A molecule released as part of an inflammatory response right after muscle injury or rigorous exercise activates muscle come cells responsible for repairing the damage, according to a study by experts at the Stanford University School of Medicine.

Treating laboratory mice with a dose from the molecule, a lipid metabolite called prostaglandin E2, soon after injury accelerates the animals’ ability to repair the damage plus regain muscle strength, the researchers reported.

However , a nonsteroidal, anti-inflammatory drug like aspirin or even ibuprofen — drugs frequently taken to reduce the muscle tenderness after injury or exercise — blocked production from the metabolite and dramatically inhibited muscle repair in the rodents, leading to diminished strength.

“Traditionally, inflammation continues to be considered a natural, but sometimes harmful, response to injury, inch said Helen Blau, PhD, professor of microbiology plus immunology and director of Stanford’s Baxter Laboratory intended for Stem Cell Biology. “But we wondered whether there can be a component in the pro-inflammatory signaling cascade that also activated muscle repair. We found that a single exposure to prostaglandin E2 has a profound effect on the proliferation of muscle tissue stem cells in living animals. We postulated that individuals could enhance muscle regeneration by simply augmenting this organic physiological process in existing stem cells already situated along the muscle fiber. ”

A papers describing the research will be published online June 12 within the Proceedings of the National Academy of Sciences . Blau, who holds the Donald E. plus Delia B. Baxter Professorship, is the senior author. Mature scientist Andrew Ho and postdoctoral scholar Adelaida Palla share lead authorship of the study.

Metabolite infiltrates muscle fiber

Muscles stem cells usually nestle quietly along the muscle fibres. They spring into action when a muscle is broken by trauma or overuse, dividing rapidly to generate sufficient muscle cells to repair the injury. But it’s not completely clear what signals present in inflammation activate the originate cells.

Prostaglandin E2, or PGE2, is really a metabolite produced by immune cells that infiltrate the muscle mass fiber as well by the muscle tissue itself in response to injury. Potent treatments have been shown to adversely affect muscle recovery, yet because they affect many different pathways, it’s been tough to identify who also the real players are in muscle regeneration.

Ho and Palla discovered a role for PGE2 in muscles repair by noting that its receptor was portrayed at higher levels on stem cells shortly after damage. They found that muscle stem cells that got undergone injury displayed an increase in the expression of a gene encoding for a receptor called EP4, which binds in order to PGE2. Furthermore, they showed that the levels of PGE2 within the muscle tissue increased dramatically within a three-day period after damage, indicating it is a transient, naturally occurring immune modulator.

To determine its mechanism of action, Ho plus Palla created a genetically engineered strain of laboratory rodents that allowed them to dynamically monitor the number and routines of muscle stem cells over time. They then studied the way the stem cells responded to leg muscle injuries caused by shot of a toxin or by application of cold temperatures. (The mice were anesthetized during the procedure and given pain alleviation during recovery. )

‘We noticed a profound effect’

“This transient pulse of PGE2 is a natural response to injury, inch said Blau. “When we tested the effect of an one-day exposure to PGE2 on muscle stem cells growing within culture, we saw a profound effect on the expansion of the cells. One week after a single one-day exposure, the amount of cells had increased sixfold compared with controls. ”

After seeing what happened in laboratory-grown cells, Ho and Palla tested the effect of a single injection associated with PGE2 into the legs of the mice after injury.

“When we gave mice a single shot associated with PGE2 directly to the muscle, it robustly affected muscle tissue regeneration and even increased strength, ” said Palla. “Conversely, if we inhibited the ability of the muscle stem cells to reply to naturally produced PGE2 by blocking the appearance of EP4 or by giving them a single dose of the nonsteroidal anti-inflammatory drug to suppress PGE2 production, the particular acquisition of strength was impeded. ”

“We are excited about this finding because it is counterintuitive, ” stated Ho. “One pulse of this inflammation-associated metabolite lingers lengthy enough to significantly affect muscle stem cell function during these animals. This could be a natural way to clinically boost muscle reconstruction. ”

The researchers next plan to check the effect of PGE2 on human muscle stem tissues in the laboratory, and to study whether and how aging impacts the stem cells’ response. Because PGE2 is also made by the fetus and placenta during pregnancy, and is approved by the meals and Drug Administration for use in the induction of work, a path to the clinic could be relatively speedy, someone said.

“Our goal has always been to find regulators associated with human muscle stem cells that can be useful in regenerative medication, ” said Blau. “It might be possible to repurpose this already FDA-approved drug for use in muscle. This could be the novel way to target existing stem cells in their indigenous environment to help people with muscle injury or trauma, or maybe to combat natural aging. ”