Jumping Jack Gene

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Dr. Mike Roberts, an associate professor in the College of Education, directs the Molecular and Applied Sciences Laboratory in the School of Kinesiology. While much of Roberts’ early career examined the physiological effects of dietary protein and nutritional supplements, he has become increasingly engaged in studying the relationship between muscle physiology and genetics. More specifically, his laboratory has been researching the LINE-1 (or Long Interspersed Nuclear Element-1) gene. Increases in LINE-1 activity have been linked to certain cancers; however, Roberts has focused on examining LINE-1 activity in skeletal muscle. Muscle cancers are exceedingly rare given that muscle cells are not constantly dividing like cells in other cancer-prone tissues. A few researchers have noted that LINE-1 activity in skeletal muscle increases with aging, and Roberts’ laboratory recently replicated these findings in both rats and humans. Currently, Roberts is seeking to determine if exercise interventions can reduce skeletal muscle LINE-1 activity and, if so, determine what this means in regard to maintaining healthy muscle with aging.

“The human genome encodes more than 20,000 genes,” Roberts explained, “and there are typically two copies of each gene: one from the mother, and one from the father. LINE-1 is what’s called a repetitive element in that there are over 500,000 copies of it in the human genome. What’s also fascinating is that this gene is a type of transposable element, or ‘jumping gene,’ termed a retrotransposon.”

‘Jumping genes’ have been known to exist since the 1950s when Barbara McClintock published her research on the contribution of transposable elements to corn kernel coloration. Though her discovery was at the time largely ignored, she was later awarded the Nobel Prize in Medicine for this discovery. Traditional transposable elements, like the ones McClintock discovered, physically remove themselves from one genomic region and re-insert themselves into a different genomic region. LINE-1 elements, on the other hand, are retrotransposons. A LINE-1 element can essentially make a copy of itself and insert the copy into a completely separate genomic region while leaving its original element in place.

“What’s interesting about LINE-1 elements is that many of them can be transcriptionally-active, or turned on,” Roberts said. “Once activated it can encode two proteins which then dock to the mRNA and chaperone it back to the genome where it nicks a random site on DNA to reverse transcribe a new copy into the genome. In non-muscle cells, this can result in catastrophe in the form of irreversible mutations. Muscle cells are unique, however, given that they have multiple nuclei. So we’re trying to sort through how age-related increases in LINE-1 may be contributing to muscle aging.”

A 2013 research paper by John Sedivy’s laboratory at Brown University demonstrated that skeletal muscle LINE-1 activity increased in older mice.

“This really grabbed our attention,” Roberts said. “Our immediate questions became whether or not this occurs in humans as well, and is it possible that this contributes to age-related muscle degeneration?”

Since 2015, Roberts’ doctoral students Matt Romero, Petey Mumford, Paul Roberson and Shelby Osburn have all performed elegant experiments to show that older rats and humans do indeed express more skeletal muscle LINE-1 mRNA.

Precisely how increased LINE-1 mRNA contributes to muscle degeneration, however, is complex, and Roberts’ laboratory is currently trying to tackle that question. Roberts has formed collaborations with some of the country’s most renowned geneticists, including Dr. Jef Boeke, who is a member of the National Academy of Sciences and Director of the Institute for Systems Genetics at New York University Langone Health. Roberts and Romero have also collaborated with Dr. John McCarthy of the University of Kentucky Medical School. Boeke provided McCarthy’s laboratory with transgenic mice, which harbor a special type of LINE-1 in their genome. McCarthy then bred these mice with another set of mice which generated offspring that only express high levels of the LINE-1 gene when given a special chemical in drinking water. Roberts has been receiving tissue from these mice to examine features of LINE-1 activity as well as muscle aging.

“Assuming this mouse model works, it will allow us to determine whether elevating LINE-1 mRNA levels in muscle directly causes muscle degeneration. If this holds true, then we believe that we’ve identified a chief genetic cause of muscle aging.”

While this may seem like a bleak reality of the aging process, Roberts believes his laboratory’s most exciting finding is that exercise reduces markers of skeletal muscle LINE-1 activity.

“We’ve seen that, whether you’re a younger or older human or rat, exercise—both weight training and endurance—decreases the expression of LINE-1 in skeletal muscle.”

Roberts’ laboratory plans on performing lifespan exercise training in rodents to determine if these patterns hold up, and then hopes to replicate the rodent findings to larger and more involved exercise interventions in humans. This research will take between five and 10 years to arrive at definitive answers. Roberts states that none of the past research endeavors or future aspirations could have been or will be possible without the talent and dedication of his doctoral students.

“Matt Romero, who recently defended his dissertation and began a post-doc internship at UCLA, has really been leading this research in my laboratory,” Roberts said. “Matt came to Auburn from New Mexico State University, and he is uniquely situated for this type of research. He has a background in both physiology and genetics.”

“Bringing these two fields together has obvious benefits when we are studying how these jumping genes affect skeletal muscle,” Romero said. “In our work, we will obviously need to employ many different models. The rat studies are tremendously helpful because rats live, eat and exercise in a controlled environment. With humans, we know what their exercise habits are when they are with us, but we don’t know what they do when they leave the laboratory.”

With regard to his Auburn laboratory experience, Romero appreciates the opportunity to forge new paths in the world of research.

“No one else is doing anything exactly like this, and it’s been great to tie my two fields together. Dr. Roberts has been a wonderful mentor, very enthusiastic and supportive. He has really allowed me to find my own niche, and I’m very proud of the work we have done in this laboratory.”

As Romero moves on to begin his UCLA fellowship, he is handing off lead research duties to doctoral student Shelby Osburn, who has been in Roberts’ laboratory since she was an undergraduate student.

“My work here has opened up so many doors for me, and Dr. Roberts and Matt have both taught me so much,” Osburn said. “Research will always be a major part of whatever I do in my future.”

Similar to Romero’s perspective, Osburn said her experiences in the laboratory have been transformative.

“We think LINE-1 damages skeletal muscle, but we do not yet know to what extent, or exactly how exercise mitigates that damage,” she said. “Answering these questions will be our next big conquest.”

Roberts’ laboratory continues to be on the cutting edge of exercise genetics, and his group has been the first in the world to demonstrate that exercise reduces the activity of what he deems a harmful genetic parasite.

"If we continue to confirm this hypothesis with our upcoming experiments, then this will provide yet another example that reinforces the current-day adage that ‘exercise is medicine,’” Roberts concluded. “While we are proud of our work thus far, the broader theme here is performing high-end research at Auburn University, which will ultimately improve the quality of life for humans.”