Exercise, fasting shown to help cells shed defective proteins – Harvard Gazette
https://news.harvard.edu/gazette/story/2019/02/exercise-fasting-shown-to-help-cells-shed-defective-proteins/
Exercise, fasting help cells shed defective proteins
Researchers
have found that vigorous exercise, fasting, and hormones improve
elimination of toxic, misfolded, unnecessary proteins in mouse and human
cells.
Discovery of previously unknown mechanism may someday aid in battle against Alzheimer’s
By Ekaterina Pesheva HMS Communications
DateFebruary 21, 2019
The body’s ability to adapt to changing conditions and shifting
physiologic demands is essential to its survival. To ensure cellular
performance and the health of the entire organism, each cell must be
able to dispose of damaged or unnecessary proteins.
Now, a study from the Blavatnik Institute at Harvard Medical School
(HMS) shows that intense exercise, fasting, and an array of hormones can
activate cells’ built-in protein-disposal systems and enhance their
ability to purge defective, toxic, or unneeded proteins.
The findings, published Feb. 19 in PNAS,
reveal a previously unknown mechanism that is triggered by fluctuations
in hormone levels, which signal changes in physiologic conditions.
“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,” said Alfred Goldberg, senior author on the study and professor of cell biology at the Blavatnik Institute.
Cellular housecleaning in disease and health
Malfunctions in the cells’ protein-disposal machinery can lead to the
accumulation of misfolded proteins, which clog up the cell, interfere
with its functions, and, over time, precipitate the development of
diseases, including neurodegenerative conditions such as amyotrophic
lateral sclerosis and Alzheimer’s.
The best-studied biochemical system used by cells to remove junk
proteins is the ubiquitin-proteasome pathway. It involves tagging
defective or unneeded proteins with ubiquitin molecules — a process
known as the “kiss of death” — marking them for destruction by the
cell’s protein-disposal unit, known as 26S proteasome.
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Past research by Goldberg’s
lab has shown that this machinery can be activated by pharmacological
agents that boost the levels of a molecule known as cAMP, the chemical
trigger that initiates the cascade leading to protein degradation inside
cells, which in turn switches on the enzyme protein kinase A. The lab’s
previous research found that cAMP-stimulating drugs enhanced the
destruction of defective or toxic proteins, particularly mutant proteins
that can lead to neurodegenerative conditions.
The new findings, however, reveal that shifts in physiological states
and corresponding changes in hormones can regulate this quality-control
process independent of drugs. Goldberg’s lab previously focused on
reining in overactive protein breakdown — excessive protein removal that
can cause muscle wasting in cancer patients or give rise to several
types of muscle atrophy. In fact, a proteasome inhibitor drug
Goldberg and his team developed to tamp down protein-disposal activity
has been widely used to treat multiple myeloma, a common blood cancer
marked by abnormal protein accumulation and overworked proteasomes.
The team’s latest work, by contrast, is focused on developing
therapies that do just the opposite — invigorate the cell’s
protein-disposal machinery when it is too sluggish. These newest
findings open the door, at least conceptually, to precisely such
treatments.
“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 that cause disease,”
said study’s lead investigator, Jordan VerPlank,
a postdoctoral research fellow in cell biology at the Blavatnik
Institute. Such treatments may not necessarily involve the 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,” 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,” he said.
It is already well known that exercise has many salutary effects, but
the researchers said the new findings hint at the possibility that
exercise and fasting could also help reduce the risk of developing
conditions associated with the accumulation of misfolded proteins, such
as Alzheimer’s and Parkinson’s. That possibility, however, remains to be
explored, the team noted.
In their experiments, the 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 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 glucago, the hormone that stimulates production of
glucose as fuel for cells and tissues during periods of food deprivation
or whenever blood sugar levels drop. 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, also known as adrenaline, 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 hearts of living rats. Similarly,
when researchers exposed mouse kidney cells 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 a variety of tissues in
response to shifting conditions, and that such changes are mediated by
fluctuations in hormone levels. This response was surprisingly rapid and
short-lived, the scientists noted. For example, exposure to the
antidiuretic hormone triggered protein breakdown in kidney cells within
five minutes and subsided to pre-exposure levels within an hour, the
experiments showed. The findings show that the diverse set of hormones
that stimulate cAMP appear to share a common mechanism that alters the
composition of cells. These have long been known to modify gene
_expression_, but this latest research reveals they also play a critical
role in cellular housecleaning by disposing of proteins that are no
longer needed.
A new twist on a classic concept
The new findings build on observations about the physiologic effects
of hormones first made by HMS 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 work includes defining the mechanism of
action of epinephrine and its role in the fight-or-flight response.
Epinephrine is one of the hormones whose action on the protein-disposal
machinery is now illuminated by Goldberg’s latest work. In a symbolic
coincidence, Goldberg’s lab occupies the very space where Cannon made
his observations on the same hormone a hundred years ago.
“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.
Study co-investigators included Jinghui Zhao and Sudarsanareddy Lokireddy, who is no longer at Harvard.
The research was made possible through tissue samples provided by colleagues in Houston, 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 Project ALS.
