PGE2 Treatment Restores Muscle Stem Cell Function in Aged Mice
PGE2 therapy shows promise in reversing muscle aging by restoring stem cell function in older mice.
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Aging populations in developed countries are facing an increasing challenge, as frailty and disability emerge as significant health concerns. Sarcopenia – the age-related loss of muscle mass and function – contributes to heightened frailty and mobility issues in older adults. Those affected are at a higher risk of hospitalization and developing additional comorbidities, often triggered by falls and fractures that lead to rapid health deterioration.
Muscle stem cells, known as myosatellite cells, play a crucial role in muscle development, repair and tissue preservation. However, these cells become dysfunctional with age.
Researchers from Sanford Burnham Prebys have been investigating how aged stem cells differ from those in younger individuals and how to reverse these age-related changes. Their latest study, published in Cell Stem Cell, demonstrated the effectiveness of treating aged mice with a naturally occurring lipid, Prostaglandin E2 (PGE2), which improved muscle regeneration and strength in older animals.
Attempting to slow muscle aging
Skeletal muscle aging is a natural aspect of growing older, marked by progressive declines in muscle strength, mass and function. Signs of sarcopenia typically emerge in an individual’s 30s or 40s and accelerate after age 60. While muscle loss is inevitable, its progression can be slowed through a healthy lifestyle that includes regular physical activity, resistance training and a protein-rich diet – or hastened by sedentary behavior and disease. In recent years, researchers have also intensified efforts to develop therapies aimed at slowing this aspect of aging.
Muscle stem cells play a vital role in the regenerative capacity of skeletal muscle. Known as satellite cells due to their anatomical location, these cells reside between muscle fibers and the surrounding extracellular matrix. As we age, satellite cell dysfunction becomes a key factor in the diminished regenerative potential of muscle tissue. The resulting muscle loss is further exacerbated by a reduced ability to repair damage – such as that caused by falls or surgeries – which can trigger a downward spiral toward frailty, disability and increased mortality.
“We knew that a major contributor [to sarcopenia] is the muscle stem cells that are needed to repair muscle damage. They become dysfunctional with age. We’ve been trying to understand how aged stem cells are different from young and how to reverse these changes,” said Dr. Yu Xin (Will) Wang, an assistant professor in the Center for Cardiovascular and Muscle Diseases, Center for Data Sciences and Cancer Metabolism and Microenvironment Program at Sanford Burnham Prebys.
In the new study, Wang and colleagues at Sanford Burnham Prebys showed that treatment with PGE2 enhanced muscle regeneration and strength in aged mice. The study also revealed how PGE2 therapy works, demonstrating that it counteracts key molecular changes associated with aging in muscle stem cells.
PGE2 treatment restores muscle stem cell function in older mice
The scientists began by examining the effects of PGE2 and its receptor EP4. Their prior research had established that, in young mice, PGE2 signals trigger muscle stem cells to regenerate in the presence of muscle injury.
In aged mice, the team found that EP4 expression on aged muscle stem cells is either lacking or reduced by half of that found in young stem cells.
“PGE2 levels in muscle also decline with age, so we see blunted signaling from reductions in both the messenger and receiver,” said Wang. “PGE2 is an alarm clock to wake up the stem cells and repair the damage. Aging essentially reduces the volume of the alarm and the stem cells have also put on ear plugs.”
However, the researchers discovered it is possible to reset the intensity of this cellular clock, thus overcoming the effects of aging.
By administering a stable form of PGE2 to aged mice after muscle injury and in conjunction with exercise, Wang and the team observed the treated mice had greater muscle mass and strength when compared to the untreated ones.
“What amazes me most is that a single dose of treatment is sufficient to restore muscle stem cell function and that the benefit lasts far beyond the duration of the drug,” said Wang. “In addition to making new muscle, the stem cells stay in the tissue, where they sustain the effect of the PGE2 and instill the muscle with further capacity to regenerate.”
The researchers found that the PGE2 treatment was able to restore stem cell function by modulating the activity of key transcription factors, which reversed many of the age-related changes observed.
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“The genes that are upregulated during the aging process are downregulated after treatment, and vice versa,” Wang said.
Beyond skeletal muscle
In addition to advancing research on muscle regeneration and combating sarcopenia and its associated health risks, Wang and his team aim to expand their research efforts to include other tissues. Their findings suggest that PGE2 plays a crucial role beyond just muscle health, acting through multiple mechanisms that could benefit various tissues in the body.
Wang emphasized, "The evidence suggests that PGE2 is not just acting on one mechanism. We've previously shown that PGE2 can also have a positive impact on muscle fibers and the neurons that innervate them."
This discovery opens the door for a broader application of PGE2 in regenerative medicine, as it has been implicated in the regenerative processes and signaling pathways of several other tissues, including the intestine, liver and others. This suggests a promising direction for restoring the regenerative capacity of aged tissues, offering a potential pathway to address the aging process more holistically.
“The ultimate goal is to improve people’s quality of life by reversing the effects of aging,” concluded Wang.
Reference: Wang YX, Palla AR, Ho ATV, et al. Multiomic profiling reveals that prostaglandin E2 reverses aged muscle stem cell dysfunction, leading to increased regeneration and strength. Cell Stem Cell. 2025. doi: 10.1016/j.stem.2025.05.012
This article is a rework of a press release issued by Sanford Burnham Prebys. Material has been edited for length and content.
