14 December 2020

Old mice got their strength back

A group of researchers from Stanford University School of Medicine has identified a protein that is the main regulator of muscle function in aging mice, and may also play a role in age-related muscle wasting in humans. Blocking this protein for a month leads to the restoration of muscle mass and strength in old mice by 15-20% and helps them to run longer on the treadmill. Conversely, an increase in protein expression in young mice causes atrophy and weakening of their muscles.

Loss of muscle mass with aging

The loss of muscle mass during aging (sarcopenia) annually leads to the loss of billions of dollars in healthcare 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 the structure and function of muscles: muscle fibers contract, and the number of mitochondria in them decreases.


Mitochondria in the muscle fibers of young mice (left), old mice from the control group (middle) and old mice that have suppressed the function of the 15-PGDH protein (right).

Helen Blau and her colleagues have long been interested in understanding muscle function after injuries and dystrophic diseases. Previously, they found that prostaglandin E2 (PGE2) can activate muscle stem cells, which are needed to repair damaged muscle fibers. In addition, PGE2 affects mature muscle fibers.

The level of PGE2 is regulated by the enzyme 15-hydroxy-prostaglandin dehydrogenase (15-PGDH), which breaks it down. The researchers used highly sensitive mass spectrometry to compare the levels of 15-PGDH and PGE2 in the muscles of young and old mice. They found that older animals had more 15-PGDH and less PGE2 than younger ones.

They found a similar pattern of 15-PGDH expression in human muscle cells: people aged 70-80 years have a higher level of 15-PGDH than people aged 20-20 years.

A previous study by Helen Blau showed that PGE2 is useful for muscle regeneration, but its short half-life makes it difficult to use in therapy. Suppression of the 15-PGDH enzyme led to a systemic increase in PGE2 levels and an increase in muscle strength in older mice.

Inhibition of 15-PGDH

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

They found that in older mice, even partial inhibition of 15-PGDH restores PGE2 to the physiological level found in young mice. Muscle fibers in treated mice became larger and stronger than before therapy, mitochondria became much larger, they looked and functioned like mitochondria in young myocytes.

Old animals after treatment could also run on the treadmill longer than untreated animals.

When the researchers conducted the reverse experiment and caused overexpression of 15-PGDH in young mice, the animals lost muscle tone and strength, and their muscle fibers decreased and became weaker – changes characteristic of aging.

Finally, the researchers observed the effect of PGE2 on human muscle fibers in vitro. They found that the introduction of PGE2 caused them to increase in diameter, and protein synthesis in muscle fibers increased – evidence that this prostaglandin acts directly on myocytes, and not on other cells of the microenvironment.

The authors intend to continue studying the aging process of muscles and find mechanisms that control the level and activity of 15-PGDH in normal aging.

Article by A.R.Palla et al. Inhibition of prostaglandin-degrading enzyme 15-PGDH rejuvenates aged muscle mass and strength is published in the journal Science.

Aminat Adzhieva, portal "Eternal Youth" http://vechnayamolodost.ru based on Stanford Medicine: Small molecule restores muscle strength, boosts endurance in old mice, study finds.

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