A new advance in long research to discover a drug that has the same health effects as exercise
Doctors have long prescribed exercise to improve and protect health. In the future, a pill could offer some of the same benefits as exercise. Now researchers have discovered new compounds that appear to be able to mimic the physical stimulus of exercise, at least in rodent cells. This discovery could lead to a new way to treat muscle wasting and other diseases such as heart failure and neurodegenerative diseases.
The researchers presented their results at the spring meeting of the American Chemical Society (ACS). It is a conference with almost 12,000 presentations on various scientific topics.
«We cannot replace movement; Movement is important at all levels,” says Bahaa Elgendy, principal investigator of the project, who presented the work at the meeting. “If I can do sports, I should do physical activity. However, there are many cases where a replacement is needed.
Exercise benefits both the mind and the body. In this case, Elgendy, a professor of anesthesiology at Washington University School of Medicine in St. Louis, and his colleagues hope that the strong physical effects, i.e. muscle performance.
Counteracts muscle loss in old age
A drug that can mimic these effects could counteract muscle loss and weakness that occurs with age, cancer, certain genetic diseases, or other reasons that prevent regular physical activity. Elgendy says it could also counteract the effects of other medications, such as new weight-loss drugs that cause both fat and muscle loss.
The metabolic changes associated with exercise begin with the activation of specialized proteins known as estrogen-related receptors (ERR), which come in three forms: ERRα, ERRβ, and ERRγ. After nearly a decade of work, Elgendy and his colleagues developed a compound called SLU-PP-332 that activates all three forms, including the most difficult target, ERRα. This type of ERR regulates exercise-induced stress adaptation and other important physiological processes in muscle. In experiments with mice, the team found that this compound increased a type of fatigue-resistant muscle fibers while improving the animals’ endurance when running on a rodent treadmill.
To identify SLU-PP-332, the researchers analyzed the structure of ERRs and how they bind to the molecules that activate them. To improve their discovery and develop patentable variations, Elgendy and his team then developed new molecules to enhance the interaction with the receptors, producing a stronger response than SLU-PP-332 can provide. In developing the new compounds, the team also optimized the molecules to obtain other desirable properties such as stability and low toxicity potential.
The team compared the effectiveness of SLU-PP-332 with that of the new compounds by examining the RNA, a measure of gene expression, of about 15,000 genes in rat heart muscle cells. The new compounds led to a greater increase in RNA abundance, suggesting they more closely simulate the effects of exercise.
More mitochondria, fewer chronic diseases
Research with SLU-PP-332 suggests that targeting ERRs could be useful in combating certain diseases. Animal studies of this preliminary compound suggest it may be helpful against obesity, heart failure or worsening kidney function 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 other neurodegenerative diseases. While SLU-PP-332 cannot enter the brain, some of the new compounds are designed to do so.
“ERRs play a fundamental role in all of these diseases,” says Elgendy. “If there is a compound that can effectively activate them, many positive effects could be achieved.”
Elgendy and his colleagues hope to test the new compounds in animal models through Pelagos Pharmaceuticals, a startup they co-founded. They are also exploring the possibility of developing the compounds as potential treatments for neurodegenerative diseases.
REFERENCE
A synthetic ERR agonist alleviates metabolic syndrome
