A pill that mimics physical exercise, offering some of the same benefits. It would be the dream drug, both for sofa fans, unable to sustain the fatigue of daily 'work outs', and for perfectionist athletes obsessed with results. Doctors have been prescribing for a long time movement as a 'medicine' to improve and protect health. In the not too distant future it could become so in every sense. At least according to what a team of scientists explains in a study presented at the ACS Spring 2024, spring meeting of the American Chemical Society. Researchers report new compounds that appear to be able to mimic the physical push of training inside rodent cells.
The function of the pill and the effects
This discovery could lead to a new way to treat problems such as muscle atrophy and other conditions, including heart failure and neurodegenerative diseases. The main researcher of the project, Bahaa Elgendy, however, clarifies from the start, clearing away easy illusions for non-patients: “We cannot replace exercise, which is important on all levels“says professor at Washington University School of Medicine St. Louis. “If a person can do physical activity, they should go ahead and do it. But there are many cases where a substitute is needed.”
Moving brings benefits to both the mind and the body. Elgendy and colleagues hope to 'synthesize' the powerful effects from a physical perspective: the ability to improve metabolism and muscle cell growth, along with improved muscle performance.
A drug that mimics these effects could compensate for the muscle atrophy and weakness that can occur as people age or have cancer, certain genetic conditions, or conditions that make them unable to engage in regular physical activity. . Or again, Elgendy suggests, the exercise-mimicking pill could also potentially counteract the effects of other drugs, such as the new slimming drugs that cause the loss of both fat and muscle.
How could this work?
How would it work? The metabolic changes associated with exercise, the researchers explain, begin with the activation of specialized proteins, known as estrogen-related receptors (Err), which come in three different forms. After about a decade of work, Elgendy and colleagues developed a compound (SLU-PP-332) that activates all three, including the most demanding version, ERRα, which 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 muscle fiber that was resistant to fatigue, while also improving the animals' endurance when running on a rodent treadmill. To identify the compound useful for the mission, the researchers carefully examined the structure of the receptors and how they bind to the molecules that activate them. Then, to improve on their discovery and develop variants that could be patented, the team designed new molecules to strengthen the interaction with the receptors and thus provoke a stronger response than SLU-PP-332 can provide. While developing the new compounds, the team also optimized the molecules for other characteristics, such as stability and low potential for toxicity.
The team compared the potency of SLU-PP-332 with that of the new molecules by examining the RNA (measure of gene expression) of approximately 15,000 genes in rat heart muscle cells. The new compounds caused a greater increase in the presence of RNA, suggesting that they more potently simulate the effects of physical exercise. Research using SLU-PP-332 suggests that targeting estrogen-related receptors could be useful against specific diseases. In detail, animal studies with this preliminary compound indicate that it may have a benefit for obesity, heart failure or decline in kidney function with age. The updated research results suggest that the new molecules could have similar effects.
The activity of the target receptors under the lens of the experts also appears to counteract harmful processes that occur in the brains of patients diagnosed with Alzheimer's and other neurodegenerative disorders. Although the compound SLU-PP-332 cannot pass into the brain, some new ones have been developed to do so. “In all these conditions, Err receptors play an important role,” Elgendy remarks. “If we had a compound capable of activating them effectively, many beneficial effects could be generated.” The team now hopes to test the new compounds in animal models through Pelagos Pharmaceuticals, a startup co-founded by the experts, who are also examining the possibility of developing the compounds as potential treatments for neurodegenerative disorders.
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