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Physical exercise improves the elimination of toxic proteins from muscles

Publicado em 28 setembro 2018

A study published in Scientific reports by researchers from the University of São Paulo (USP) in Brazil, in association with colleagues in the United States and Norway, shows that lack of muscle stimulation results in an accumulation of inadequately processed proteins in muscle cells and consequently leads to weakness muscular or debilitating

This is a typical condition of muscle dysfunction that affects the elderly or individuals suffering from sciatic nerve injury, something usually verified in bedridden patients or workers who spend long hours sitting.

Of the tests with rats with induced lesion of the sciatic nerve, which, therefore, stopped receiving stimuli, the researchers found that this accumulation was caused by the deterioration of autophagy, the cellular machinery responsible for identifying and eliminating proteins and toxins. damaged The analysis of a group of rats undergoing an aerobic training regimen prior to injury allowed the scientists to demonstrate that physical exercise can keep the autophagic system prepared and facilitate its activity when necessary, as in the case of muscle dysfunction due to to the lack of encouragement

"Daily exercise sensitizes the autophagic system, facilitating the elimination of proteins and organelles that are not functional in the muscles.The elimination of these dysfunctional components is very important, when they accumulate they become toxic and contribute to the deterioration and death of muscle cells. " said Julio Cesar Batista Ferreira, professor at the Institute of Biomedical Sciences of the university (ICB-USP) and principal investigator of the study.

Ferreira offered an analogy to help explain the autophagy of muscle cells. "Imagine that the muscles work in a similar way to a refrigerator, which needs electricity to work, if this signal stops because you disconnect the refrigerator or block the neurons that supply the muscles, in a short time, you will find that the food in the refrigerator and the proteins in the muscles will start to spoil at different speeds depending on their composition, "said the researcher, who received support from the São Paulo Research Foundation – FAPESP.

"At this point, an early warning mechanism, present in the cells but not yet in the refrigerators, activates the autophagic system, which identifies, isolates and incinerates the defective material, preventing the propagation of the damage. receives the correct electrical signal for long periods, the early warning mechanism stops working properly and this contributes to the collapse of the cells. "

Food spoiled in a broken refrigerator corresponds to proteins that instead of performing their own function form toxic aggregates, which begin to kill cells. Autophagy can isolate these proteins and destroy them in lysosomes, intracellular organelles that degrade and recycle waste.

"Without autophagy, there is a cascade effect that leads to cell death," said Juliane Cruz Campos. Campos developed part of the study described in Scientific reports during his research PhD. First author of the article, she is currently dedicated to postdoctoral research under the supervision of Ferreira with a grant from FAPESP.

Experiment – method

In the last study, the rats underwent sciatic nerve ligation surgery, creating an effect equivalent to the compression of the sciatic nerve in humans. The pain it causes prevents the individual from using the affected leg and, finally, the affected muscles become weak and atrophy.

Before the surgical procedure, the rats were divided into two groups. One remained sedentary and the other received physical training that consisted of running at 60% of the maximum aerobic capacity for one hour a day, five days a week.

After four weeks of training, surgery was performed and it was discovered that muscle dysfunction induced by sciatic nerve injury was less aggressive in the aerobic exercise group than in the sedentary group. The functional and biochemical parameters in the affected muscles were also evaluated at that time.

"The physical training increased the autophagic flow and, therefore, reduced the levels of dysfunctional proteins in the muscles of the animals.At the same time, exercise improved the contractility properties of muscle tissue," said the FAPESP fellow.

"Exercise is a transitory stress that leaves a memory in the organism, in this case through the autophagic system," explained Ferreira. "When the body is subject to other types of stress, it is better prepared to respond and combat the effects."

Proof of concept

The researchers conducted two other experiments designed to investigate more deeply the link between exercise and autophagy. One experiment used mice in which the ATG7 gene related to autophagy was silenced in the skeletal muscle.

ATG7 encodes a protein responsible for synthesizing a vesicle called autophagosome that forms around dysfunctional organelles and transports them to the lysosome, where they are broken down and digested.

This experiment validated the importance of autophagy in muscle biology because ATG7 knockout mice that had not undergone sciatic nerve ligation showed, however, muscle dysfunction.

In the other experiment, the muscles of rats with sciatic nerve injury and control rats (without the lesion) were treated with a drug called chloroquine, which inhibits autophagy by raising the lysosomal pH (alkalinity) and therefore prevents the degradation of defective proteins.

"The tests showed less muscle strength in the control animals treated with the drug than in the untreated group." Chloroquine had no effect on the muscles of rats with sciatic nerve injury, demonstrating that the inhibition of autophagy is critical for muscle dysfunction caused by lack of stimulation, "said Ferreira.

The researchers note that their studies do not aim to find a treatment for sciatica, one of the most common types of pain. The idea is to use the experimental model in future research to understand the cellular processes involved in muscle dysfunction. This will facilitate the development of new drugs and non-pharmacological interventions capable of minimizing or reversing an increasingly serious problem in contemporary societies, namely, muscle weakness and atrophy due to lack of movement, especially among the elderly.

"If we can identify a molecule that selectively keeps the autophagic system on alert, similar to what happens during physical exercise, we can develop a drug that can be administered to people with muscle dysfunction due to lack of stimulation." with immobilized limbs, people who are bedridden for long periods and even patients with [degenerative] muscle diseases, "said Ferreira.

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