Painkillers like ibuprofen and aspirin are often a part of an athlete’s post-exercise regimen after intense workouts. Sore muscles, aches, and stiffness can be more manageable by taking these drugs – collectively called non-steroidal anti-inflammatory drugs, or NSAIDS – to reduce inflammation and pain.

But research suggests that the anti-inflammatory effects of these painkillers might cause more harm than good by preventing muscle repair and regeneration after injury or exercise.

New CIRM-funded research

A new study from Stanford Medicine supports these findings and suggests that a component of the inflammatory process is necessary to promote muscle regeneration. Their study was funded in part by a CIRM grant and was published this week in the Proceedings of the National Academy of Sciences.

Muscle stem cells are scattered throughout skeletal muscle tissue and remain inactive until stimulation triggers division. When muscles are damaged or injured, an inflammatory response involving a cascade of immune cells, molecules and growth factors activates these stem cells, prompting them to regenerate muscle tissue.

The Stanford team found that a molecule called Prostaglandin E2, or PGE2, is released during the inflammatory response and stimulates muscle repair by directly targeting the EP4 receptor on muscle stem cells. The interaction between PGE2 and EP4 causes muscle stem cells to divide and robustly regenerate muscle tissue.

PGE2-mediated muscle repair

Senior author on the study, Dr. Helen Blau, explained her team’s interest in PGE2-mediated muscle repair in a news release,

“Traditionally, inflammation has been considered a natural, but sometimes harmful, response to injury. 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.”

Further studies in mice revealed that injury increased PGE2 levels in muscle tissue and increased EP4 receptor expression on muscle stem cells. This led the authors to test whether a pulse of PGE2 could stimulate muscle stem cells to regenerate muscle tissue.

Confirmation

Their hunch proved right. Co-first author Dr. Adelaida Palla explained,

“When we gave mice a single shot of PGE2 directly to the muscle, it robustly affected muscle regeneration and even increased strength. 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.”

Their research not only adds more evidence against using NSAID painkillers like ibuprofen and aspirin to treat sore muscles, but also suggests that PGE2 could be a natural therapeutic strategy to boost muscle regeneration.

PGE2 is already approved by the US Food and Drug Administration (FDA) to induce labor in pregnant women, and Dr. Blau hopes that further research in her lab will pave the way for repurposing PGE2 to treat muscle injury and other conditions.

“Our goal has always been to find regulators of human muscle stem cells that can be useful in regenerative medicine. 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.”