the drug could then force the expanded population of stem cells to repopulate muscle cells."
Overall, these findings suggest that turning inflammatory signals off and on in regenerating muscles might enhance the ability of injured or diseased skeletal muscles to self-repair. Moreover, the findings can boost drug research and discovery efforts.
"This is an example of how we can identify nuclear effectors of external signals by deciphering the pathway (molecular effectors) that transmit the signal to the chromatin," Puri says.
The next step for the researchers, according to Puri, is to narrow down the chromatin target of this intervention, in order to increase the specificity of the intervention (that is, identify new specific and effective strategies to expand the number of muscle stem cells).
"Continued success of this research will be measured by improving the control of muscle stem cells number and function in mice, by specific pharmacological strategies that can be translated into trial for human disease," concludes Puri.