Mouse on an exercise bike
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We are all aware of the health benefits of regular exercise, but what if we could reap the rewards of a good workout without any of the effort? Michigan Medicine researchers have found that a conserved class of proteins known as Sestrins can mimic many of the beneficial effects of exercise on metabolism in flies and mice, and boost their physical endurance. The findings could eventually help scientists to devise strategies that combat muscle wasting due to aging or disease. “These results indicate that Sestrin is a key integrating factor that drives the benefits of chronic exercise to metabolism and physical endurance … Sestrin may serve as a promising therapeutic molecule for obtaining exercise-like benefits such as improving mobility and metabolism,” commented the researchers, headed by Myungjin Kim, PhD, a research assistant professor in the department of molecular & integrative physiology, and first author of the team’s published paper in Nature Communications, which is titled, “Sestrins are evolutionarily conserved mediators of exercise benefits.”

As the percentage of older members in the population continues to increase, so do concerns about keeping an aging population healthy and mobile. In fact, elderly people put mobility as their biggest age-related concern, the authors stated. “Mobility is important both for direct health reasons (e.g., preventing falls, retaining access to relatives and health care providers) and for psychological reasons, as it is highly correlated with retained morale personal satisfaction and morale.”

One promising therapeutic intervention that can help to hold back age-related functional decline is endurance exercise, they noted. But endurance exercise isn’t suitable for everyone. While evidence in humans and other animals suggests that endurance exercise has substantially protective effects on measures of healthspan, not everyone can train to the level needed to achieve the resulting health benefits, perhaps due to age, injury, or illness. “Therefore, generation of therapeutic mimetics to induce the benefits of exercise could provide broad ranging benefits to the medical community,” the researchers suggested.

Sestrins are small, stress-inducible proteins that are found throughout the animal kingdom. Mammals express three Sestrins (Sesn1-3), while the fruit fly Drosophila expresses a single Sestrin molecule, dSesn. Both dSesn and mammalian Sesn1 are expressed primarily in skeletal and cardiac muscles. “Researchers have previously observed that Sestrin accumulates in muscle following exercise,” Kim commented. Kim, working with professor Jun Hee Lee, PhD, and a team of researchers, were interested in finding out more about Sestrin’s link with exercise, and first turned to study dSesn in Drosophila.

To do this, their first step was to generate a workout program for training the flies. “We established a protocol for endurance training and measuring physical endurance in Drosophila, which represents the first chronic exercise model in an invertebrate system,” they wrote. Taking advantage of Drosophila flies’ normal instinct to climb up and out of a test tube, collaborators Robert Wessells, PhD, assistant professor & recruitment officer, and Alyson Sujkowski, staff scientist and lab manager, at Wayne State University, developed a type of fly treadmill. The team trained the flies on the treadmill for for three weeks, and compared the ability of normal, control animals to run and fly with that of flies that were bred to lack the ability to make Sestrin (Sestrin-/- flies). They found that the Sestrin-deficient Drosophila didn’t build up their endurance in the same way as the control flies.

“Flies can usually run around four to six hours at this point and the normal flies’ abilities improved over that period,” said Lee. “Three weeks of exercise training substantially extended running endurance …” In contrast, Lee noted, “ … the flies without Sestrin did not improve with exercise.”

The team then overexpressed muscle Sestrin in another group of flies, and found that even without any endurance training, just the extra Sestrin was enough to give the animals exercise abilities above and beyond those of trained flies. In fact, flies with overexpressed Sestrin didn’t develop more endurance even when they did exercise. “These results indicate that muscle-specific Sestrin induction is both necessary and sufficient for mediating the endurance benefit of chronic exercise,” the team stated.

Based on their findings in flies, the investigators wanted to see if Sestrin was also required to build up exercise endurance in mice. They found that in normal, wild type mice, running distance, speed, and endurance gradually increased, as expected, as a result of training. However, they found that animals lacking all three mouse Sestrin proteins (triple knockout, or TKO mice) showed no improvements in running distance and speed as a result of training. “When subjected to forced treadmill running, TKO mice performed very poorly with dramatically reduced running time and distance,” the scientists stated.

The beneficial effects of Sestrin extended beyond improved endurance. The studies showed that mice without Sestrin lacked the improved aerobic capacity, improved respiration, and fat burning that are typically associated with exercise. “Rates of oxygen consumption (VO2) remained low throughout forced running and recovery, and maximal aerobic capacity (VO2max) was substantially reduced in TKO mice while basal oxygen consumption rate was unaltered … Therefore, exercise-induced VO2 (ΔVO2) was almost cut in half in TKO mice.” Lee further commented, “We propose that Sestrin can coordinate these biological activities by turning on or off different metabolic pathways. This kind of combined effect is important for producing exercise’s effects.”

Interestingly, a lack of Sestrin in the Drosophila flies only marginally impacted on overall lifespan. This result mirrors findings from previous studies in humans and mice, which have suggested that endurance exercise training improves healthspan but “is not effective for extending maximal lifespan,” the authors explained. In their newly reported studies in Drosophila, the team stated that “ … exercise training improved running capacity and flight performance, but did not increase longevity.”

Lee also worked with collaborator Pura Muñoz-Cánoves, PhD, a senior research professor at Pompeu Fabra University in Spain, to demonstrate that muscle-specific Sestrin can help to prevent atrophy in an immobilized muscle, for example when a limb is in a cast for a long period of time. “This independent study again highlights that Sestrin alone is sufficient to produce many benefits of physical movement and exercise,” said Lee.

As to whether Sestrin supplements might be available any time soon, Lee suggests not. “Sestrins are not small molecules, but we are working to find small molecule modulators of Sestrin.” Scientists will also need to continue research to understand how exercise produces Sestrin in the body. “This is very critical for future study and could lead to a treatment for people who cannot exercise,” Kim noted.

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