Exciting news for exercise enthusiasts and casual gym-goers: researchers at the University of Michigan have found a protein called Sestrin that has the potential to induce some of the most positive effects of exercise without any training or conditioning. 

The laboratory of Jun Hee Lee, an associate professor of molecular and integrative physiology, is conducting the research. His work focuses on Sestrin, which is produced naturally by cells in response to various environmental stresses, including exercise.

In the future, researchers hope the protein can be used to combat muscle decline in the elderly or people who are immobile.

According to Lee, previous research has shown that Sestrin is linked to metabolism and his lab has been investigating its role in different stress responses for more than 10 years. Recently, research into the protein has linked it to the benefits of exercise-induced stress.

“It has been known that this protein has various metabolic functions, so our idea was that this protein somehow can connect how cells respond to different stresses, so we have been studying this molecule in various stress contexts,” Lee said. “It is known that exercise induces physical and oxidative stress inside muscles, so we thought that maybe Sestrin, as a stress response molecule, can be beneficial for organisms.”

Lee said previous research demonstrated exercise training increases synthesis of Sestrin. His team tested this idea in fruit flies as well.

“We saw more Sestrin after exercise,” Lee said. “Our research showed that more physical activity increases the Sestrin and no physical activity decreases the Sestrin.”

Lee’s lab also collaborated with researchers in Spain to investigate the potential role of Sestrin in muscle atrophy as people age. 

“When we performed those studies in flies and mice we also had a chance to collaborate with a Spanish school who actually focused on the muscle-wasting condition, so their focus is muscle atrophy,” Lee said. “What they found is whenever they immobilize the muscle … they see this Sestrin protein expression is diminished.”

Lee said the collaborators found a correlation between induced Sestrin expression and preventing muscle loss in aging populations.  

“(Sestrin) very dramatically attenuated muscle loss during disuse and even after aging,” Lee said. “So combined with these two stories we think that Sestrin plays a very important role in muscle biology, especially in the focus of physical movement.”

LSA senior Eric Mettetal worked in Lee’s lab for two years and contributed to this project. Mettetal said it is important to understand the mechanisms behind Sestrin expression now that its potential benefits are known.

“Understanding the mechanisms will help us learn ways of potential therapeutic approaches in the future,” Mettetal said. “If Sestrin has been shown to be this important component of how our body responds positively with regards to exercise and if Sestrin has all these beneficial effects regarding metabolism, if we can find a way to harness the power of Sestrin in a sense and its therapeutic potential, this could have really great implications for potential therapies in the future.”

Lee said he planned to uncover these mechanisms of Sestrin expression now that their benefits are so clear.

“It is very exciting because just by altering this singular gene and protein we were able to recapitulate many of the benefits of exercise,” Lee said. “Our goal is to understand how this protein synthesis is regulated and how this protein activity is regulated … by exercise or maybe in the future pharmacologically.”

Lee and his team investigated the specific effects Sestrin has on exercise ability by creating two types of flies: a Sestrin knockout that produced no protein and another which upregulated Sestrin production automatically without exercise. 

These flies were then exercised the same way as the normal wild-type group, the phenotype of the fly’s natural form. The Sestrin knockouts demonstrated no improved endurance over time compared to normal flies.

“We put them on the same exercise scheme,” Lee said, “but exercise didn’t have benefits for these knockout flies … they don’t improve endurance after training.”

Lee said flies that were engineered to overproduce Sestrin out-performed well-conditioned normal flies, even before they underwent specific exercise training.

“When we expressed this protein inside flies, first we had full body expression, and then we found that even without exercise they were performing much better,” Lee said. “When it is overexpressed in muscles specifically it was producing exercise, like extension of endurance.”

Lee said his team then studied Sestrin in mice, using wild-type mice and mice that did not have Sestrin. Lee elaborated on the metabolic effects exercise has on normal mice and how a lack of Sestrin severely diminishes these effects.

“After endurance exercise training the (normal mice) are consuming oxygen in a more efficient way,” Lee said. “They are burning fat … only after vigorous exercise do they burn glucose, but these Sestrin-deficient mice actually have problems in that kind of switching, so even when they are walking they cannot burn the fat, they use glucose.”

Myungjin Kim, a research assistant professor in the department of molecular and integrative physiology, contributed to this project. Kim said the researchers had to incentivize exercise as part of the regiment with mice and found a lack of Sestrin hinders exercise ability. 

“The (mice) are tested on the treadmill, so we give them a very mild electric shock to run,” Kim said. “The Sestrin knockout mice have very inefficient respiratory capacity in their muscles.”

Reporter Hannah Mackay can be reached at mackayh@umich.edu.

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