Scientists at Harvard Medical School have found that intense exercise, brief periods of fasting, and a variety of hormones can increase cells’ ability to break down superfluous, faulty, or toxic proteins. The discovery has identified previously unrecognized physiologically mediated switches for triggering the cellular machinery that can clear the decks of unwanted proteins so that cells can adapt to changing conditions.

The researchers, headed by Jordan VerPlank, PhD., a postdoctoral research fellow in cell biology at the Blavatnik Instituite at Harvard Medical School, suggest the findings could lead to the development of novel strategies for boosting cells’ ability to get rid of misfolded proteins that are characteristic of disorders such as Alzheimer’s disease or amyotrophic lateral sclerosis (ALS). “We believe our findings set the stage for therapies that harness the cells’ natural ability to dispose of proteins and thus enhance the removal of toxic proteins that cause disease,” VerPlank commented.

“Our findings show that the body has a built-in mechanism for cranking up the molecular machinery responsible for waste-protein removal that is so critical for the cells’ ability to adapt to new conditions,” added Alfred Goldberg, PhD, professor of cell biology in the Blavatnik Institute at Harvard Medical School, and senior author on the team’s published study in PNAS, which is titled, “26S proteasomes are rapidly activated by diverse hormones and physiological states that raise cAMP and cause Rpn6 phosphorylation.”

At the cellular level, the body’s ability to adapt to changing conditions and physiological demands requires that cells can identify and dispose of damaged or unnecessary proteins. Eating, sleeping, and exercise are all basic activities that require cells to change their protein composition in response to changing demands on cells and tissues. If these protein disposal mechanisms don’t function properly then abnormally folded proteins can build up in cells, potentially leading to diseases that are characterized by the accumulation of misfolded or toxic proteins.

The most widely studied cellular mechanism that carries out this protein housekeeping function is the ubiquitin-proteasome system (UPS), through which damaged, or unwanted proteins are tagged with ubiquitin, which effectively represents a “kiss of death” that condemns the proteins to destruction by the protein-disposal unit known as the 26S proteasome. It had been widely assumed that the rate of protein degradation by this system was dependent on the rate of ubiquitination, but, as the authors pointed out, “there is growing evidence that protein half-lives can also be altered through changes in proteasome activity under different physiological and pathological conditions.”

Prior work in Goldberg’s lab had demonstrated that the ubiquitin-proteasome pathway can be activated by pharmacological agents that increase the intracellular messenger molecule cAMP, which turns on the enzyme protein kinase A (PKA). The Goldberg team’s research showed that cAMP-stimulating drugs can increase clearance of abnormal or superfluous proteins, including those that can lead to certain neurodegenerative disorders that are characterized by misfolded proteins.

The latest findings reported in PNAS indicate that these natural protein turnover processes can also be regulated and driven by changes in physiological states and hormones, and hint at how it may be possible to develop new approaches to boosting protein disposal. This is in contrast with most previous work by the Goldberg lab and by others, which has historically focused largely on how to put the brakes on runaway protein breakdown, a process that can cause muscle wastage in cancer, or lead to other forms of muscle atrophy.

In their latest research, VerPlank, Goldberg, and colleagues demonstrated how exercise, hormones, and fasting can ramp up the breakdown of toxic proteins, and—in theory— potentially help to reduce the risk of developing diseases, such as Alzheimer’s disease and Parkinson’s disease, which are characterized by misfolded proteins.

The team analyzed the effects of exercise on cells taken from the thigh muscles of four human volunteers before and after a vigorous cycling session. They found that after exercise the cells’ proteasomes showed molecular evidence—including increased cAMP levels—of enhanced protein degradation. Equivalent changes were demonstrated in the muscles of anesthetized rats that were stimulated to contract repeatedly. A relatively short period of fasting was another physiological shift, with proteasome activity in the muscle and liver cells of mice increasing in animals that hadn’t eaten for 12 hours. “The increase in proteasome activity in mouse muscles and liver were clearly evident by 12 h after food was removed from fed animals and thus represents a rather rapid metabolic response to food deprivation,” the team wrote. “This timing suggests that a similar enhancement of proteolysis should also occur in humans in these tissues after an overnight fast (i.e., between dinner and breakfast).

In a separate round of experiments the researchers showed that exposing rat liver cells to the hormone glucagon, which is involved in regulating blood glucose levels, similarly stimulated proteasome activity and increased cells’ capacity to destroy misfolded proteins. Liver cells exposed to epinephrine (adrenaline) also exhibited marked increases in cAMP and 26S proteasome activity and protein degradation. Epinephrine is the “fight or flight” hormone that stimulates the liver and muscle to mobilize energy reserves during periods of physiology stress. Epinephrine exposure in addition resulted in increased proteasome activity in rat hearts, while mouse kidney cells exposed to the antidiuretic hormone vasopressin demonstrated higher levels of protein degradation.

The findings collectively indicate that the clearance of proteins by cells in different tissues can increase and decrease very quickly in response to physiological cues, under the regulation of a variety of hormones, the authors suggested. And while changes in protein degradation occurred rapidly in response to hormonal triggers, they were also generally short lived. Exposure to vasopressin ramped up protein breakdown in the mouse kidney cells within minutes, but the effects also subsided to pre-exposure levels within an hour.

“These studies clearly demonstrate not only that proteasome activity can rise and fall in various tissues (from renal collecting ducts to skeletal muscle) upon exposure to diverse hormones that raise cAMP, but also that these responses are surprisingly rapid,” the authors wrote.

They say their studies strongly suggest that physiological cues such as fasting, exercise, or other conditions that raise cAMP levels might have beneficial effects in terms of boosting the clearance of toxic proteins and increasing protein degradation in diseases in which proteasome function is diminished. However, they noted, “a fundamental question raised by these findings is why the cells’ degradative capacity, especially its ability to destroy misfolded or damaged proteins, is not normally maintained at maximal levels to provide cell protection, and why in exercise and fasting is the capacity to destroy such proteins activated by cAMP and PKA.”

The reported findings also provide new insights into the workings of cells natural quality control mechanisms, which could potentially be stimulated to boost the clearance of disease-causing proteins. “This is truly a new way of looking at whether we can turn up the cellular vacuum cleaner,” Goldberg said. “We thought this would require the development of new types of molecules, but we hadn’t truly appreciated that our cells continually activate this process. The beauty and the surprise of it is that such new treatments may involve churning a natural endogenous pathway and harnessing the body’s pre-existing capacity to perform quality control.”

The team’s findings build on the results of hormone research carried out 100 years ago by Harvard Medical School physician Walter Cannon, who elucidated the mechanism of action of epinephrine and its role in the fight or flight response. Goldberg’s lab today sits in the space where Cannon made his observations on epinephrine.

“We think ours is truly a neoclassical discovery that builds on findings and observations made right here, in this very building, nearly a century ago,” Goldberg said.

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