Inflammatory molecule essential to muscle regeneration in mice, researchers find

June 12, 2017, Stanford University Medical Center
Credit: CC0 Public Domain

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 strength, the researchers reported.

However, a nonsteroidal, anti-inflammatory drug like aspirin or ibuprofen—drugs frequently taken to reduce the after injury or exercise—blocked production of the metabolite and dramatically inhibited 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 in living animals. We postulated that we could enhance by simply augmenting this natural physiological process in existing stem already located along the muscle fiber."

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

Metabolite infiltrates muscle fiber

Muscle stem cells usually nestle quietly along the . They spring into action when a muscle is damaged by trauma or overuse, dividing rapidly to generate enough to repair the injury. But it's not entirely clear what signals present in inflammation activate the stem cells.

Prostaglandin E2, or PGE2, is a metabolite produced by immune cells that infiltrate the muscle fiber as well by the itself in response to injury. Anti-inflammatory treatments have been shown to adversely affect muscle recovery, but because they affect many different pathways, it's been tough to identify who the real players are in muscle regeneration.

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

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

'We saw a profound effect'

"This transient pulse of PGE2 is a natural response to injury," said Blau. "When we tested the effect of a one-day exposure to PGE2 on muscle stem cells growing in culture, we saw a profound effect on the proliferation of the cells. One week after a single one-day exposure, the number 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 of PGE2 into the legs of the mice after .

"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 or trauma, or even to combat natural aging."

Explore further: Stem cells may be the key to staying strong in old age

More information: Andrew T. V. Ho el al., "Prostaglandin E2 is essential for efficacious skeletal muscle stem-cell function, augmenting regeneration and strength," PNAS (2017).

Related Stories

Stem cells may be the key to staying strong in old age

June 6, 2017
University of Rochester Medical Center researchers have discovered that loss of muscle stem cells is the main driving force behind muscle decline in old age in mice. Their finding challenges the current prevailing theory ...

Regenerating muscle from stem cells

October 28, 2016
A microscopic image of a mouse leg that has been reconstructed with a stem cell transplant shows what may one day help patients regrow new muscle after a major surgery.

Scientists speed up muscle repair—could fight dystrophy

October 5, 2016
Athletes, the elderly and those with degenerative muscle disease would all benefit from accelerated muscle repair. When skeletal muscles, those connected to the bone, are injured, muscle stem cells wake up from a dormant ...

Exercise may have therapeutic potential for expediting muscle repair in older populations

June 17, 2016
Here's another reason why you should hit the gym regularly as you grow older: A new report appearing online in The FASEB Journal shows that regular exercise plays a critical role in helping muscles repair themselves as quickly ...

At the right place at the right time—new insights into muscle stem cells

September 17, 2012
Muscles have a pool of stem cells which provides a source for muscle growth and for regeneration of injured muscles. The stem cells must reside in special niches of the muscle for efficient growth and repair.

Scientist identify first steps in muscle regeneration

May 20, 2016
Scientists from Monash University's Australian Regenerative Medicine Institute ARMI have found the first real evidence of how muscles may be triggered to regenerate or heal when damaged. The research could open the way to ...

Recommended for you

Gene mutation found to cause macrocephaly and intellectual deficits

November 13, 2018
The absence of one copy of a single gene in the brain causes a rare, as-yet-unnamed neurological disorder, according to new research that builds on decades of work by a University at Buffalo biochemist and his colleagues.

Can scientists change mucus to make it easier to clear, limiting harm to lungs?

November 12, 2018
For healthy people, mucus is our friend. It traps potential pathogens so our airways can dispatch nasty bugs before they cause harm to our lungs. But for people with conditions such as cystic fibrosis (CF) and chronic obstructive ...

Mutations, CRISPR, and the biology behind movement disorders

November 12, 2018
Scientists at the RIKEN Center for Brain Science (CBS) in Japan have discovered how mutations related to a group of movement disorders produce their effects. Published in Proceedings of the National Academy of Sciences, the ...

Researchers explain how your muscles form

November 12, 2018
All vertebrates need muscles to function; they are the most abundant tissue in the human body and are integral to movement.

Salmonella found to be resistant to different classes of antibiotics

November 12, 2018
Brazil's Ministry of Health received reports of 11,524 outbreaks of foodborne diseases between 2000 and 2015, with 219,909 individuals falling sick and 167 dying from such diseases. Bacteria caused most outbreaks of such ...

High fat diet has lasting effects on the liver

November 9, 2018
Consuming a high-fat, high-sugar diet causes a harmful accumulation of fat in the liver that may not reverse even after switching to a healthier diet, according to a new study by scientists from Weill Cornell Medicine and ...


Please sign in to add a comment. Registration is free, and takes less than a minute. Read more

Click here to reset your password.
Sign in to get notified via email when new comments are made.