Summary: Scientists are developing compounds that mimic many of the physiological benefits of physical exercise, offering a potential therapeutic route for conditions such as muscle atrophy, heart failure, obesity-related muscle loss, and neurodegenerative disease. The lead molecule, SLU-PP-332, and newly designed derivatives activate estrogen-related receptors (ERRs), key regulators of muscle metabolism and growth, and show promise in preclinical models for reproducing exercise-like changes in muscle cells.
This approach could provide an alternative for people who cannot perform regular exercise because of advanced age, chronic illness, injury, or other limitations. Supported by grants from the National Institutes of Health, the research represents a major step toward medicines that reproduce important aspects of exercise physiology.
Key Facts:
- SLU-PP-332 Compound: A small molecule that activates the three estrogen-related receptors—ERRα, ERRβ and ERRγ—which are central to exercise-induced adaptations in muscle.
- Potential Medical Applications: By simulating the metabolic and structural effects of exercise, these compounds may help treat muscle weakness, sarcopenia, obesity-associated muscle loss, heart failure, and possibly some neurodegenerative conditions.
- Next Steps: Lead compounds are being advanced and optimized for stability and safety, with plans to test them in animal models through Pelagos Pharmaceuticals, a company founded by members of the research team, and to explore development for neurodegenerative disease treatment.
Source: American Chemical Society
Exercise is a powerful medicine, but not everyone can take it. New research aims to reproduce key benefits of exercise in drug form.
Researchers report progress on molecules that, in rodent cells and animal tests, reproduce biochemical and functional features of physical training. While these compounds are not a substitute for the broad health benefits of being active, they may offer targeted therapeutic effects where exercise is impractical or impossible.
“We cannot replace exercise; exercise is important on all levels,” says Bahaa Elgendy, the project’s principal investigator and a professor of anesthesiology at Washington University School of Medicine in St. Louis. “If someone can exercise, they should. But many patients need alternatives, and that is where an exercise-mimicking drug could help.”
Exercise remodels muscle by activating specific signaling pathways and nuclear receptors that change gene expression, mitochondrial function, and muscle fiber composition. Central among those receptors are the estrogen-related receptors (ERRα, ERRβ, and ERRγ), which coordinate metabolic remodeling and stress adaptation in muscle. Over roughly a decade of work, Elgendy and colleagues designed SLU-PP-332 to engage all three ERR isoforms, including the most elusive target, ERRα.
In mouse studies, SLU-PP-332 increased the proportion of fatigue-resistant muscle fibers and improved endurance performance on a treadmill, demonstrating functional benefits consistent with exercise training. To extend those findings and create compounds suitable for drug development, the team analyzed ERR structures and how activating molecules bind the receptors. They then engineered new derivatives to strengthen receptor interaction, increase potency, and improve pharmacological properties such as stability and reduced toxicity risk.
Comparative tests measured RNA changes across roughly 15,000 genes in rat heart muscle cells to gauge how closely each compound reproduced exercise-like gene expression. Several of the new molecules produced stronger RNA signatures associated with exercise than SLU-PP-332, indicating more robust activation of ERR-driven programs.
Preliminary studies with SLU-PP-332 suggest that ERR activation can counter metabolic dysfunctions tied to obesity, reduce markers of heart failure, and blunt age-related declines in kidney function in animal models. Since ERR pathways also modulate processes implicated in neurodegeneration, the team prioritized developing some derivatives capable of crossing the blood–brain barrier—an attribute SLU-PP-332 lacks—so the compounds might be evaluated for neuroprotective effects in future studies.
“ERRs are central to many of the cellular programs that exercise turns on,” Elgendy explains. “A compound that safely activates these receptors could deliver a range of beneficial outcomes across muscle, metabolic, cardiac, and possibly brain health.”
The researchers plan to advance the most promising candidates into animal testing through Pelagos Pharmaceuticals, the startup they co-founded to support preclinical development and eventual clinical translation. Their goals include confirming efficacy, defining safety profiles, and exploring therapeutic applications for muscle wasting, metabolic disease, heart failure, and select neurodegenerative disorders.
Funding: This work was supported by the National Institute on Aging of the National Institutes of Health under Award Numbers R21AG065657 and RF1AG077160.
About this neuropharmacology research news
Author: Emily Abbott
Source: American Chemical Society
Contact: Emily Abbott, American Chemical Society
Image: The image is credited to Neuroscience News
Original Research: The findings were presented at the ACS Spring 2024 meeting.