Doctors have recommended exercise for years as a way to improve and maintain health. However, a pill could eventually provide some of the same advantages as physical activity.

Researchers presented new compounds at the American Chemical Society (ACS) conference that, at least in mouse cells, may replicate the physical drive of exercise. This finding may lead to a unique approach to treating heart failure and neurological disorders as well as muscular atrophy in humans.

Exercise has long been advised by doctors to maintain and enhance health. Someday, a medication could provide some of the same benefits as physical activity. Recently, scientists have reported on new substances that, at least in mouse cells, seem to be able to mimic the physical boost that comes from exercising.

Exercise is beneficial for both the mind and the body. Bahaa Elgendy, a professor of anesthesiology at Washington University School of Medicine in St. Louis, and his colleagues want to replicate exercise’s profound physical benefits, namely its potential to promote muscle cell metabolism and development, as well as muscular function.

“We cannot replace exercise; exercise is important on all levels,” adds Elgendy.

“If I can exercise, I should go ahead and get the physical activity. But there are so many cases in which a substitute is needed.”

A medicine that can mimic these actions might help to balance muscular atrophy and weakening that can develop as individuals age or are unable to exercise regularly due to cancer, certain hereditary diseases, or other causes. Elgendy believes it may also counteract the effects of other treatments, such as new weight-reduction meds that promote both fat and muscle loss.

Exercise causes metabolic changes that activate specific proteins called estrogen-related receptors (ERRs), which are classified into three types: ERRα, ERRβ, and ERRγ.

After a decade of investigation, Elgendy and his colleagues produced a molecule dubbed SLU-PP-332 that activates all three forms, including the most demanding target, ERRα. This form of ERR controls exercise-induced stress modification and other physiological processes in muscle.

In mouse studies, they discovered that this chemical enhanced a fatigue-resistant kind of muscle fiber while simultaneously boosting the animals’ endurance while running on a rodent treadmill.

To find SLU-PP-332, the team looked at the structure of the ERRs and how they attach to molecules that activate them.

Then, to build on their finding and generate patentable variants, Elgendy and his colleagues created additional compounds to increase the contact with the receptors, resulting in a greater reaction than SLU-PP-332.

When creating novel compounds, they tuned the molecules for other desired properties such as stability and low toxicity.

The research team compared the efficacy of SLU-PP-332 to the new chemicals by analyzing RNA, a measure of gene expression, from over 15,000 genes in rat heart muscle cells. The novel chemicals caused a higher rise in the presence of the RNA, suggesting that they more effectively mimic the effects of exercise.

SLU-PP-332-based research reveals that targeting ERRs might be beneficial in the treatment of particular disorders. Animal studies using this early chemical suggest that it may help with obesity, heart failure, and age-related kidney function loss. The current study findings show that the new chemicals may have comparable effects.

ERR activity also seems to counteract brain-damaging processes in people with Alzheimer’s disease and other neurodegenerative disorders. While SLU-PP-332 cannot enter the brain, several of the new chemicals were designed to do so.

“In all of these conditions, ERRs play a major role,” Elgendy notes. “If you have a compound that can activate them effectively, you could generate so many beneficial effects.”

Elgendy and his colleagues want to test the novel chemicals in animal models via Pelagos Pharmaceuticals, a venture they co-founded. They are also investigating the prospect of using the chemicals as therapies for neurological illnesses.

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