Exercise benefits our health and stamina. However, the precise molecular signals exercise transmits throughout the body have not yet been clarified. Researchers have now mapped several of the molecules that could mediate these useful effects in our muscles. They hope that this knowledge can identify new treatments for diseases related to impaired muscle function and other health problems.
Physical activity is healthy. Exercise leads to many beneficial changes in the body, which is why exercise remains the most effective way of treating people with a variety of chronic diseases such as type 2 diabetes, cardiovascular diseases and dementia. Since people with illness may have difficulty exercising for various reasons, researchers are currently trying to understand the molecular signals behind the benefits of exercise. A Danish research group has now in collaboration with researchers in Sydney, Australia come closer to this goal.
“A few years ago, we narrowed down the most obvious candidates for muscle molecules to about 500. In the new study, we whittled down this number further by examining the effects across three species (mice, rats and humans). The function of one molecule in human muscles that is activated by exercise, STIM1, was not known. We now hope that finding activation of these new muscle molecules can both help us understand and ultimately help to create pharmaceutical treatments that can mimic exercise,” explains a main author, Erik A. Richter, Professor, Department of Nutrition, Exercise and Sports, University of Copenhagen.
Identical in mice, rats and humans
The researchers used phosphoproteomics to determine which molecules exercise activates. Phosphorylation occurs constantly in the cells of the body. When a phosphate group attaches to the amino acids in a protein, the structure changes, causing the protein to be activated or deactivated. The researchers can use mass spectrometry to measure which proteins are phosphorylated in connection with exercise to identify which proteins change their activity.
“We made a breakthrough a few years ago when we used human muscle biopsies to identify about 1000 phosphorylation sites on 500 proteins, all of which were affected by cycling. This time we compared the human samples with samples from mice running on treadmills and rats whose muscles were electrically stimulated. We found common phosphorylation sites in all three species and thereby the most obvious candidates,” explains Lykke Sylow, Assistant Professor, Department of Exercise, Nutrition and Sports, University of Copenhagen and the other Danish author.
Mechanisms conserved across species are important. Evolution ensures that well-functioning structures are preserved and propagated. A notable common denominator among mice, rats and humans regarding exercise is the phosphorylation of the protein STIM1 – at two sites.
“We identified STIM1 and then tried to manipulate proteins in the muscles of fruit flies. STIM1 is important there too so that the fruit flies do not get tired when flying. So if parallels can be drawn between fruit flies and humans, this indicates that STIM1 is necessary for the muscles to function normally and not get tired too quickly during activity,” explains Lykke Sylow.
The unknown 90%
Although the researchers found that STIM1 alters activity during exercise, based on the phosphorylation pattern during exercise, its function in human muscles has not been determined. However, based on types of cells other than muscle, STIM1 is known to regulate calcium metabolism, and previous experiments have shown precisely that the metabolism of calcium is crucial for adapting muscles to physical activity.
“The calcium balance is decisive for the functioning of our muscles and is regulated by a very intricate transport system in and out of the cells. When you are very tired, calcium levels in the muscles increase, which probably inactivates STIM1 but activates the pumps that pump calcium back into their stores. So the calcium balance can apparently be influenced by influencing STIM1. We do not know exactly how this works, but we hope to learn more about this by studying the structure and activity of STIM1 in more detail,” explains Lykke Sylow.
The research on STIM1 is only a small yet significant step in understanding how the body reacts molecularly to exercise. In their first study, in which the researchers identified 1000 phosphorylation sites and 500 proteins through phosphorylation patterns, as many as 90% of the proteins were previously unknown in connection with exercise. Although there is still a long way to go, the researchers are optimistic.
“The groundbreaking results of the study clearly give us deeper insight into how muscles function. We are now testing whether we can find any similarities between different types of physical exercise, including strength training, sprinting and endurance training. Such studies not only contribute to general biological knowledge but can also potentially help us in developing pharmaceutical methods to help people who, for various reasons, cannot exercise, to give them at least some of the same benefits that exercise provides,” says Erik A. Richter.
Calcium balance plays an important role in other organs and cells, and imbalance is the cause of many serious diseases. In the future, these findings can therefore also be used to better understand the calcium balance in tissues other than muscle and in other contexts than exercise, including various diseases.
“Phosphoproteomics reveals conserved exercise-stimulated signaling and AMPK regulation of store-operated calcium entry” has been published in EMBO Journal. In 2017, the Novo Nordisk Foundation awarded a grant to Erik A. Richter for the project Defining the AMPK-mediated Signalling Network and its Function. In 2018, the Foundation awarded a grant to Lykke Sylow for an excellence project for young researchers within endocrinology and metabolism.
