New research from Stanford Medicine has found that a single, short-term exposure to a signaling molecule involved in inflammation, coupled with exercise, can restore muscle strength in old mice.

The molecule, called prostaglandin E2, or PGE2, is part of the body’s natural healing process initiated after damage or exercise.

The study isn’t the first to implicate PGE2 in mitigating the age-related loss of muscle strength. But it is the first to show that even a brief exposure to PGE2 rejuvenates muscle stem cells by erasing biochemical tags on their DNA that accumulate during aging. These tags — which are passed down to a cell’s daughters during division — hamper the expression of genes involved in self-renewal, survival and muscle stem cell function.

Essentially, a single injection of PGE2 brokers the exchange in muscle stem cells of a lifetime’s worth of genetic bookmarks and dog-eared pages for a crisp new set of instructions that not only enhances the function of individual muscle stem cells but is also passed down to their descendants.

Although the research was conducted in mice, the findings have implications for the more than 15% of people over 60 who suffer from an age-related loss of strength and muscle wasting phenomenon called sarcopenia. In addition, it might aid those with muscle wasting diseases such as Duchenne muscular dystrophy. Tantalizingly, it may also benefit healthy older adults who want to maintain muscle strength in their later years.

“A single injection of prostaglandin E2 shortly after muscle injury causes an increase in muscle mass and strength two weeks later,” said Helen Blau, PhD, professor of microbiology and immunology. “And it creates a heritable memory: The resulting remarkable increase in stem cell function is conveyed to their progeny — their cellular children and grandchildren. If the muscles are injured again, with a toxin or through exercise, the stem cells remain rejuvenated and can meet the need for regeneration. It would be terrific if we could confer a similar increase in function and strength in aged people, who develop anabolic resistance, or an inability to build strength, irrespective of exercise.”

Blau, who directs the Baxter Laboratory for Stem Cell Biology and is the Donald E. and Delia B. Baxter Foundation Professor, is the senior author of the research, which was published online June 12 in Cell Stem Cell. Former senior scientists Yu Xin (Will) Wang, PhD, Adelaida Palla, PhD, and Andrew Ho, PhD, are the lead authors of the study.

The life of a muscle stem cell
Blau and her colleagues have been on the hunt for molecules involved in age-related muscle weakness for years. They have focused on muscle stem cells, which nestle along muscle fibers and jump into action when muscles are damaged by exercise (a natural process) or trauma. Often, when activated muscle stem cells divide, one daughter cell remains a muscle stem cell to maintain the pool of stem cells, and the other develops into a progenitor cell called a myoblast that can give rise to specialized cells to repair the damage. But as we age, muscle stem cells become increasingly unable to perform their duties — either dying during or after cell division or committing both daughters to becoming myoblasts, which depletes the stem cell pool.

“We’ve shown in the past that two-thirds of these old stem cells are dysfunctional,” Blau said. “They die prematurely before they can repair any damage. We wondered whether the PGE2 signaling pathway could rescue them from this fate.”

Previous studies in Blau’s lab determined that PGE2 plays a potent role in activating muscle stem cells after injury. Another molecule, 15-PGDH, which breaks down PGE2, increases in abundance as mice age. As PGE2 levels fall, muscles become less able to regenerate and contract more weakly, and connections between the muscles and the surrounding nerves are impeded — all of which conspire to cause the animals to grow weaker. Blau coined the term gerozyme to describe 15-PGDH’s role as a master regulator of muscle aging.

Blocking the activity of 15-PGDH in 24-month-old laboratory mice significantly enhanced the aged animals’ leg strength and endurance when they were running on a treadmill (laboratory mice typically live about 26 to 30 months). The improvement in endurance suggests that the gerozyme may play a key role in the aging of other tissues including the heart and lungs and that its inhibition may have bodywide beneficial effects.

In the current study, the researchers explored exactly how PGE2 turns the clock back in old muscle stem cells. When they grew muscle stem cells from old mice in the laboratory, they saw in time-lapse movies that the cells divided more robustly and lived longer — up to six generations — after exposure to PGE2. An in-depth look at the cells’ inner workings showed why: The expression of genes involved in cell death pathways or premature specialization was elevated in untreated aged muscle stem cells but not in PGE2-treated aged stem cells.

A deep dive into the genomes of the cells found that the DNA of aged muscle stem cells was more open in a distinct set of genetic regions — allowing access to nuclear machinery essential to gene expression necessary to produce proteins associated with cell death and precocious commitment. In contrast, younger muscle stem cells or old muscle stem cells treated with PGE2 packaged their DNA in conformations that render a different set of genetic regions open — promoting the expression of genes involved in cell division, self-renewal and regeneration. These patterns of DNA packaging are governed in part by chemical tags on the DNA that are passed down from mother to daughter cells during cell division.

“PGE2 is restoring the cells’ viability and ability to divide and rejuvenating their ability to regenerate and repair muscle damage,” Blau said. “And it does so by inducing a heritable molecular memory.”

The effect of this PGE2-induced molecular memory in old mice (all animals were more than 25 months old) was dramatic. A single injection of a modified PGE2 into leg muscles of aged mice two days after toxin-induced muscle injury triggered muscle stem cells to spring into action; two weeks after the injury, the treated animals’ leg muscles had more muscle stem cells, were bulkier and were significantly more powerful than those of the untreated animals.

“This was really quite exciting,” Blau said. “But a toxin-induced injury doesn’t really reflect what is happening in our daily lives. So, we experimented with a more natural, exercise-induced injury, caused by running on a treadmill. This is a good kind of injury that in younger people or animals helps build muscle mass, but the muscle stem cells of older people are generally unable to meet this need.”

Muscle gain
They found that aged animals that were treated with a more stable form of PGE2 that is not readily broken down by 15-PGDH and that exercised regularly on a downhill treadmill for two weeks (a type of exercise called eccentric exercise that promotes muscle growth) gained more muscle and were markedly stronger than those of controls two weeks after regular exercise had concluded.

Blau and her colleagues are now studying whether similar molecular changes govern muscle strength in humans.

“We’re comparing healthy older people with those with sarcopenia to identify the molecular signature in muscle stem cells and muscle fibers that distinguishes each state, looking for key pathways that have gone awry,” Blau said. “Can we identify who might be most at risk for future muscle wasting? And who may benefit most from drug treatment? The jury is out for now, but the implications of this research are very exciting.”

Source: https://med.stanford.edu/news/all-news/2025/06/muscle-aging.html