Researchers have identified new compounds that appear to mimic the physical benefits of exercise within rodent cells, potentially leading to a new way to treat muscle atrophy and other medical conditions in people, including heart failure and neurodegenerative diseases.
This discovery could be especially beneficial for those who are unable to engage in regular physical activity due to age, cancer, genetic conditions, or other factors.
Bahaa Elgendy, the project’s principal investigator and a professor of anesthesiology at Washington University School of Medicine in St. Louis, emphasizes the importance of exercise, stating, “We cannot replace exercise; exercise is important on all levels. 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.”
The researchers focused on specialized proteins called estrogen-related receptors (ERRs), which play a crucial role in the metabolic changes associated with exercise. After nearly a decade of work, they developed a compound named SLU-PP-332 that activates all three forms of ERRs, including the most challenging target, ERRα. In experiments with mice, this compound increased fatigue-resistant muscle fibers and improved the animals’ endurance on a treadmill.
Building upon this discovery, the team designed new molecules to strengthen the interaction with the receptors and provoke a stronger response than SLU-PP-332. They also optimized the molecules for other desirable characteristics, such as stability and low potential for toxicity. When comparing the potency of SLU-PP-332 with the new compounds, the researchers found that the new compounds prompted a greater increase in gene expression, suggesting they more potently simulate the effects of exercise.
Research using SLU-PP-332 indicates that targeting ERRs could be useful against specific diseases, such as obesity, heart failure, and age-related decline in kidney function. The new compounds could potentially have similar effects. Additionally, ERR activity appears to counter damaging processes in the brain associated with Alzheimer’s disease and other neurodegenerative conditions. Some of the new compounds were developed to pass into the brain, which SLU-PP-332 cannot do.
Elgendy and his colleagues plan to test the new compounds in animal models through their startup company, Pelagos Pharmaceuticals, and are exploring the possibility of developing the compounds as potential treatments for neurodegenerative disorders.