The new discovery could be a treatment for neurodegenerative diseases and heart failure.
An Egyptian researcher and a group of colleagues at Washington University in St. Louis have developed a new chemical compound that can mimic the physical enhancement resulting from exercise, which could lead to a new way to treat muscle atrophy and other medical conditions, including heart failure and neurodegenerative diseases. Scientists have long known that exercise improves health and protects it, but in the future, pills may provide some of the same benefits as exercise. According to results presented at the American Chemical Society's Spring meeting, the drug that mimics these effects could compensate for muscle atrophy and weakness.
It may also be beneficial for older individuals or those affected by cancer or certain genetic conditions or other reasons that make them unable to engage in regular physical activity. It can also be used to counteract the effects of other medications, such as new weight loss drugs that cause loss of both fat and muscle, according to the study's lead author, Dr. Baha El-Gendy, an Egyptian-born researcher and professor at Washington University in St. Louis.
### Mimicking Physiological Effects of Exercise
El-Gendy explained that "the drug does not replace exercise, which offers benefits for both physical and mental health. Exercise is important at all levels, and if I can exercise, I should engage in physical activity, but there are many cases where an alternative is needed." He noted that "the new compound can only mimic the physiological effects of exercise, meaning the ability of exercise to enhance muscle cell metabolism and growth, as well as improve muscle performance."
The metabolic changes associated with exercise begin with the activation of specialized proteins known as estrogen-related receptors (ERRs). When exercising, the body undergoes various metabolic changes to support increased energy demands. Estrogen-related receptors are part of a family of proteins involved in coordinating gene expression related to energy metabolism. When activated by exercise, these receptors help coordinate the expression of genes involved in processes such as glucose and fat metabolism, mitochondrial function, and oxidative metabolism.
### Three Receptors
Essentially, these receptors act as a switch that activates metabolic pathways to enhance energy production and usage during exercise, ensuring that the body has the energy it needs to perform physical activities effectively. These receptors come in three forms: ERRα, ERRβ, and ERRγ.
After nearly a decade of work, the Egyptian researcher and his colleagues developed a compound called SLU-PP-332, which activates all three forms, including the most challenging target known as ERRα. This receptor, or estrogen-related receptor alpha, plays a crucial role in regulating various aspects of cellular metabolism, including energy production and is closely related to estrogen hormone receptors (ERs) but can function independently of estrogen signaling.
This type of receptor mediates adaptation to exercise-induced stress and other important physiological processes in muscles. In experiments conducted on mice, the team found that this compound increases a type of muscle fiber resistant to fatigue while improving the animals' endurance when running on a treadmill.
To determine the expected benefits of SLU-PP-332, the researchers examined the structure of estrogen-related receptors and how they interact with the molecules that activate them. El-Gendy and his team designed new molecules to enhance the interaction with the receptors, thereby eliciting a stronger response than SLU-PP-332 could provide.
When developing the new compounds, the team enhanced the molecules to achieve other desirable properties, such as stability and reduced likelihood of toxicity.
### Improved Compounds
The team compared the effectiveness of SLU-PP-332 with the effectiveness of the new compounds by examining ribonucleic acid (RNA), a measure of gene expression from about 15,000 genes in mouse heart muscle cells. The new compounds led to a greater increase in RNA presence, indicating that they mimic the effects of exercise more effectively.
Research suggests that targeting estrogen-related receptors could be beneficial in treating certain diseases. Studies conducted on animals containing this initial compound suggest it may have benefits against obesity, heart failure, or declining kidney function with aging. Results also indicate that the enhanced compounds could have similar effects.
The study also states that the activity of estrogen-related receptors resists harmful processes occurring in the brains of patients diagnosed with Alzheimer's disease and those suffering from other neurodegenerative conditions. While SLU-PP-332 cannot cross the blood-brain barrier, which restricts the passage of substances and foreign molecules to the brain, some of the new compounds have been developed to do just that.
El-Gendy hopes to test the new compounds in other animal models, and his team is also exploring the potential development of these compounds as treatments for neurodegenerative disorders.
