Strenuous exercise, fasting, hormones improve the elimination of unnecessary, toxic and misfolded proteins in mouse and human cells



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The body's ability to adapt to changing conditions and changing physiological requirements is essential for survival. To do this, each cell must be able to get rid of damaged or unnecessary proteins – a quality control mechanism essential for cellular performance and the health of the entire body.

At present, a Harvard Medical School study shows that intense exercise, fasting and a set of hormones can activate the cell-integrated protein destruction system and improve their ability to purge defective proteins, toxic or useless.

The results, published on February 19 in PNAS, reveal a mechanism until then unknown used by the body to quickly activate the molecular machinery responsible for the removal of unwanted proteins, allowing cells to adapt their protein content to new requirements. The study shows that this mechanism is triggered by fluctuations in hormone levels, which signal changes in physiological conditions.

"Our results show that the body has an integrated mechanism to activate the molecular machinery responsible for the removal of residual proteins, an essential element for cells to adapt to the new conditions," said Alfred Goldberg, author Main of the study. and Professor of Cell Biology at the Blavatnik Institute of Harvard Medical School.

Cell house cleaning in illness and health

Malfunctions in the mechanism of protein removal from cells can lead to the accumulation of misfolded proteins, which clog the cell, interfere with its functions and, over time, precipitate the development of diseases, including neurodegenerative diseases such as ALS and Alzheimer's disease.

The best-studied biochemical system used by cells to remove unwanted proteins is the ubiquitin-proteasome pathway. This involves labeling defective or useless proteins with ubiquitin molecules, a process known as "kiss of death," which marks the destruction of proteins by the protein's destruction unit. cell, the proteasome 26S.

Previous research conducted by Goldberg's laboratory has shown that this machinery can be activated by pharmacological agents increasing the levels of a molecule called cAMP, an intracellular messenger, which in turn activates the protein kinase A enzyme. .

Previous work by the team has shown that cAMP-stimulating drugs improve the destruction of defective or toxic proteins, particularly mutant proteins that can lead to neurodegenerative states.

The new findings however reveal that this quality control process is continuously regulated, independently of drugs, by changes in physiological state and corresponding changes in hormones.

Previous research, including that of Goldberg's lab, has focused primarily on reducing excessive protein degradation, a state of excessive protein extraction that may cause muscle loss in cancer patients, or cause multiple types of muscle atrophy. In fact, a proteasome inhibitor drug, developed by Goldberg and his team, has been widely used for the treatment of multiple myeloma, a type of blood cancer characterized by abnormal accumulation of protein and overwork. proteasomes.

The team's latest work, on the other hand, is focused on developing therapies that do exactly the opposite – reinvigorating the mechanism of removing cell proteins when it's too slow. These latest discoveries open the door – at least conceptually – to such treatments.

"We believe that our results pave the way for the development of therapies that exploit the natural ability of cells to eliminate protein and thus improve the elimination of the toxic proteins that cause disease," said Jordan VerPlank, researcher Main of the study, postdoctoral researcher in cells. biology at the Blavatnik Institute of Harvard Medical School.

The team said that such treatments would not necessarily involve the design of new molecules, but would boost the cell's intrinsic ability to control quality.

"It's really a new way to see if we can improve the cellular vacuum," Goldberg said. "We thought this would require the development of new types of molecules, but we did not really understand that our cells are continually activating this process.

"The beauty and surprise is that these new treatments may involve transforming a natural endogenous pathway and exploiting the body's pre-existing ability to perform quality control," he added.

The researchers said that this exercise already had many beneficial effects, but new findings also suggest that exercise and fasting could help reduce the risk of developing conditions associated with misfolded protein accumulation. , such as Alzheimer's and Parkinson's diseases. This possibility however remains to be explored in subsequent research, noted the team.

In their experiments, the researchers analyzed the effects of exercise on the cells obtained from the thigh muscles of four human volunteers before and after intense sports activity. After exercise, the proteasomes of these cells exhibited significantly more molecular markers of increased protein degradation, including greater amounts of cAMP, the chemical trigger that initiates the cascade leading to protein breakdown in cells. The same changes were observed in the muscles of anesthetized rats whose hind limbs were stimulated to contract several times.

Fasting, even for short periods, had a similar effect on the mechanism of cell protein degradation. Fasting increased proteasome activity in the muscle and liver cells of mice deprived of food for 12 hours, the equivalent of a nocturnal fasting.

In another series of experiments, researchers exposed mouse liver cells to glucagon, a hormone that stimulates glucose production as a fuel for cells and tissues during periods of starvation or when the blood sugar drops. The researchers observed that exposure to glucagon stimulated proteasome activity and enhanced the ability of cells to destroy misfolded proteins.

Exposure to epinephrine, a fight or flight hormone, had a similar effect. Epinephrine, or adrenaline in common language, is responsible for stimulating the liver and muscles to mobilize energy stores to stimulate heart rate and muscle strength during periods of physiological stress. Hepatic cells treated with epinephrine exhibited a marked increase in cAMP, as well as increased 26S proteasome activity and protein degradation. Exposure to epinephrine also stimulated proteasome activity – a marker of protein degradation – in rat hearts. Similarly, when researchers exposed mouse kidney cells to vasopressin – the antidiuretic hormone that helps the body retain water and prevent dehydration – they also observed higher levels of protein degradation.

Taken together, these results demonstrate that the rate of protein degradation can increase and decrease rapidly in a variety of tissues in response to changing conditions and that these changes are mediated by fluctuations in hormone levels. This response was also surprisingly fast and short-lived, the scientists noted. For example, exposure to antidiuretic hormones triggered protein breakdown in kidney cells in less than five minutes and regained its pre-exposure level in one hour, experiments showed.

The results show that a set of hormones that stimulate intracellular messenger cAMP seem to share a common mechanism that changes cell composition. It has long been known that cAMP stimulating hormones alter gene expression, but these latest researches reveal that they also play a crucial role in the cellular "household" by eliminating the proteins that are not present in the cells. No longer needed.

A new twist on a classic concept

Even the most mundane activities – eating, sleeping, exercising – require the cells of our body that they modulate their composition minute by minute in order to cope with the new requirements, while maintaining smooth functioning of the cell and avoiding damage. The new research reveals that some of these protective changes occur in the protein-killing system of our cells, where misfolded or useless proteins are rapidly eliminated and the new proteins sought are synthesized rapidly.

The new findings are based on observations of the physiological effects of hormones formulated for the first time by the Harvard Medical School physician, Walter Cannon, nearly a century ago and elegantly captured in his book The Wisdom of the Body (1932). Some of Cannon's most notable works include defining the mechanism of action of the hormone epinephrine and its role in the body's combat response – an essential survival mechanism characterized by a cascade of physiological changes in times of high stress .

Epinephrine is one of the hormones whose action on the mechanism of protein removal from cells is now illuminated by Goldberg's latest work. In a symbolic movement of coincidence, Goldberg's lab occupies the very space where Cannon made his historical observations on the same hormone a hundred years ago.

"We believe that our discovery is truly a neoclassical discovery that builds on the discoveries and observations made right here, in this very building, almost a century ago," Goldberg said.


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More information:
Jordan J.S. VerPlank et al, 26S Proteasomes are rapidly activated by various hormones and physiological conditions that increase the cAMP level and cause phosphorylation of Rpn6. Proceedings of the National Academy of Sciences (2019). DOI: 10.1073 / pnas.1809254116

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