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Developmental Biology - Waste Protein Disposal

How Exercise/Fasting Keep Us Healthy

Intense exercise, fasting and an array of hormones, activate cells' disposal system to purge defective or toxic proteins...

The body's ability to adapt to changing conditions and shifting physiologic demand is essential to human survival. In order to do so, each cell in our body must be able to dispose of damaged or unnecessary proteins. This process of quality-control is made effective by critical mechanisms in cellular performance.
Now, a study from Harvard Medical School shows intense exercise, fasting and an array of hormones can activate cells' built-in protein disposal system and enhance our ability to purge defective, toxic or unneeded proteins.

The findings, published in PNAS, reveal a previously unknown mechanism used by the body to rapidly turn on junk-protein removal. This allows cells to adapt their protein content to meet new demands. The study shows this mechanism is triggered by fluctuations in hormone levels, signalling changes in physiologic condition.
"Our findings show that the body has a built-in mechanism for cranking up the molecular machinery responsible for waste-protein removal so critical to the cells' ability to adapt to new conditions."

Alfred Goldberg, senior author on the study and professor of cell biology in the Blavatnik Institute at Harvard Medical School.

Cellular House Cleaning in Disease and Health

Malfunctions in the cells' protein-disposal machinery can lead to accumulation of misfolded proteins, which clog up the cell and interfere with its functions. Over time, misfolded proteins precipitate development of diseases, such as ALS and Alzheimer's.

Biochemical cell systems remove junk proteins with the ubiquitin-proteasome pathway. Defective or unneeded proteins are tagged with ubiquitin molecules and marked for destruction:

• A cell's protein-disposal unit is known as 26S proteasome
26S Proteasome machinery can be pharmacologically boosted
• Rising levels of cAMP then switch on the enzyme protein kinase A.
The team's previous work had shown that cAMP-stimulating drugs enhance destruction of defective or toxic proteins, particularly mutant proteins that can lead to neurodegenerative conditions. However, the new findings, reveal this quality control process is regulated independently of drugs, operating instead by shifts in physiological states which correspond to changes in hormones.

Past research, including work from Goldberg's lab, has focused predominantly on reining in overactive protein breakdown - excessive protein removal can cause muscle wasting in cancer patients or give rise to several types of muscle atrophy. In fact, Goldberg's team had developed a proteasome inhibitor drug to tamp down activity in cell protein-disposal machinery. The inhibitor is still widely used for treating multiple myeloma, a common type of blood cancer, marked by abnormal protein accumulation and overworked proteasomes. The team's latest work, now focuses on therapies to invigorate cell protein disposal machinery when it becomes too sluggish.
"We believe our findings set the stage for the development of therapies that harness the cells' natural ability to dispose of proteins and thus enhance the removal of toxic proteins causing disease."

Jordan VerPlank, a postdoctoral research fellow in cell biology, Blavatnik Institute at Harvard Medical School, and study lead investigator.

Such treatments may not necessarily involve design of new molecules but instead stimulate the cell's built-in capacity for quality control.
"This is truly a new way of looking at whether we can turn up the cellular vacuum cleaner. 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 stimulating a natural endogenous pathway and harnessing the body's pre-existing capacity to perform quality control.

Alfred L. Goldberg PhD, Department of Cell Biology, Harvard Medical School, Boston, Massachusetts, USA.

The new findings also hint at the possibility that exercise and fasting could help reduce the risk of developing conditions associated with accumulation of misfolded proteins — as in Alzheimer's and Parkinson's. The team notes this possibility remains to be explored in subsequent research.

Researchers analyzed the effects of exercise on cells obtained from the thigh muscles of four human volunteers before and after vigorous biking. Following exercise, the proteasomes of these cells showed dramatically more molecular marks of enhanced protein degradation, including greater levels of cAMP, the chemical trigger that initiates a cascade that leads to protein degradation inside cells. The same changes were observed in the muscles of anesthetized rats whose hind legs were stimulated to contract repeatedly.
Fasting - even for brief periods - produced a similar effect on the cells' protein-breakdown machinery. Fasting increased proteasome activity in the muscle and liver cells of mice deprived of food for 12 hours - the equivalent of an overnight fast.

In another round of experiments, the researchers exposed the liver cells of mice to glucagon - the hormone that stimulates the production of glucose as fuel for cells and tissues during periods of food deprivation or whenever blood sugar levels drop down. The researchers observed that glucagon exposure stimulated proteasome activity and enhanced the cells' capacity to destroy misfolded proteins.

Exposure to the fight-or-flight hormone epinephrine produced a similar effect. Epinephrine, or adrenaline in common parlance, is responsible for stimulating the liver and muscle to mobilize energy reserves to boost heart rate and muscle strength during periods of physiologic stress. Liver cells treated with epinephrine showed marked increases in cAMP, as well as enhanced 26S proteasome activity and protein degradation. Epinephrine exposure also boosted proteasome activity - a marker of protein degradation - in the working hearts of rats. Similarly, when researchers exposed the kidney cells of mice to vasopressin - the antidiuretic hormone that helps the body retain water and prevents dehydration - they observed higher levels of protein degradation as well.
Taken together, these findings demonstrate that the rate of protein degradation can rise and fall swiftly in response to fluctuations in hormone levels. The response was surprisingly rapid and short-lived. For example, exposure to antidiuretic hormone triggered protein breakdown in kidney cells within five minutes and subsided to pre-exposure levels within an hour.

cAMP stimulating hormones have long been known to modify gene expression, but this latest research reveals they also play a critical role in cellular "house cleaning" by disposing of proteins that are no longer needed.

A new twist on a classic concept

Eating and sleeping, as well as exercise, requires that cells in our body modulate their composition minute by minute to cope with new demands, all in the name of maintaining proper cellular function and averting harm. The new research reveals that some of these protective shifts occur in our cells' protein disposal system. Here misfolded or unneeded proteins are removed promptly and new ones synthesized swiftly.

These new findings are built on observations about physiologic effects of hormones first made by Harvard Medical School physician Walter Cannon in 1932. Cannon elegantly captured this in his book The Wisdom of the Body. Some of his most notable work includes defining the mechanism of action of the hormone epinephrine and its role in the body's fight-or-flight response - a key survival mechanism marked by a cascade of physiologic changes during times of high stress.
Epinephrine is one of the hormones whose action on the cells' protein-disposal machinery is now illuminated by Goldberg's latest work. In a twist of symbolic coincidence, Goldberg's lab occupies the very space where Cannon made his historic observations on the same hormone.

Most studies of proteolysis by the ubiquitin-proteasome pathway have focused on the regulation by ubiquitination. However, we showed that pharmacological agents that raise cAMP and activate protein kinase A by phosphorylating a proteasome subunit enhance proteasome activity and the cell’s capacity to selectively degrade misfolded and regulatory proteins. We investigated whether similar adaptations occur in physiological conditions where cAMP rises. Proteasome activity increases by this mechanism in human muscles following intense exercise, in mouse muscles and liver after a brief fast, in hepatocytes after epinephrine or glucagon, and renal collecting duct cells within 5 minutes of antidiuretic hormone. Thus, hormones and conditions that raise cAMP rapidly enhance proteasome activity and the cells’ capacity to eliminate damaged and preexistent regulatory proteins.

Pharmacological agents that raise cAMP and activate protein kinase A (PKA) stimulate 26S proteasome activity, phosphorylation of subunit Rpn6, and intracellular degradation of misfolded proteins. We investigated whether a similar proteasome activation occurs in response to hormones and under various physiological conditions that raise cAMP. Treatment of mouse hepatocytes with glucagon, epinephrine, or forskolin stimulated Rpn6 phosphorylation and the 26S proteasomes’ capacity to degrade ubiquitinated proteins and peptides. These agents promoted the selective degradation of short-lived proteins, which are misfolded and regulatory proteins, but not the bulk of cell proteins or lysosomal proteolysis. Proteasome activities and Rpn6 phosphorylation increased similarly in working hearts upon epinephrine treatment, in skeletal muscles of exercising humans, and in electrically stimulated rat muscles. In WT mouse kidney cells, but not in cells lacking PKA, treatment with antidiuretic hormone (vasopressin) stimulated within 5-minutes proteasomal activity, Rpn6 phosphorylation, and the selective degradation of short-lived cell proteins. In livers and muscles of mice fasted for 12–48 hours cAMP levels, Rpn6 phosphorylation, and proteasomal activities increased without any change in proteasomal content. Thus, in vivo cAMP-PKA–mediated proteasome activation is a common cellular response to diverse endocrine stimuli and rapidly enhances the capacity of target tissues to degrade regulatory and misfolded proteins (e.g., proteins damaged upon exercise). The increased destruction of preexistent regulatory proteins may help cells adapt their protein composition to new physiological conditions.

Jordan J. S. VerPlank, Sudarsanareddy Lokireddy, Jinghui Zhao, and Alfred L. Goldberg.

The authors declare no conflict of interest.

The research was made possible through tissue samples provided by colleagues in Houston, Texas, Copenhagen and Sydney.

The work was supported by grants from the National Institutes of Health's National Institute of General Medical Sciences under grants R01 GM051923-20 and F32 GM128322, the Cure Alzheimer's Fund, the Muscular Dystrophy Association (MDA-419143), Genentech and by Project ALS.

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Feb 25 2019   Fetal Timeline   Maternal Timeline   News  

Epinephrine, or adrenaline in common parlance, is responsible for stimulating the liver and muscle to mobilize energy reserves to boost heart rate and muscle strength during periods of physiologic stress. Liver cells treated with epinephrine showed increases in cAMP, and enhanced 26S proteasome activity and protein degradation, thus "cleaning out" damaged proteins. Image credit: Mark Chodzko

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