Stanford researchers have found that a metabolite stimulates mouse muscle stem cells to proliferate after injury, and anti–inflammatory drugs, frequently taken after exercise, block its production and inhibit muscle repair.

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

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

However, a nonsteroidal, anti–inflammatory drug like aspirin or ibuprofen – drugs frequently taken to reduce the muscle soreness after injury or exercise – blocked production of the metabolite and dramatically inhibited muscle repair in the mice, leading to diminished strength.

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

A paper describing the research was published online June 12 in the Proceedings of the National Academy of Sciences journal.

Blau, who holds the Donald E. and Delia B. Baxter Professorship, is the senior author. Senior scientist Andrew Ho, PhD, and postdoctoral scholar Adelaida Palla, PhD, share lead authorship of the study.

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

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

The researchers next plan to test the effect of PGE2 on human muscle stem cells in the laboratory, and to study whether and how aging affects the stem cells’ response. Because PGE2 is also produced by the fetus and placenta during pregnancy, and is approved by the Food and Drug Administration for use in the induction of labor, a path to the clinic could be relatively speedy, they said.

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