Researchers report new compounds that appear capable of mimicking the physical drive of exercise—at least in rodent cells. This discovery could lead to a new way to treat muscular dystrophy and other medical conditions in humans, including heart failure and neurodegenerative diseases
Doctors have been prescribing physical exercises for their patients for a long time to improve and protect health. In the future, a pill may offer some of the same benefits as exercise. Now, researchers are reporting new compounds that appear to be able to mimic the physical drive of exercise—at least in rodent cells. This discovery could lead to a new way to treat muscular dystrophy and other medical conditions in people, including heart failure and neurodegenerative diseases.
The researchers presented their results at the spring meeting of the American Chemical Society (ACS). ACS Spring 2024. This is a hybrid convention that takes place virtually and physically between March 17 and 21; It includes almost 12,000 presentations on a variety of scientific topics.
"We cannot replace physical activity; Physical activity is important at all levels," says Bahaa Elgandi, the main researcher of the project, who presented the work at the conference. "If I can exercise, I have to continue and get the physical activity. But there are so many cases where a replacement is required."
Physical activity is beneficial for both mind and body. In this case, Allegandi, a professor of anesthesiology at Washington University School of Medicine in St. Louis, and his colleagues hope to replicate its powerful physical effects—namely, the ability of exercise to improve metabolism and muscle cell growth, along with improving muscle performance.
A drug capable of mimicking these effects could offset the muscle atrophy and weakness that can occur as people age or suffer from cancer, certain genetic conditions or other reasons why they are unable to exercise regularly. It can also counteract the effects of other drugs, such as new weight-loss drugs that cause the loss of both fat and muscle, according to Allegandi.
The metabolic changes associated with physical activity begin with the activation of special proteins, known as estrogen-related receptors (ERRs), which come in three forms: ERRα, ERRβ, and ERRγ. These receptors are found in muscle, heart and brain tissues, and are known to regulate a wide variety of genes related to metabolism, immunity, inflammation, homeostasis, development, cellular growth and reproduction. However, they turned out to be very difficult to tune. Exercise is one of the only ways known today to activate ERRs.
After about a decade of work, Elgandi and his colleagues developed a compound called SLU-PP-332, which activates all three forms, including the most challenging target, ERRα. This type of ERR regulates adaptation to exercise-induced stress and other important physiological processes in muscle. In experiments with mice, the team found that this compound increased a type of fatigue-resistant muscle fiber, improving the animals' endurance when they ran on a rodent treadmill.
ERR activity also appears to counteract harmful processes occurring in the brain in patients diagnosed with Alzheimer's disease and those suffering from other degenerative conditions of the nervous system. While SLU-PP-332 cannot enter the brain, some new compounds have been developed to do so.
"In all these situations, ERRs have a central role," says Elgandi. "If there is a compound that can activate them effectively, so many beneficial effects can be created."
According to Alangadi, this does not mean that SLU-PP-332 is a perfect substitute for exercise, but it appears to activate a molecular pathway that confers many of the benefits of exercise on the heart, brain and kidneys.
Some of the new compounds similar to SLU-PP-332 are even designed to cross the blood-brain barrier, possibly delivering a drug to the brain that can keep the cells there in top shape.
"Many people can't exercise, and a pill can be extremely helpful for mimicking or enhancing the effects of exercise for older people, people with certain diseases, or those who are dealing with muscle loss from the use of other medications," says Elgandi in a clip from the American Chemical Society conference on YouTube.
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