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Researchers seek to help prevent and treat disease by studying the effects of exercise

With the aid of an NIH grant, researchers at the School of Medicine are using bioinformatics to identify crucial molecular pathways associated with exercise

The long-term goal of modifying those molecules is to develop medical interventions which mimic the effects of exercise in the body.
The long-term goal of modifying those molecules is to develop medical interventions which mimic the effects of exercise in the body.

University researchers are taking part in an unprecedented research project centered on the biological effects of exercise after receiving a grant from the National Institutes of Health and joining a national consortium of research institutions that includes Stanford University, the University of Florida and Duke University. They are applying Big Data and machine learning techniques, which are methods used to analyze large amounts of often complex data, to a robust molecular map in order to identify the prominent molecules involved in exercise. The long-term goal of modifying those molecules is to develop medical interventions which mimic the effects of exercise in the body.

In 2010, Zhen Yan, director of the Center for Skeletal Muscle Research at the University’s Robert M. Berne Cardiovascular Research Center, and other prominent scientists were invited to a roundtable discussion hosted by the NIH to discuss the future of exercise research. The researchers addressed the mutual consensus that regular physical activity is crucial to fighting numerous chronic conditions, including cardiovascular diseases, diabetes, obesity and depression, among others. The scientists at the conference thus agreed on the importance of conducting further research to determine the deeper molecular causes facilitating exercise’s well-documented benefits.

“Exercise seems to be a regular physical activity and seems to be one of the most effective interventions, but the million dollar question is why exercise is so good,” Yan said. 

In 2016, the NIH’s constituent institutions allocated a total of $170 million to form the Molecular Transducers of Physical Activity Consortium, which consists of multiple educational institutions including the University. MoTrPAC aims to collectively track the molecular mechanisms elicited by exercise in order to better understand how it impacts the health of the body’s tissues and organs. 

Identifying and understanding the particular mechanisms instigated by exercise may allow healthcare providers to apply the findings to prescribe more specific exercise recommendations for their patients. Knowing the exact mechanisms could also allow for treatments which imitate the beneficial bodily effects of exercise for those with limited mobility.

“If we understand the mechanism, we will not only be able to ... manipulate or employ exercise intervention, but we can also use modern medical science to come up with strategies that mimic exercise for people who cannot — for whatever the reason — exercise regularly,” Yan said.

The University’s research team is building their studies off results from NIH’s phase one trials, which involved constructing a molecular map of biological molecules which have been shown to improve and preserve the health of the body’s tissues and organs. Phase one used animal studies and “multi-omics,” which is a methodology they used to analyze bulks of molecular data.

The first step of Yan and the team is to take this molecular map from the NIH and filter through it to identify the exact molecular mechanism responsible for exercise’s health benefits. The team is utilizing machine learning algorithms and Big Data methods to search for the particular molecules that are produced or released into circulation upon performing physical activity.

“Our task is to find a specific route in that map that is critical for this journey,” Yan said.

Upon narrowing down the search to the anticipated candidate molecules, the next step would be to manipulate their expression in animal models by using gene editing to activate or inactivate the expression of the identified molecules in animals. The physiological response of the animals would be consequently observed to determine if the targeted molecule is indeed responsible for eliciting the physiological responses caused by exercise. 

The research team is composed of scientists from multiple disciplines, including genetics, bioinformatics and neuroscience, in attempts to gain an increasingly holistic understanding of the mechanisms responsible for exercise’s benefits. 

Dr. John Lukens, assistant professor and researcher at University’s Department of Neuroscience and the Center for Brain Immunology and Glia, is focusing on how the presence of exercise strengthens connections in the brain and results in improved cognitive function. He plans to change the expression of the molecular pathways identified by bioinformatics methods and consequently put the animals through cognition tasks.

“[Exercise] has also been shown to be really important to prevent things like cognitive decline and things like Alzheimer's disease and that's been appreciated for a long time, but nobody really knows how that works,” Lukens said.

Adding a neurological angle to Yan’s project, Lukens plans to study the animals’ behavior and quantity of neurons in their brains to gain a deeper understanding of how performing exercise impacts mental health conditions such as anxiety and depression. 

“[We will conduct] post analysis, looking at the brains to see if they have any kind of loss of neurons, neurodegeneration, which is the underlying cause of most known brain disorders or mental diseases,” Lukens said.

In addition, combining the effects of regularly performing exercise with stimulation of target molecular pathways will open up new experimental possibilities as factors like changes in hormone levels, oxygen intake and sleep are already induced by the act of exercise alone.

“We just don’t understand the molecular players involved, but if we can identify those, combining exercise and target pathways, you might have a synergistic effect that can really make a difference in somebody’s life,” Lukens said.

A challenge which the team expects to encounter is effectively using bioinformatics to sift through NIH’s broad molecular dataset in order to identify intended beneficial pathways. 

Yan believes that the current pandemic highlights the importance of maintaining a healthy lifestyle that incorporates exercise.

“If anything, the COVID-19 pandemic is a wake-up call that we should really take advantage of a healthy lifestyle, including regular exercise to stay healthy and … be prepared to deal with the current pandemic and future challenges,” Yan said.