Physical exercises increase the pool of muscle stem cells, responsible for muscle tissue regeneration and maintenance. To understand the molecular mechanism behind this phenomenon, scientists investigated the functions and metabolic characteristics of these cells, in mice submitted to endurance exercise training. They found that the beneficial effects of exercise are associated with metabolic reprogramming of stem cells, including reduced mitochondrial respiration. Inhibition of mitochondrial oxygen consumption promotes increased self-renewal in control muscle stem cells, improving muscle regenerative capacity.

The study was carried out by post-doc Phablo Abreu, under the supervision of Professor Alicia Kowaltowski, from the Instituto de Química at USP and a member of the RIDC Redoxoma, and the results were published in the Journal of Cachexia, Sarcopenia and Muscle.

“For the first time we have been able to see metabolic changes in the mitochondria of muscle stem cells of animals submitted to endurance exercise, and we also have managed to change the fate of these stem cells, altering their metabolism in vitro,” said Kowaltowski.

The loss of muscle mass is one of the main indicators of unhealthy aging in humans and also occurs in several serious diseases. People with some types of tumors, for instance, develop cachexia, characterized by weight loss and muscle atrophy. “That is why preserving muscle mass is so important. Understanding what governs muscle stem cell fate, and the mechanisms involved, is fundamental to improve therapies that preserve muscles in the long term.”

For Phablo Abreu, who is also a physical educator, “this work opens a front for new research on exercises. For example, we know that muscle stem cells decrease in aging, so what will happen if an elderly person exercises?” And he advises everyone: “exercise!”

Inhibition of mitochondrial respiration

In the study, young adult mice were submitted to incremental speed running exercises on a motorized treadmill for five weeks, five days a week, 60 minutes per day. The researchers then carried out experiments in vivo and in vitro, to investigate the function, differentiation, and metabolic characteristics of muscle stem cells, also called satellite cells.

Initially, they found that exercised animals had better physical conditioning, consumed more oxygen, burned more calories, and moved more, compared to sedentary control animals. They also observed that at the end of the period of physical training, the animals showed a significant reduction in body mass. “The reduction in body mass was linked to abdominal fat tissue reduction and muscle mass preservation, confirming what is already well known: that aerobic exercise is an excellent tool for fat mass loss and control of weight loss diets”, Phablo Abreu said.

At the cellular and molecular level, the researchers investigated the expansion of the stem cell pool in exercised animals. Satellite cells remain in a quiescent, dormant state, and are activated in response to a stimulus, such as an injury, for instance. As Phablo explains, these cells can become muscle cells, or produce more satellite cells. In the first case, the process is called differentiation; in the second, self-renewal. “Self-renewal markers were increased in the stem cells of the exercised animals. We saw that exercise was enhancing stemness in adult tissues, which is important for tissue regeneration and maintenance of function throughout life”.

Indeed, analyzing injured tissues, they saw that the exercised animal muscles have better regenerative efficiency, with accelerated muscle repair, fewer inflammatory cells, and less fibrosis induction, compared to control animal muscles.

The next step was to study the metabolic status of isolated stem cells, since these cells are anchored in mature muscle tissue, which consumes more oxygen and generates more energy after aerobic training. The researchers measured the respiration of cells in exercised and sedentary animals and saw that all respiratory parameters were decreased in the stem cells of the exercised animals. “To our surprise, mitochondrial respiration, which shows metabolism in general, was much lower in the stem cells of exercised animals. This is unexpected because the rest of the muscle respires more. But nobody had ever measured it, so we didn’t know what was going to happen”, Kowaltowski said.

To prove the relation between decreased mitochondrial respiration and satellite cell self-renewal, the researchers artificially inhibited the control cell respiration and saw that they became more self-renewing. “When the respiration of a control cell is inhibited, all the self-renewal markers look like those of an exercised cell.” This demonstrates that self-renewal is promoted by respiratory repression seen in exercised cells. They also transplanted these cells into an animal and saw that they generated less inflammation after injury, behaving like the cells of the exercised animals.

Although they were able to partially reproduce the effects of exercise in cells in vitro, the researchers warn: “We do not have an ’exercise pill’ yet. This intervention is not applicable in humans, since we used a poison, antimycin, to inhibit mitochondrial respiration in these cells. But, with this study, we took important steps to understand how exercise and the muscle stem cells metabolism improve muscle regeneration and keep the muscle healthy, and may become an important therapeutic target.”

 The article The Satellite Cell Self-Renewal in Endurance Exercise is Mediated by Inhibition of Mitochondrial Oxygen Consumption, by Phablo Abreu and Alicia J. Kowaltowski, can be accessed here.