Doctors have long recommended exercise as one of the best ways to protect or improve health. Now, a new study has shown that in the future we could have a pill that provides benefits similar to those of physical exercise. The authors of the work have reported on novel compounds that seem capable of mimicking the physical boost provided by exercise, as observed in rodent cells.
This finding could also open a new way to treat muscle atrophy and other medical conditions in people, including heart failure and neurodegenerative diseases. The results of this research will be presented at the spring meeting of the American Chemical Society (ACS), which will be held from March 17 to 21.
“We cannot replace exercise; Exercise is important at all levels. If I can exercise, I should. But there are many cases in which a substitute is needed,” said Bahaa Elgendy, principal investigator of the project and professor of anesthesiology at Washington University in St. Louis, who will present the work at the meeting.
Exercise benefits both the mind – emotional and psychological well-being – and the body. In this case, Elgendy and her team seek to replicate its powerful physical effects and, specifically, exercise’s ability to improve metabolism and muscle cell growth, as well as muscle performance.
A drug that can mimic these effects could compensate for muscle atrophy and weakness that occur with aging or as a result of cancer, certain genetic conditions, or other reasons why people cannot engage in regular physical activity. It could also counteract the adverse effects of some medications, such as new weight loss treatments that cause fat and muscle loss, according to Elgendy.
A potential therapy against obesity or heart failure
The metabolic changes associated with exercise begin with the activation of specialized proteins, known as estrogen-related receptors (ERRs), which exist in three forms: ERRα, ERRβ and ERRγ. After about a decade of work, Elgendy and her team developed a compound called SLU-PP-332, which activates all three forms, including the most challenging target, ERRα. This type of ERR 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 fatigue-resistant muscle fiber, also improving the animals’ endurance when running on a rodent treadmill.
To identify SLU-PP-332, the researchers examined the structure of ERRs and how they bind to the molecules that activate them. Then, to improve their discovery and develop variants that could be patented, Elgendy and her team designed new molecules to strengthen the interaction with the receptors and thus provoke a stronger response than what SLU-PP-332 can provide.
The team compared the potency of SLU-PP-332 with that of the new compounds by looking at RNA, a measure of gene expression, of about 15,000 genes in rat heart muscle cells. The new compounds caused a greater increase in the presence of RNA, suggesting that they simulate the effects of exercise more potently.
Animal studies with this preliminary compound indicate that it could be beneficial against obesity, heart failure or the deterioration of kidney function that occurs with age
Research with SLU-PP-332 suggests that targeting ERRs could be useful against specific diseases. Animal studies with this preliminary compound indicate that it could be beneficial against obesity, heart failure or the deterioration of kidney function that occurs with age. The results of the updated research suggest that the new compounds could have similar effects.
ERR activity also appears to counteract harmful processes that occur in the brains of patients diagnosed with Alzheimer’s disease and those who have other neurodegenerative conditions. Although SLU-PP-332 cannot pass into the brain, some new compounds have been developed to do so.
“In all of these conditions, ERRs play an important role,” says Elgendy. “If you have a compound that can activate them effectively, you could generate many beneficial effects.” Elgendy and her team hope to test the new compounds in animal models through Pelagos Pharmaceuticals, a new company they have co-founded. They are also exploring the possibility of developing the compounds as potential treatments for neurodegenerative disorders.
