AGÊNCIA FAPESP – It is consensus among specialists that the regular practice of physical exercise it is essential to ensure the quality of life and longevity. However, little is known about how this habit affects the functioning of muscle cells. A new study conducted at the Institute of Biomedical Sciences at University of Sao Paulo (ICB-USP) helps to understand, at the cellular level, how physical activity contributes to the maintenance of physical fitness even during aging.
According to the work, supported by FAPESP and published in the journal Proceedings of the National Academy of Sciences (PNAS)the answer is inside mitochondria. This important cellular component, responsible for supplying cells with energy, is constantly remodeling thanks to a phenomenon called mitochondrial dynamics. This organelle can split in two or join a similar one through processes called mitochondrial fission and fusion. Based on this dynamic, the distribution and function of hundreds or thousands of mitochondria present in muscle cells are coordinated.
Through experiments with a very simple model organism, the soil worm Caenorhabditis elegans, the researchers observed that, during aging, fragmented mitochondria (which are dysfunctional) accumulate in muscle cells. But when exercise is practiced regularly throughout life, the frequency of fused mitochondria increases, which benefits both mitochondrial metabolism and cellular functioning, thus contributing to the maintenance of muscle physiology during aging.
“In our work, we have shown that, in muscles, a single session of physical exercise rapidly induces mitochondrial fission. And then, after a recovery period, mitochondrial fusion occurs. Lifelong daily sessions promote the emergence of connected mitochondria, thereby delaying mitochondrial fragmentation and the decline in physical conditioning observed during aging. Thus, exercise and mitochondrial dynamics have shown an important association with the maintenance of muscle function in senescence. It was the missing proof of concept,” says Julio Cesar Batista Ferreira, professor at ICB-USP and research coordinator.
In previous studies, the group had already shown that exercise works in the treatment of cardiovascular disease by promoting the appearance of fused mitochondria in the heart (read more at: agency.fapesp.br/25695/).
But it was still necessary to understand how physical activity affects the aging of healthy organisms. And for this, the researchers chose to use the nematode C. elegans, which is considered an excellent experimental model for studying aging (read more at: agency.fapesp.br/38284/).
“It is very laborious and expensive to carry out an aging study by following individuals or rodents for years, for a lifetime. The advantage of C. elegans is that it bears a number of similarities to humans, but has a life cycle of only 25 days. In this way it was possible to show, for the first time, what happens to an organism that exercises throughout its life and what are the critical cellular events involved in the process,” says Ferreira.
According to the researcher, mitochondrial dynamics are important for maintaining the quantity and quality of mitochondria in the cell and, consequently, the proper functioning of the muscles. Through proteins called GTPases that “cut” and “glue” the mitochondria, fusion or fission of these organelles occurs. “In this way, under conditions of stress, proteins remove the part of the mitochondria that is not working to be destroyed and unite the functional part with other mitochondria. It is in this dynamic of fission and fusion that mitochondrial segregation and the correct functioning of cells take place”.
The study results indicate that both connectivity and the mitochondrial fission and fusion cycle are essential for maintaining fitness and responsiveness to exercise during ageing.
One of the first steps in the study was to develop an exercise protocol for worms. “Generally, these organisms live in a solid medium (in the wild they live on land and in research labs they live in jelly). When we transfer them to a liquid medium, we observe that they increase the frequency of the wave associated with higher energy expenditure, similar to what happens to us humans when we exercise,” says Ferreira.
In this way, the researchers demonstrated that the daily exposure of the worms to the liquid environment results in a series of physiological and biochemical adaptations similar to those observed in humans and exercised rodents. “We found that, when exercised throughout life, the mitochondrial fusion and fission process remains intact during senescence, unlike sedentary worms which accumulate fragmented and dysfunctional mitochondria as early as 10 days of age, when they are considered senile. Regular exercise causes the worm to have a better quality of life, which we measure with different indicators, such as muscle function, mobility, food intake and resistance to different types of stress throughout life. All indicators are better in the worms that have exercised,” he says.
According to Ferreira, even worms that regularly swam into adulthood but became sedentary in old age showed better indicators than those that had always been sedentary. “This happens because there is a cellular memory created by the daily stimuli of physical activity, which depends on the process of mitochondrial fission and fusion and protects these organisms during aging,” she explains.
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Using genetic engineering techniques, the researchers turned off key genes involved in the process of ‘cutting’ and ‘gluing’ mitochondria in worms. This genetic modification has caused accelerated aging, and for these organisms, exercise has started to have a toxic effect, as the remodelling, segregation and removal of dysfunctional mitochondria does not occur. “This confirms the importance of mitochondrial dynamics both for senescence and for the practice of physical activity,” says Ferreira.
In a second part of the study, the researchers investigated whether increased longevity is accompanied by improved fitness in the worms. For this reason, experiments were conducted with strains of worms capable of living up to 40 days thanks to punctual alterations of the genome. Surprisingly, exercise had a toxic effect on four of the five strains of long-lived worms tested in the study.
“We wanted to understand whether increased longevity is associated with the same mechanism for improving fitness and exercise responsiveness throughout life. This is a crucial question as the world’s population is living longer. However, the study showed that longevity is not necessarily related to quality of life. It is worth mentioning that there is no human equivalent for these genetically modified worms and that they live almost twice as long as wild worms,” Ferreira tells Agência Fapesp.
Only one strain of long-lived worms (out of five studied) showed improvement in lifelong fitness. This strain expresses a constitutively active enzyme called AMPK (adenosine monophosphate activated protein kinase), which acts as a metabolic sensor in cells, regulating energy and mitochondrial metabolism. In general, the production of this protein tends to decrease with age.
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“In this experiment, only the worms that had active AMPK throughout their lives (thanks to mutations made in the lab) lived and swam better for longer. However, when we genetically turned off the proteins that regulate mitochondrial dynamics, the effects of AMPK were abolished. In this case, the worms showed reduced fitness and, consequently, a decline in muscle function in old age,” says Ferreira.
Experiments with AMPK suggest that activation of this enzyme may mimic some benefits of exercise by regulating mitochondrial dynamics. “Targeting mechanisms to optimize mitochondrial fission and fusion, as well as AMPK activation, may represent promising strategies for healthy aging, through improvement of muscle biochemical and contractile functions,” says the researcher.
Ferreira explains that the regular physical exercise contributes to healthy ageing, as it regulates the main systems that underlie proper cellular functioning, including mitochondrial dynamics. “However, we know that regular physical activity practice is still extremely low in the population. Certainly public policies that use scientific information are needed to encourage this habit. Furthermore, we cannot forget that pharmacological interventions capable of controlling such processes have the potential to treat various diseases associated with aging,” she says.
The group coordinated by Ferreira at the ICB-USP has, in recent years, developed a molecule called SAMBA capable of facilitating mitochondrial fusion and, consequently, improving the quality of life of animals with heart failure (read more on: agency.fapesp.br/29602/). The compound is currently undergoing preclinical testing for safety and efficacy.
The article Exercise preserves fitness during aging through AMPK and mitochondrial dynamics can be read at: www.pnas.org/doi/10.1073/pnas.2204750120.
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