Blocking protein restores strength, endurance in old mice, study finds


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According to a study conducted by researchers at Stanford University school of Medicine, blocking the activity of a single protein in old mice for one month restores mass and strength to the animals ' withered muscles and helps them run longer on the treadmill. Conversely, increased protein expression in young mice causes atrophy and weakening of their muscles.


"The improvement is really quite impressive," said Helen Blau, Ph. D., Professor of Microbiology and immunology. "Old mice are about 15-20% stronger after one month of treatment, and their muscle fibers look like young muscles. Given that people lose about 10% of their muscle strength in a decade after about 50, this is quite remarkable."


Protein has not previously been involved in aging. The researchers show that the amount of a protein called 15-PGDH is elevated in old muscles and is widely expressed in other old tissues. The experiments they conducted with human tissue offer hope for future treatment of muscle weakness that occurs with age.



Blau, a Professor at the Donald E. and Delia B. Baxter Foundation and Director of the Baxter stem cell biology laboratory, is the senior author of the study, which will be published online December 10 in the journal Science . The lead author is senior researcher Adelaide Palla, PhD.


Loss of muscle mass during aging


The loss of muscle mass during aging is known as sarcopenia, and it costs billions of dollars in health care every year in the United States, as people lose the ability to take care of themselves, fall more often, and become less mobile. This is due to changes in muscle structure and function: muscle fibers contract, and the number and function of cellular power plants, known as mitochondria, are reduced.


Blau and her colleagues have long been interested in understanding muscle function after muscle injuries and diseases such as Duchenne muscular dystrophy. They previously discovered that a molecule called prostaglandin E2 can activate muscle stem cells, which act to repair damaged muscle fibers.


"We wondered if this same pathway might have implications for aging," Blau said. "We were surprised to find that PGE2 not only enhances stem cell function during regeneration, but also acts on Mature muscle fibers. It plays an important dual role."

Prostaglandin E2 levels are regulated by 15-PGDH, which cleaves 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, 15-PGDH levels were elevated in the muscles of older animals, while prostaglandin E2 levels were lower.


They found a similar pattern of 15-PGDH expression in human muscle tissue, as people aged 70 to 80 had higher levels of expression than people aged 20 to 20.


"From our previous work, we knew that prostaglandin E2 is useful for regenerating young muscles," Palla said. "But its short half-life makes it difficult to use in therapy. When we suppressed 15-PGDH, we observed a systemic increase in prostaglandin E2 levels, which resulted in improved muscle mass in older mice."


Inhibition of 15-PGDH


The researchers injected mice with a small molecule that blocks the activity of 15-PGDH daily for one month, and evaluated the effect of the treatment on old and young animals .


"We found that in older mice, even partial inhibition of 15-PGDH restores prostaglandin E2 to the physiological levels found in younger mice," Blau said. "The muscle fibers in these mice are larger and stronger than before the treatment. Mitochondria were more numerous, looked and functioned like mitochondria in young muscles."


Treated animals were also able to run on the treadmill longer than untreated animals.


When Palla and her colleagues performed the reverse experiment-overexpression of 15-PGDH in young mice-the opposite happened. The animals lost muscle tone and strength, and their muscle fibers contracted and became weaker, just like in older animals.


Finally, the researchers observed the effect of prostaglandin E2 on human muscle tubes - immature muscle fibers growing in laboratory dishes. They found that treatment of muscle tubes with prostaglandin E2 caused them to increase in diameter, and protein synthesis in muscle tubes increased-evidence that prostaglandin E2 acts directly on muscle cells, and not on other cells in the tissue microenvironment.



"It is clear that this single regulator, 15-PGDH, has a strong effect on muscle function," Blau said. "We hope that these results can lead to new ways to improve human health and affect the quality of life of many people. This is one of my main goals."


Blau and Palla are studying more about what controls 15-PGDH levels and activity in normal aging and how this can affect the function of other tissues in the body.


"Mice perform better on the treadmill, but it requires more than just an increase in muscle strength," Blau said. "Other organ systems are also involved , such as the heart and lungs. This implies an overall improvement in the function of the entire animal."

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