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Sestrin Proteins May Provide Benefits of Exercise in Absence of Need to Work Out; Possible Small-Molecule Modulators of Sestrins Might Help Combat Muscle Wasting Due to Age or Disease

Whether it be a brisk walk around the park or high-intensity training at the gym, exercise does a body good. But what if you could harness the benefits of a good workout without ever moving a muscle? Researchers at Michigan Medicine at the University of Michigan and collaborators, studying a class of naturally occurring proteins called Sestrins have found that these proteins can mimic many of exercise's effects in flies and mice. The findings could eventually help scientists combat muscle wasting due to aging and other causes. The results of the researchers’ work were published online on January 13, 2020 in Nature Communications. The open-access article is titled “Sestrins Are Evolutionarily Conserved Mediators of Exercise Benefits.” "Researchers have previously observed that Sestrin accumulates in muscle following exercise," said Myungjin Kim, PhD, a Research Assistant Professor in the Department of Molecular & Integrative Physiology at Michigan Medicine. Working with Professor Jun Hee Lee, PhD, Dr. Kim and a team of collaborating researchers wanted to learn more about the protein's apparent link to exercise. Their first step was to encourage a group of flies to work out. Taking advantage of Drosophila flies' normal instinct to climb up and out of a test tube, collaborators Robert Wessells, PhD, and Alyson Sujkowski, both of Wayne State University in Detroit, developed a type of fly treadmill. Using it, the team trained the flies for three weeks and compared the running and flying abilities of normal flies with those of flies bred to lack the ability to make Sestrin. "Flies can usually run around four to six hours at this point and the normal flies' abilities improved over that period," says Dr. Lee. "The flies without Sestrin did not improve with exercise."

What's more, when the scientists overexpressed Sestrin in the muscles of normal flies, essentially maxing out their Sestrin levels, the scientists found those flies had abilities above and beyond those of the trained flies, even without exercise. In fact, flies with overexpressed Sestrin didn't develop more endurance when exercised.

The beneficial effects of Sestrin included more than just improved endurance. Mice without Sestrin lacked the improved aerobic capacity, improved respiration, and fat burning typically associated with exercise.

"We propose that Sestrin can coordinate these biological activities by turning on or off different metabolic pathways," says Dr.Lee. "This kind of combined effect is important for producing exercise's effects."

According to the researchers, “Sestrins are small stress-inducible proteins that are found throughout the animal kingdom. Mammals express three Sestrins (Sesn1-3), while Drosophila and C. elegans express one Sestrin orthologue (dSesn and cSesn, respectively). dSesn and mammalian Sesn1 are predominantly expressed in skeletal and cardiac muscle.”

“Importantly, Sestrin expression is further increased by exercise training in both humans and mice. Once induced, Sestrins coordinate metabolic homeostasis by regulating multiple signaling pathways. Through its intrinsic oxidoreductase activity and by regulating autophagy, Sestrin can function as an antioxidant to reduce oxidative damage in cells. In addition, through activation of AMPK and modulation of GAP activity towards Rags (GATOR) protein complexes, Sestrins inhibit target of rapamycin complex 1 (TORC1)/S6 kinase (S6K) signaling.”

“Importantly, while Sestrins downregulate TORC1/S6K signaling, they strongly activate TORC2/AKT signaling, independently of the TORC1 regulation. Interestingly, exercise-inducible Sestrins activate both AMPK and AKT effectors that are also upregulated by endurance exercise training. Indeed, upregulation of AMPK signaling and insulin-TORC2/AKT mediates the protective activities of Sestrins against insulin resistance and diabetes. However, none of the former studies examined the actual genetic and physiological roles of Sestrins in the response to exercise.”

Dr. Lee also helped another collaborator, Pura Muñoz-Cánoves, PhD, of Pompeu Fabra University in Spain, to demonstrate that muscle-specific Sestrin can also help prevent atrophy in a muscle that's immobilized, such as the muscle atrophy that occurs when a limb is in a cast for a long period of time.

"This independent study (https://www.nature.com/articles/s41467-019-13832-9) again highlights that Sestrin alone is sufficient to produce many benefits of physical movement and exercise," says Dr. Lee.

Could Sestrin supplements be on the horizon? Not quite, says Dr. Lee. "Sestrins are not small molecules, but we are working to find small molecule modulators of Sestrin."

Additionally, adds Dr. Kim, scientists still don't know 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."

[Press release] [Nature Communicatios article]