Contributes to fitness during the aging process.
The study was supported by FAPESP. An article describing this has been published in the Proceedings of the National Academy of Sciences (PNAS).
According to the authors, the answer lies in mitochondria, membrane-bound organelles that generate most of the chemical energy needed to power the cell’s biochemical reactions.
power house of cell
Mitochondria are constantly being remodeled in processes that include fission and fusion. Mitochondrial dynamics control the distribution and functioning of hundreds or thousands of mitochondria in muscle cells.
The researchers investigated the role of mitochondrial dynamics during exercise in the model organism Caenorhabditis elegans, a simple, well-studied microscopic nematode worm species.
The results point to a build-up of fragmented and therefore dysfunctional mitochondria in muscle cells during aging. Regular exercise throughout the subject’s life increases the frequency of mitochondrial fusion, benefiting both mitochondrial metabolism and cellular functioning sufficiently to maintain muscle physiology even in old age.
“In the study, we demonstrated that a single exercise session rapidly induced mitochondrial fission in muscle, followed by a period of recovery by mitochondrial fusion. Daily sessions throughout life led to the appearance of connected mitochondria, delayed fission, and observed during aging.” favors a decline in physical fitness.
In short, we confirmed that Exercise and mitochondrial dynamics are significantly associated with the maintenance of muscle function in chronicity. It was the proof of concept we were looking for,” Julio César Batista Ferreira, last author of the article and a professor at ICB-USP, told Agnia FAPESP.
Previous research from the group has shown that aerobic exercise protects the heart by removing dysfunctional mitochondria and promoting mitochondrial fusion in cardiac cells (read more at agencia.fapesp.br/25890).
The next step was to find out how exercise affects aging in healthy organisms. To do this, the researchers decided to use C. elegans, an experimental model organism often used in metabolism and aging research (read more at agentia.fapesp.br/38425).
“Aging studies that follow people or rodents over years are laborious and expensive. The advantage of C. elegans is that it has many similarities with humans but its life cycle lasts only 25 days, so we are the first to The bars were able to show over time what happens to an organism that exercises over a lifetime, identifying key cellular events in the process,” Ferreira explained.
Mitochondrial quantity and quality, and therefore good muscle functioning, are profoundly affected by mitochondrial dynamics, he said. Fission and fusion are assisted by proteins known as GTPases that divide and divide mitochondria.
“Under stressful conditions, they remove non-functional parts of mitochondria for destruction and functional parts join with other mitochondria. Mitochondrial isolation and substantial cell function result from these fission and fusion dynamics,” he said.
The study results suggest that mitochondrial connectivity and the fission-fusion cycle are essential for maintaining physical fitness and the ability to respond to exercise during aging.
training protocol
In designing the study, the researchers developed an exercise training protocol for the worms. “These organisms mostly live in solid medium [such as soil in nature or gelatin in the laboratory], When we move them into a liquid medium, we find that they increase the frequency of their bending or undulating motion, expending more energy doing so, just as humans do when exercising,” Ferreira said. .
Daily exposure of worms to liquid medium resulted in physiological and biochemical adaptations similar to those observed in humans and rodents after exercise training.
“When they exercised throughout their lives, mitochondrial fission and fusion remained integral in senescence, while fragmented and inactive mitochondria accumulated in sedentary insects at about ten days of life, when they are considered old. References to regular exercise indicators being measured well. Such as muscle function, motility, food intake, and resistance to various types of stress. All these indicators were better in the physically active worms,” he said.
According to Ferreira, the indicators for worms that swam regularly until adulthood but became sedentary when they became older were better than those that had always been sedentary. “The reason is the cellular memory created by daily stimulation of physiological activity from mitochondrial fission and fusion. This protects the organism during aging,” he said.
accelerated aging
Genetic engineering techniques were used to “switch off” key genes. Involved in mitochondrial fission and fusion. This genetic modification resulted in accelerated aging, and exercise became toxic to these insects Since remodeling, isolation and removal of dysfunctional mitochondria did not occur. “This confirms the importance of both mitochondrial dynamics and the benefits of regular exercise,” Ferreira said.
In the second part of the study, the researchers examined whether increased longevity was accompanied by improvements in physical fitness, experimenting with worm offspring capable of living up to 40 days due to changes in parts of their genomes. Surprisingly, Exercise had long-term toxic effects on four of the five genotypes tested.
“We wanted to find out whether the increase in lifespan is associated with improvements in physical fitness and response to exercise throughout one’s life. This is an important matter, given the worldwide increase in human longevity.
However, studies have shown that longevity does not necessarily correlate with quality of life. It should be taken into account that nothing in humans matches these genetically modified worms, which live almost twice as long as wild-type worms,” Ferreira said.
metabolic sensor
Only one long-lived offspring (of the five included in the study) showed improvements in fitness over the course of their entire lives. This lineage expressed more AMP-activated protein kinase (AMP stands for adenosine monophosphate), or AMPK, a constitutively active enzyme that acts as a metabolic sensor in cells, regulating energy and mitochondrial metabolism. AMPK production declines with age.
“In this experiment, only worms with lifelong active AMPK [thanks to mutations produced in the laboratory] Lived and swam better for longer.
Furthermore, when we genetically deleted the proteins controlling mitochondrial dynamics, the effects of AMPK were abolished. In this case, the worms exhibited less physical fitness and consequently decreased muscle function in old age,” Ferreira said.
Experiments with AMPK suggest that activation of the enzyme may mimic some of the benefits of exercise through regulation of mitochondrial dynamics. “Mechanisms that optimize mitochondrial fission and fusion, as well as AMPK activation, may be part of promising strategies for healthy aging, improving muscle contraction and biochemical functions,” Ferreira said.
Regular exercise contributes to healthy aging by regulating mitochondrial dynamics and other systems on which good cellular functioning is based.
“As we know, however, only a small fraction of the population exercises regularly. There is a need for science-based public policy to encourage the habit. Furthermore, we must not forget that the processes involved are pharmacological interventions. could control and potentially treat many aging-related diseases,” he said.
In recent years, the group led by Ferreira at ICB-USP has developed a molecule called “SAMβA” that facilitates mitochondrial fusion and improves the quality of life for animals with heart failure (Agencia.fapesp Read more at .br/29842). The compound is currently undergoing preclinical trials to ensure safety and efficacy.
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