Receptor makes mice strong and slim

Mouse on exercise wheel (stock image).

Increasing abdominal girth and shrinking muscles are two common side effects of aging. Researchers at the University of Bonn have discovered a receptor in mice that regulates both effects. Experiments with human cell cultures suggest that the corresponding signaling pathways might also exist in humans. The study, which also involved researchers from Spain, Finland, Belgium, Denmark and the USA, has now been published in the journal Cell Metabolism.

On their surface, cells carry numerous different "antennas," called receptors, which can receive specific signal molecules. These then trigger a specific reaction in the cell. One of these antennas is the A2B receptor. The surfaces of some cells are virtually teeming with it, for example in the so-called brown adipose tissue. Brown adipose tissue, unlike its white-colored counterpart, is not used to store fat. Instead, it burns fat and thereby generates heat.

"In our publication we took a closer look at the A2B receptors in brown adipose tissue," explains Prof. Dr. Alexander Pfeifer from the Institute of Pharmacology and Toxicology at the University Hospital Bonn. "In the course of this we discovered an interesting association: The more A2B a mouse produces, the more heat it generates." Which means the A2B antennas somehow seem to increase the activity of the brown fat cells. But a second observation was even more exciting: Despite their increased fat burning, the animals weigh hardly less than mice with fewer receptors. "They are slimmer, but at the same time have more muscles," explains Pfeifer.

Muscles like a young mouse

In fact, the researchers were able to show that the muscle cells of mice also carry the A2B receptor. When this is stimulated by a small molecule agonist, muscle growth in the rodents is increased. "The receptor regulates both fat burning and muscle development," emphasizes Pfeifer's colleague Dr. Thorsten Gnad, the lead author of the study.

As they age, mice increasingly lose muscle mass -- similar to humans. And just like us, they also tend to gain a lot of fat around the hips over the years. However, if they receive the agonist that activates the A2B receptor, these aging effects are inhibited: Their oxygen consumption (an indicator of energy dissipation) increases by almost half; moreover, after four weeks of treatment they have as much muscle mass as a young animal. "A2B activation can therefore reverse both aging effects to a certain extent," explains Gnad.

In order to see whether the results were also meaningful for humans, the researchers examined human cell cultures and tissue samples. They found that in people with a large number of A2B receptors, the brown adipose tissue works at a higher rate. At the same time, their muscle cells consume more energy, which may indicate that they are also more active and may be more likely to be regenerated.

"Obesity is a growing problem worldwide," emphasizes Prof. Pfeifer. "Every extra pound not only increases the risk of developing diabetes, but also the risk of high blood pressure, vascular damage and therefore heart attacks and strokes. These problems are further exacerbated by muscles that shrink over the years, as they further reduce the body's energy requirements both at rest and in motion." In addition, poor muscle strength has an immense impact on the everyday life of older people, as they are increasingly restricted in their mobility.

The pharmacologists explain that the prospect of having a receptor on hand that might be able to slow down both of these age-related phenomena is therefore highly exciting. However, further research would first have to show to what extent the human mechanisms actually resemble those in mice. Additionally, there is currently no activator of A2B approved for use in humans. This means that little is known about any side effects of such a treatment. "We found no signs of adverse reactions in mice," says Pfeifer. "However, the meaningfulness of the results is, of course, also limited on this matter."

Gnad emphasizes that the success of the study is also the result of good cooperation with numerous international partners: "Nowadays, it is almost impossible to work on complex issues comprehensively without such cooperation."

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Materials provided by University of Bonn. Note: Content may be edited for style and length.

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Journal Reference:

1. Thorsten Gnad, Gemma Navarro, Minna Lahesmaa, Laia Reverte-Salisa, Francesca Copperi, Arnau Cordomi, Jennifer Naumann, Aileen Hochhäuser, Saskia Haufs-Brusberg, Daniela Wenzel, Frank Suhr, Naja Zenius Jespersen, Camilla Scheele, Volodymyr Tsvilovskyy, Christian Brinkmann, Joern Rittweger, Christian Dani, Mathias Kranz, Winnie Deuther-Conrad, Holger K. Eltzschig, Tarja Niemi, Markku Taittonen, Peter Brust, Pirjo Nuutila, Leonardo Pardo, Bernd K. Fleischmann, Matthias Blüher, Rafael Franco, Wilhelm Bloch, Kirsi A. Virtanen, Alexander Pfeifer. Adenosine/A2B Receptor Signaling Ameliorates the Effects of Aging and Counteracts Obesity. Cell Metabolism, 2020; DOI: 10.1016/j.cmet.2020.06.006

A replacement for exercise?

Mouse in exercise wheel (stock image).

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?

Michigan Medicine researchers studying a class of naturally occurring protein called Sestrin have found that it 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.

"Researchers have previously observed that Sestrin accumulates in muscle following exercise," said Myungjin Kim, Ph.D., a research assistant professor in the Department of Molecular & Integrative Physiology. Kim, working with professor Jun Hee Lee, Ph.D. and a team of researchers wanted to know more about the protein's apparent link to exercise. Their first step was to encourage a bunch of flies to work out.

Taking advantage of Drosophila flies' normal instinct to climb up and out of a test tube, their collaborators Robert Wessells, Ph.D. and Alyson Sujkowski 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 ability of normal flies with that 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 Lee. "The flies without Sestrin did not improve with exercise."

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

The beneficial effects of Sestrin include 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 Lee. "This kind of combined effect is important for producing exercise's effects."

Lee also helped another collaborator, Pura Muñoz-Cánoves, Ph.D., 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 type that occurs 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," says Lee.

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

Additionally, adds 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."

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Materials provided by Michigan Medicine - University of Michigan. Original written by Kelly Malcom. Note: Content may be edited for style and length.

Exercise: Psych patients' new natural prescription

Psych patients' new natural prescription

When it comes to inpatient treatment of a range of mental health and mood disorders -- from anxiety and depression to schizophrenia, suicidality and acute psychotic episodes -- a new study suggest that physical exercise is so effective at alleviating patient symptoms that it could reduce patients' time admitted to acute facilities and reliance on psychotropic medications.

"The general attitude of medicine is that you treat the primary problem first, and exercise was never considered to be a life or death treatment option. Now that we know it's so effective, it can become as fundamental as pharmacological intervention," explains David Tomasi, a lecturer at the University of Vermont, psychotherapist and inpatient psychiatry group therapist at the University of Vermont Medical Center and lead researcher of the study.

Practitioners at inpatient psychiatric facilities -- often crowded, acute settings in which patients experience severe distress and discomfort -- typically prescribe psychotropic medications first, rather than natural remedies like physical exercise, to alleviate patients' symptoms such as anger, anxiety and depression. In fact, Tomasi estimates that only a handful of inpatient psychiatric hospitals in the U.S. provide psychotherapist-supported gym facilities exclusively for these patients. Instead, practitioners rely on classical psychotherapeutic and pharmacological frameworks to treat psychiatric symptoms, which they monitor to determine when a patient is ready to be discharged from the facility.

Tomasi, in collaboration with UVMMC's Sheri Gates and Emily Reyns, built a gym exclusively for roughly 100 patients in the medical center's inpatient psychiatry unit, and led and introduced 60-minute structured exercise and nutrition education programs into their treatment plans. The psychotherapists surveyed patients on their mood, self-esteem and self-image both before and after the exercise sessions to gauge the effects of exercise on psychiatric symptoms.

Patients reported lower levels of anger, anxiety and depression, higher self-esteem, and overall improved moods. Tomasi, Gates and Reyns found an average of 95 percent of patients reported that their moods improved after doing the structured exercises, while 63 percent of the patients reported being happy or very happy, as opposed to neutral, sad or very sad, after the exercises. An average of 91.8 of patients also reported that they were pleased with the way their bodies felt after doing the structured exercises.

"The fantastic thing about these results is that, if you're in a psychotic state, you're sort of limited with what you can do in terms of talk therapy or psychotherapy. It's hard to receive a message through talk therapy in that state, whereas with exercise, you can use your body and not rely on emotional intelligence alone" explains Tomasi.

"The priority is to provide more natural strategies for the treatment of mood disorders, depression and anxiety," he adds. "In practice, we hope that every psychiatric facility will include integrative therapies -- in our case, exercise in particular -- as the primary resource for their patients' psycho-physical wellbeing."

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Materials provided by University of Vermont. Note: Content may be edited for style and length.