Could popping a pill bring someone similar benefits to running on a treadmill or doing resistance training? In new research, scientists moved one step closer to making this a reality and developing a drug that can mimic some of the cellular effects of exercise.
The goal is to make a drug that flips switches in human cells that would normally be activated by exercise. These switches help maintain and regenerate muscle mass and boost the activity of cells' power houses, for example, said principal investigator Bahaa Elgendy, an associate professor of medicinal chemistry and anesthesiology at Washington University School of Medicine in St. Louis.
Being able to trigger these cellular changes without exercise would be useful for older people, people with muscle-wasting disorders and those who might lose muscle mass while taking weight-loss-inducing drugs, such as Ozempic, he told Live Science.
Broadly, it's intended for those who face major physical barriers to exercising. "We're hoping that this can help all of these cases," said Elgendy, who's also the co-founder of Pelagos Pharmaceuticals, a startup aimed at developing these exercise-mimicking drugs, or so-called exercise mimetics.
In a video interview, Elgendy added that the medicines would also be useful for those too busy to get enough exercise or who are "lazy, like myself."
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In previous research, Elgendy and colleagues found a molecule that turns on these exercise switches in cells in lab dishes and in animals. More recently, they've used that molecule as a starting point to develop new compounds that are more potent at mimicking the cellular effects of exercise. They presented these findings Monday (March 18) at the American Chemical Society's (ACS) spring meeting. The work represents a small step toward bringing these drugs to patients.
"This is an early-stage drug discovery program; it's not complete yet," Elgendy said. "If everything goes well, we're hoping [to start human trials] in the next couple of years."
The researchers' quest began with looking for molecules capable of plugging into structures on cells known as "estrogen-related receptors" (ERRs). These are similar to estrogen receptors in terms of their protein and genetic makeup, but despite their name, ERRs don't respond to the hormone estrogen. Rather, they're orphan receptors, meaning scientists don't know what naturally binds to them, Elgendy said.
However, these receptors can be found throughout the body, and they're particularly important in tissues with high energy demands, like skeletal muscles,the heart and brain. For instance, studies of mice's skeletal muscle suggest activating the receptors helps boost the production of fuel by cells' mitochondria, increase the animals' exercise endurance and help cells switch to burning fats instead of sugars.
ERRs come in three flavors — alpha, beta and gamma — and in the past, scientists had found ways of activating the beta and gamma receptors with human-made compounds. But alpha, known to be very prevalent in the brain and in skeletal muscle, proved difficult to target.
"There was a claim that it was not druggable," Elgendy said. But a new molecule made by the team, named SLU-PP-332, can activate all three flavors of ERRs, and alpha most potently. The researchers described the compound in a previous paper published in March 2023 in the journal ACS Chemical Biology.
In lab-dish studies, the compound boosted skeletal muscle's metabolism, and in mice, it improved the rodents' endurance for running and increased their number of fatigue-resistant muscle fibers.
In their latest work, the team iterated upon SLU-PP-332, designing new molecules that would fit more snugly in the three receptors and have higher potency without risking unintended effects. ERRs have a hand in a variety of cellular functions, and are found in cancerous as well as healthy cells. So as they continue drug development, the researchers will have to check that they're primarily mimicking exercise effects without inadvertently tripping other wires in the body.
The team is now testing their newest generation of molecules in animals. They're starting by studying mice whose biology mimics aspects of human heart failure, obesity and kidney dysfunction, to see whether the new compounds could help treat the conditions.
There's also evidence that the ERR alpha receptor is relevant to Alzheimer's disease, as its activity has been linked to lower levels of misfolded proteins in the brain. Treating Alzheimer's and other neurodegenerative disorders is an avenue the team is interested in exploring, Elgendy said.
However, for now, "this is not a drug," he said. "It's never been tested in humans." The researchers have a lot of work to do to test the molecules in animals, see how they're processed by the body and make any necessary tweaks before moving the candidate drugs into people. "Translation takes a lot of time," Elgendy said.
This article is for informational purposes only and is not meant to offer medical advice.
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