Stanford Researchers Find Culprit In Muscle Aging And How To Knock It Down
By Deborah Borfitz
March 17, 2021 | For well over a decade now, scientists have been experimenting with “couch potato” drugs that could confer the benefits of exercise without having to flex a muscle. The latest candidate is a small molecule inhibitor impeding the degradation of prostaglandin E2 (PGE2), recently shown to act directly on mature muscle fibers to prevent deleterious molecular changes that arise with aging, according to Helen Blau, professor of microbiology and immunology and director of the Baxter Laboratory for Stem Cell Biology at Stanford University School of Medicine.
In gel form, PGE2 is already being used to induce labor and treat respiratory distress in newborns, says Blau. It now appears that restoring PGE2 later in life could be a way to rejuvenate aging muscles and possibly treat conditions such as age-related muscle atrophy (sarcopenia), Duchenne muscular dystrophy, and other myopathies.
The Stanford researchers previously discovered that PGE2 regulates muscle stem cells and enhances regeneration, and another group showed that knocking out the enzyme responsible for PGE2 synthesis has harmful effects on muscles, says Blau. Her team has now found that levels of PGE2 are lower in older than younger mice while levels of the prostaglandin-degrading enzyme 15-PGDH are elevated, and that partially blocking its activity can restore their strength and endurance.
Expression levels of each prostaglandin was measured using liquid chromatography coupled to tandem mass spectrometry and revealed that elevated 15-PGDH was causative of lowered PGE2, according to Adelaida Palla, Ph.D., senior research scientist at Stanford University. It was unmistakably a driver of muscle atrophy. This was apparent when the gene encoding the enzyme was overexpressed in young mice, causing their muscles to shrink and weaken within a month.
Based on an analysis of publicly available microarray data for young and aged human muscle samples, the researchers also showed 15-PGDH levels rise with aging in people, Blau says. “This is not just a mouse phenomenon.”
The study is newly published in Science (DOI: 10.1126/science.abc8059). Overexpression of 15-PGDH in young mice induced muscle loss, and its short-term inhibition reversed muscle wasting associated with aging. Notably, inhibiting 15-PGDH restored PGE2 in aged muscles to physiological levels characteristic of young muscles. This restoration of PGE2 to youthful levels led to a pronounced increase in strength in elderly mice.
Blau notes that the 15-PGDH inhibitor had a notably robust effect on muscle strength—a roughly 15% gain in the aged mice after one month of treatment. “Humans after the age of 50 lose 10%-15% of their muscle strength and mass per decade, so if they could get that back with a short-term treatment… it would be really remarkable.”
This is the first time 15-PGDH has been tied to aging and, since elevated expression of the marker is detectable in multiple organs, the findings have broad relevance, says Blau. The suggestion is that 15-PGDH might be “a more generalizable marker, a hallmark of aging.”
Master Regulator?
As shown in the recent study, even partially inhibiting 15-PGDH levels restored PGE2 to a youthful level in old mice, making their muscle fibers grow larger so they could run longer on a treadmill, Blau continues. Exercise of this sort involves many body organs—including the heart, lungs, brain, and skin—“so it may be a master regulator of aging.”
A small molecule inhibitor of 15-PGDH was formerly used to promote tissue regeneration in mouse models of colon and liver injury by increasing level of PGE2, Blau says. Since PGE2 stimulates stem cells, the Stanford team reasoned that the same pathway might also be important in aging.
It came as a welcome surprise that elevating PEG2 by inhibiting 15-PGDH led to body-wide improvement in aged mice, she notes. PGE2 has a “very short” half-life, making it difficult to translate into a therapy. “You would have to inject it right into the muscles.”
Inhibiting 15-PGDH raises PGE2 only to levels the body natively sees at a younger age, adds Blau. In the experiment with mice, researchers decreased enzyme activity 30% to 50% for a roughly twofold increase in PGE2—the level seen in young adult mice.
PGE2 levels likely differ person to person, based in part on their exercise habits, says Blau. The beauty of the 15-PGDH inhibitor is “you don’t have to exercise to get the benefits.”
The target audience is not the lazy people, however, but elderly individuals who have had a fall or been bedridden by sickness. “They get weak so quickly and this could help restore their strength so they can be mobile and function, even for a short period, which is really important,” says Blau. “Once they’re on a downhill track they end up being institutionalized because they can’t get off the toilet.”
Clinical Trials Planned
Blau founded the biotech company Myoforte Therapeutics in 2017 to pursue the development of drugs that build muscle strength and capitalize on the body’s own healing mechanisms. The goal of the Stanford University spinoff is to make medicines in compliance with Current Good Manufacturing Practice regulations of the U.S. Food and Drug Administration, she says.
The company was initially focused on the treatment of local muscle atrophy, but has since expanded to multi-systemic conditions, she says. The shift was prompted by the discovery that PGE2 has a role to play in aging and debilitating, muscle-wasting diseases.
The first step is to demonstrate that the effects seen in mice are comparable in humans, Blau says. The initial target is sarcopenia, a major public health problem. Clinical trials could get underway in 2022.
Sarcopenia affects about 15% of individuals aged 65 or older, she says, and leads to a greater incidence of falls, reduced independence, and increased morbidity. Muscle stem cells are key drivers of muscle regeneration, and subpopulations of them exhibit potent regenerative capacity, especially with aging.
“If I could impact quality of life with something that I discovered in my lab it would be so gratifying, a dream come true for me,” says Blau, who has spent most of her career answering more fundamental questions about health and disease.