Manipulating the muscles

Scientists unravel the molecular link between damage-induced inflammation and muscle regeneration

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LAJOLLA, Calif.—A team of scientists at Sanford-Burnham MedicalResearch Institute, led by Pier Lorenzo Puri, recently unlocked themolecular messengers that translate inflammatory signals into thegenetic changes that tell muscle stem cells to differentiate.

Bydiscovering the fundamental mechanisms that could be manipulated toenhance how muscle stem cells regenerate injured or diseased muscles,the researchers say these findings could lead to new treatments fordiseases like muscular dystrophy.

"Thisstudy helps us understand how muscle stem cells decipher externalsignals and elaborate them to turn genes on and off," explainsPuri, who is also an associate faculty member at the DulbeccoTelethon Institute in Rome.

Puritells ddn that the team has been working for three years onthis specific work, but "it is at least eight years we have beenworking on the broader concept of deciphering the signaling by whichexternal signals influence the epigenetic status of adult muscle stemcells."

Accordingto Puri, there can be several applications for the findings of theresearch, including the treatment of neuromusculardiseases—specifically, extending muscle stem cell capability toregenerate diseased muscles.

Undernormal circumstances, adult stem cells reside in muscle tissue, wherethey can differentiate into a number of different cell types. Puriexplains that after an injury (or even a strenuous workout), musclesare inflamed as cells and molecules flood the area to control damageand begin repairs.

"Somemuscle stem cells differentiate when called upon to replace muscletissue damaged by injury or genetic disease, becoming new musclecells, while others make more stem cells," he says.

Moreover,Puri notes that the researchers recently uncovered the molecularmessengers that translate inflammatory signals into the geneticchanges that tell muscle stem cells to differentiate.

"Nowwe're applying this information to help patients with musculardystrophies, a group of genetic diseases characterized by progressivemuscle loss," he explains.

Asthe research began, Puri says the team believed the end result wasthought to be possible because of the invivo data (response ofmice to treatment) and Chromatin immunoprecipitation experimentsshowing the same pattern of response to inhibitors of distincteffectors of the TNF-p38-Polycomb pathway.

Puri'sfindings begin with an inflammatory molecule called tumor necrosisfactor (TNF), which initiates a chain reaction of molecular eventswhen it wakes up a protein called p38 alpha MAPK.

Thisprotein is known to play a role in many processes, but here Puri andhis colleagues show that TNF tells p38 alpha MAPK to enter thenucleus, where it keeps a damper on the part of the genome thatdefines the identity of muscle cells.

"Essentially,p38 alpha MAPK determines whether stem cells loitering in adultmuscle tissue keep refreshing the pool of stem cells or differentiateinto functioning muscle cells," Puri says.

Accordingto Puri, this information on p38 alpha MAPK's role in muscle isimportant because it gives researchers a target to artificially dialthe stem cell population up or down. In this study they used achemical inhibitor and antibodies directed against TNF to block thep38 alpha MAPK activity specifically in stem cells, thus producingmore stem cells.

Puripoints out that anti-TNF antibodies provide a potential mechanism togenerate more muscle stem cells in muscular dystrophy patients,especially since they are already FDA-approved to treat septic shockand arthritis. The team verified their discoveries in a mouse modelof Duchenne muscular dystrophy.

"Inmuscular dystrophy patients, the pool of stem cells capable ofregenerating new muscle becomes exhausted," says Puri. "Herewe've found a strategy to refresh the pool by modulating p38 alphaMAPK. Since the effect of this treatment is reversible, withdrawingthe drug could then force the expanded population of stem cells torepopulate muscle cells."

Overall,these findings suggest that turning inflammatory signals off and onin regenerating muscles might enhance the ability of injured ordiseased skeletal muscles to self-repair. Moreover, the findings canboost drug research and discovery efforts.

"Thisis an example of how we can identify nuclear effectors of externalsignals by deciphering the pathway (molecular effectors) thattransmit the signal to the chromatin," Puri says.

Thenext step for the researchers, according to Puri, is to narrow downthe chromatin target of this intervention, in order to increase thespecificity of the intervention (that is, identify new specific andeffective strategies to expand the number of muscle stem cells).

"Continuedsuccess of this research will be measured by improving the control ofmuscle stem cells number and function in mice, by specificpharmacological strategies that can be translated into trial forhuman disease," concludes Puri.



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