Researchers have developed compounds that could mimic some of the health benefits of exercise. One day, these could result in new treatments for muscle atrophy, heart failure, and neurodegenerative diseases. Experiments on rodents have proven encouraging. In the not so distant future, these compounds could be as simple to use as popping a pill.

“I don’t like exercise and I know many people don’t or can’t,” Professor Bahaa Eldien Elgendy of the Washington University School of Medicine and lead author of the new study told ZME Science.

“Our motivation comes from the immense health benefits associated with regular exercise. Exercise has been shown to improve various aspects of health, such as cardiovascular function, metabolism, mental well-being, and overall quality of life. However, not everyone is able to engage in regular physical activity due to various barriers, such as age, physical limitations, or medical conditions.”

“This could lead to improved management and prevention of chronic diseases, enhanced cardiovascular function, increased metabolism, and better mental health. Additionally, exercise mimetics could potentially be used as a complement to traditional exercise programs, augmenting the effects and allowing individuals to attain even greater improvements in their health and fitness.”

Mimicking Exercise Through Biochemistry

Exercise triggers changes in our metabolism through the activation of specific proteins called estrogen-related receptors (ERRs). These come in three forms: ERRα, ERRβ, and ERRγ. After nearly ten years of research, Elgendy and his team created a compound named SLU-PP-332. While it activates all three of these receptors, the main target was the difficult-to-activate ERRα. This receptor plays a crucial role in managing the body’s response to exercise stress and other vital muscle functions.

“It required tremendous effort from so many scientists. It takes a village to develop a drug,” said Elgendy, highlighting the challenges of drug discovery.

In experiments on mice, the researchers found that SLU-PP-332 increased the production of a type of muscle fiber that resists fatigue, enhancing the mice’s endurance on a treadmill.

To develop SLU-PP-332, the team meticulously analyzed the structure of ERRs and their binding process with activating molecules. The researchers then used the lessons they learned to craft newer molecules improve upon this interaction. With these, they aimed for a stronger effect than what SLU-PP-332 could achieve. These new compounds show improved stability and reduced toxicity.

“Activation of ERRs by compounds like SLU-PP-332 can lead to increased mitochondrial biogenesis, improved energy metabolism, and enhanced oxidative capacity in cells. These effects are reminiscent of the benefits typically induced by physical activity, as exercise itself can increase mitochondrial function and metabolism in skeletal muscle cells,” said Elgendy.

“By activating ERRs, SLU-PP-332 essentially “tricks” the cells into behaving as if they have experienced exercise, even in the absence of actual physical activity. This activation of ERRs can potentially lead to improved metabolic health, increased endurance, and other benefits similar to those observed with regular exercise.”

By examining RNA from approximately 15,000 genes in rat heart muscle cells, the researchers compared the effectiveness of SLU-PP-332 to that of the new compounds. The new molecules led to a significant increase in RNA signaling, indicating that more genes were activated, including those that mimic the effects of exercise.

Future frontiers

Preliminary studies suggest these new compounds could combat obesity, heart failure, and age-related decline in kidney function. Moreover, they might offer a new approach to treating neurodegenerative disorders like Alzheimer’s disease, thanks to their ability to influence processes in the brain.

However, there is no substitute for proper exercise. The effect of rigorous physical activity is completely holistic, triggering changes throughout the body from the nervous system to muscles to individual cells. You’ll still need to break a sweat in order to gain the full range of benefits that comes with exercise. But for those who are unable to exercise due to physical limitations, these compounds could have a massive impact on quality of life.

The researchers note that these SLU-PP-332-like compounds are a proof of concept. Although the results so far are extremely promising, they want to test the new compounds using animal models, which could later pave the way for clinical trials.

“We are in early phase of development and we anticipate to face challenges as in every drug discovery program. To overcome this challenge, we are conducting rigorous preclinical testing  to ensure safety and efficacy in future human trials. More animal models will be chosen carefully to mimic human physiology closely, and multiple animal models will be used for better validation,” said Elgendy.

The findings were presented this week’s spring meeting of the American Chemical Society (ACS).