Posted on Oct 12, 2023, 6 p.m.
Stanford Medicine researchers have found that a drug that boosts strength in injured or aging mice restores connections between nerves and muscle fibers, their findings published in the journal Science Translational Medicine suggest ways to combat weakness in humans due to aging, injury, or disease.
The anti-aging molecule blocks the activity of an aging-associated gerozyme called 15-PGDH which naturally increases in muscles with age. Levels of this gerozyme also increase in the muscles after nerve damage and it is prevalent in muscle fibers of those with neuromuscular diseases.
This study showed that damaged motor neurons can be induced to regenerate in response to a drug treatment, and after treatment lost strength and muscle mass can be at least partially regained, at least in mice. If these results can be reproduced in humans, the drug may one day be used to help prevent the loss of muscle strength due to aging, disease, or injury. This can be especially relevant to sarcopenia, or debilitating muscle frailty which affects around 30% of those over the age of 80 years old and costs nearly $380 billion annually in America alone.
“There is an urgent, unmet need for drug treatments that can increase muscle strength due to aging, injury, or disease,” said Helen Blau, PhD, professor of microbiology and immunology. “This is the first time a drug treatment has been shown to affect both muscle fibers and the motor neurons that stimulate them to contract in order to speed healing and restore strength and muscle mass. It’s unique.”
In 2021, the same group showed that blocking the activity of 15-PGDH in aged mice significantly enhanced leg strength and endurance during treadmill testing, but exactly how this was happening was less clear. The new research shows that the effect is due to restoring lost connections between the nerves and muscles. The lost connections called neuromuscular junctions are how the brain signals muscles to contract, but with age, some of these connections are lost, causing muscle contractions to become less powerful and muscles to atrophy.
Typically most people will lose muscle mass and strength with age, especially after the age of 50, and some people can lose as much as 50% per decade. But conditions other than aging can also destabilize these connections such as muscle-wasting diseases, and disuse of muscles due to bedrest after illness or injury.
Other research has also shown that PGE2 molecules are critical to the function of stem cells in muscle fibers that repair damage, including the microtears from exercise that lead to increases in muscle mass and strength. Levels of 15-PGDH were shown to break down PGE2 with age, but loss of strength with aging could be overcome by inhibiting the degrading activity of the gerozyme 15-PGDH.
“PGE2 is part of the body’s natural healing mechanism, and its levels increase in muscle after injury,” Blau said. “We wanted to learn how age triggers an increase in 15-PGDH, and therefore the degradation and loss of PGE2.”
“We found that when you cut the nerve that innervates the leg muscles of mice, the amount of 15-PGDH in the muscle increases rapidly and dramatically,” Blau said. “This was an exciting new insight. But what surprised us most was that when these mice are treated with a drug that inhibits 15-PGDH activity, the nerve grows back and makes contact with the muscle more quickly than in control animals, and that this leads to a faster recovery of strength and function.”
Additional research showed that treatment with a drug restored neuromuscular junctions lost during aging and increased muscle function and strength in aged mice. Discrete clumps of 15-PGDH were also identified in the muscle fibers of people with several types of neuromuscular disorders, suggesting that the gerozyme may have a role in causing human disorders. The researchers hope to launch human clinical trials within the near future and plan to investigate how neural growth is stimulated by blocking 15-PGDH activity at a molecular level.
“Our next steps will be to examine whether blocking 15-PGDH function in people with spinal muscular atrophy can increase lost muscle strength in combination with gene therapy or other treatments,” Blau said. “We are also looking at ALS to see if something like this might help these patients. It’s really exciting that we are able to affect both muscle function and motor neuron growth.”
Blau is an inventor of several patents related to the research and a co-founder, and consultant, as well as an equity holder of Epirium Bio, which has licensed patents regarding 15-PGDH inhibition to improve muscle strength.
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