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The notion of substituting the physical and mental health benefits of exercise with a pill may seem far-fetched, but for many individuals unable to engage in regular physical activity due to aging, illness, or disability, this could be a life-changing advancement.

“We cannot replace exercise; exercise is important on all levels,” says study principal investigator Bahaa Elgendy, a professor of anesthesiology at Washington University School of Medicine in St. Louis who is presenting the work at the meeting, in a media release. “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.”

Exercise can boost muscle metabolism, growth, and performance. Researchers aim to replicate these effects pharmacologically to help counteract the muscle deterioration and weakness that come with various conditions, including cancer and genetic disorders. Such a drug could also mitigate the muscle loss associated with certain weight loss medications.

Women exercising

The secret behind the exercise pill lies in the activation of estrogen-related receptors (ERRs), proteins that play a pivotal role in the body’s response to physical activity. After a decade of research, Elgendy’s team developed SLU-PP-332, a compound capable of activating all three forms of ERR, including the challenging ERRα, which is crucial for muscle stress adaptation among other physiological processes. In mouse experiments, SLU-PP-332 showed promising results, enhancing fatigue-resistant muscle fibers and boosting endurance.

To refine their discovery and create patentable variations, the researchers engineered new molecules that interact more effectively with ERRs, aiming for enhanced responses and better properties like stability and low toxicity potential. These new compounds have shown even greater efficacy in preliminary tests, simulating the exercise effect more potently by influencing gene expression in rat heart muscle cells.

SLU-PP-332 and its successors have shown potential in animal studies for addressing obesity, heart failure, and age-related kidney decline. Moreover, ERR activity might combat the brain damage seen in Alzheimer’s disease and other neurodegenerative conditions. While SLU-PP-332 itself cannot cross into the brain, some of the newer compounds are designed to do so, broadening the potential therapeutic applications.

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

Elgendy’s team is not stopping here. Through their startup, Pelagos Pharmaceuticals, they plan to further test these compounds in animal models, with an eye toward developing treatments for neurodegenerative disorders. This research marks a significant step forward in the quest to provide medical alternatives for those who cannot benefit from exercise, promising a future where the effects of physical activity might be just a pill away.

This innovative research, which could pave the way for treating muscle atrophy, heart failure, and neurodegenerative diseases, was unveiled at the American Chemical Society’s (ACS) Spring 2024 meeting in New Orleans.

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