Loss of a specific enzyme boosts fat metabolism and exercise endurance
in mice

Date:
August 13, 2020
Source:
Harvard Medical School
Summary:
Blocking the activity of a fat-regulating enzyme in the muscles
of mice leads to an increased capacity for endurance exercise,
according to the results of a new study.



FULL STORY ========================================================================== Sugars and fats are the primary fuels that power every cell, tissue
and organ.

For most cells, sugar is the energy source of choice, but when nutrients
are scarce, such as during starvation or extreme exertion, cells will
switch to breaking down fats instead.


==========================================================================
The mechanisms for how cells rewire their metabolism in response to
changes in resource availability are not yet fully understood, but new
research reveals a surprising consequence when one such mechanism is
turned off: an increased capacity for endurance exercise.

In a study published in the Aug. 4 issue of Cell Metabolism, Harvard
Medical School researchers identified a critical role of the enzyme,
prolyl hydroxylase 3 (PHD3), in sensing nutrient availability and
regulating the ability of muscle cells to break down fats. When
nutrients are abundant, PHD3 acts as a brake that inhibits unnecessary
fat metabolism. This brake is released when fuel is low and more energy
is needed, such as during exercise.

Remarkably, blocking PHD3 production in mice leads to dramatic
improvements in certain measures of fitness, the research showed. Compared
with their normal littermates, mice lacking the PHD3 enzyme ran 40 percent longer and 50 percent farther on treadmills and had higher VO2 max,
a marker of aerobic endurance that measures the maximum oxygen uptake
during exercise.

The findings shed light on a key mechanism for how cells metabolize
fuels and offer clues toward a better understanding of muscle function
and fitness, the authors said.

"Our results suggest that PHD3 inhibition in whole body or skeletal
muscle is beneficial for fitness in terms of endurance exercise
capacity, running time and running distance," said senior study author
Marcia Haigis, professor of cell biology in the Blavatnik Institute at
HMS. "Understanding this pathway and how our cells metabolize energy
and fuels potentially has broad applications in biology, ranging from
cancer control to exercise physiology." However, further studies are
needed to elucidate whether this pathway can be manipulated in humans
to improve muscle function in disease settings, the authors said.



========================================================================== Haigis and colleagues set out to investigate the function of PHD3,
an enzyme that they had found to play a role regulating fat metabolism
in certain cancers in previous studies. Their work showed that, under
normal conditions, PHD3 chemically modifies another enzyme, ACC2, which
in turn prevents fatty acids from entering mitochondria to be broken
down into energy.

In the current study, the researchers' experiments revealed that PHD3
and another enzyme called AMPK simultaneously control the activity of
ACC2 to regulate fat metabolism, depending on energy availability.

In isolated mouse cells grown in sugar-rich conditions, the team found
that PHD3 chemically modifies ACC2 to inhibit fat metabolism. Under
low-sugar conditions, however, AMPK activates and places a different,
opposing chemical modification on ACC2, which represses PHD3 activity and allows fatty acids to enter the mitochondria to be broken down for energy.

These observations were confirmed in live mice that were fasted to
induce energy-deficient conditions. In fasted mice, the PHD3-dependent
chemical modification to ACC2 was significantly reduced in skeletal
and heart muscle, compared to fed mice. By contrast, the AMPK-dependent modification to ACC2 increased.

Longer and further Next, the researchers explored the consequences when
PHD3 activity was inhibited, using genetically modified mice that do
not express PHD3. Because PHD3 is most highly expressed in skeletal
muscle cells and AMPK has previously been shown to increase energy
expenditure and exercise tolerance, the team carried out a series of
endurance exercise experiments.



==========================================================================
"The question we asked was if we knock out PHD3," Haigis said, "would
that increase fat burning capacity and energy production and have a
beneficial effect in skeletal muscle, which relies on energy for muscle function and exercise capacity?" To investigate, the team trained young, PHD3-deficient mice to run on an inclined treadmill. They found that these
mice ran significantly longer and further before reaching the point of exhaustion, compared to mice with normal PHD3. These PHD3-deficient mice
also had higher oxygen consumption rates, as reflected by increased VO2
and VO2 max.

After the endurance exercise, the muscles of PHD3-deficient mice had
increased rates of fat metabolism and an altered fatty acid composition
and metabolic profile. The PHD3-dependent modification to ACC2 was nearly undetectable, but the AMPK-dependent modification increased, suggesting
that changes to fat metabolism play a role in improving exercise capacity.

These observations held true in mice genetically modified to specifically prevent PHD3 production in skeletal muscle, demonstrating that PHD3 loss
in muscle tissues is sufficient to boost exercise capacity, according
to the authors.

"It was exciting to see this big, dramatic effect on exercise capacity,
which could be recapitulated with a muscle-specific PHD3 knockout,"
Haigis said. "The effect of PHD3 loss was very robust and reproducible."
The research team also performed a series of molecular analyses to
detail the precise molecular interactions that allow PHD3 to modify ACC2,
as well as how its activity is repressed by AMPK.

The study results suggest a new potential approach for enhancing exercise performance by inhibiting PHD3. While the findings are intriguing,
the authors note that further studies are needed to better understand
precisely how blocking PHD3 causes a beneficial effect on exercise
capacity.

In addition, Haigis and colleagues found in previous studies that in
certain cancers, such as some forms of leukemia, mutated cells express significantly lower levels of PHD3 and consume fats to fuel aberrant
growth and proliferation. Efforts to control this pathway as a potential strategy for treating such cancers may help inform research in other
areas, such as muscle disorders.

It remains unclear whether there are any negative effects of PHD3 loss. To
know whether PHD3 can be manipulated in humans -- for performance
enhancement in athletic activities or as a treatment for certain
diseases -- will require additional studies in a variety of contexts,
the authors said.

It also remains unclear if PHD3 loss triggers other changes, such as
weight loss, blood sugar and other metabolic markers, which are now
being explored by the team.

"A better understanding of these processes and the mechanisms underlying
PHD3 function could someday help unlock new applications in humans,
such as novel strategies for treating muscle disorders," Haigis said.

Additional authors on the study include Haejin Yoon, Jessica Spinelli,
Elma Zaganjor, Samantha Wong, Natalie German, Elizabeth Randall, Afsah
Dean, Allen Clermont, Joao Paulo, Daniel Garcia, Hao Li, Olivia Rombold, Nathalie Agar, Laurie Goodyear, Reuben Shaw, Steven Gygi and Johan Auwerx.

The study was supported by the National Institutes of Health (grants R01CA213062, P30DK036836, R25 CA-89017 and P41 EB015898), Ludwig Center
at Harvard Medical School, Glenn Foundation for Medical Research,
Ecole Polytechnique Fe'de'rale de Lausanne and the Fondation Suisse de Recherche sur les Maladies Musculaires.


========================================================================== Story Source: Materials provided by Harvard_Medical_School. Original
written by Kevin Jiang.

Note: Content may be edited for style and length.


========================================================================== Journal Reference:
1. Haejin Yoon, Jessica B. Spinelli, Elma Zaganjor, Samantha J. Wong,
Natalie J. German, Elizabeth C. Randall, Afsah Dean, Allen Clermont,
Joao A. Paulo, Daniel Garcia, Hao Li, Olivia Rombold, Nathalie
Y.R. Agar, Laurie J. Goodyear, Reuben J. Shaw, Steven P. Gygi,
Johan Auwerx, Marcia C. Haigis. PHD3 Loss Promotes Exercise Capacity
and Fat Oxidation in Skeletal Muscle. Cell Metabolism, 2020; 32
(2): 215 DOI: 10.1016/ j.cmet.2020.06.017 ==========================================================================

Link to news story: https://www.sciencedaily.com/releases/2020/08/200813155827.htm

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