Fight Aging!

The researchers involved in today's research have been investigating the role of prostaglandin E2 (PGE2) in muscle stem cell function for some years. PGE2 levels decline with age, and this appears to be sufficient to cause a sizable fraction of the characteristic loss of muscle mass and strength that accompanies aging, a condition known as sarcopenia. Other lines of evidence point to loss of stem cell function in muscle tissue as the most important proximate cause of sarcopenia.

The best way to establish whether or not a mechanism is important in aging and loss of function is to block, remove, or reverse it and see what happens. Thus researchers identified 15-PGDH as a regulator of PGE2; forcing a reduction in 15-PGDH levels in old mice causes an increase in PGE2 to youthful levels, and a corresponding improvement in muscle function. This may be mediated in part by improved stem cell function, but the data from treated mice, such as the improved mitochondrial function observed in muscle cells, shows that other mechanisms are involved as well.

Small molecule restores muscle strength, boosts endurance in old mice, study finds

Previously, researchers found that a molecule called prostaglandin E2 can activate muscle stem cells that spring into action to repair damaged muscle fibers. "We wondered whether this same pathway might also be important in aging. We were surprised to find that PGE2 not only augments the function of stem cells in regeneration, but also acts on mature muscle fibers. It has a potent dual role." Prostaglandin E2 levels are regulated by 15-PGDH, which breaks down prostaglandin E2. The researchers used a highly sensitive version of mass spectrometry, a method for differentiating closely related molecules, to determine that compared with young mice, the 15-PGDH levels are elevated in the muscles of older animals, and the levels of prostaglandin E2 are lower. They found a similar pattern of 15-PGDH expression in human muscle tissues, as those from people in their 70s and early 80s expressed higher levels than those from people in their mid-20s.

The researchers administered a small molecule that blocks the activity of 15-PGDH to the mice daily for one month and assessed the effect of the treatment on the old and young animals. "We found that, in old mice, even just partially inhibiting 15-PGDH restored prostaglandin E2 to physiological levels found in younger mice. The muscle fibers in these mice grew larger, and were stronger, than before the treatment. The mitochondria were more numerous, and looked and functioned like mitochondria in young muscle." Treated animals were also able to run longer on a treadmill than untreated animals. When researchers performed the reverse experiment - overexpressing 15-PGDH in young mice - the opposite occurred. The animals lost muscle tone and strength, and their muscle fibers shrank and became weaker, like those of old animals.

Finally, the researchers observed the effect of prostaglandin E2 on human myotubes -immature muscle fibers - growing in a lab dish. They found that treating the myotubes with prostaglandin E2 caused them to increase in diameter, and protein synthesis in the myotubes was increased - evidence that prostaglandin E2 worked directly on the muscle cells, not on other cells in the tissue microenvironment. "It's clear that this one regulator, 15-PGDH, has a profound effect on muscle function. We're hopeful that these findings may lead to new ways to improve human health and impact the quality of life for many people. That's one of my main goals."