RESEARCH ARTICLE SUMMARY
◥IMMUNOMETABOLISM
Interleukin-13 drives metabolic conditioning
of muscle to endurance exercise
Nelson H. Knudsen, Kristopher J. Stanya, Alexander L. Hyde, Mayer M. Chalom, Ryan K. Alexander,
Yae-Huei Liou, Kyle A. Starost, Matthew R. Gangl, David Jacobi, Sihao Liu, Danesh H. Sopariwala,
Diogo Fonseca-Pereira, Jun Li, Frank B. Hu, Wendy S. Garrett, Vihang A. Narkar, Eric A. Ortlund,
Jonathan H. Kim, Chad M. Paton, Jamie A. Cooper, Chih-Hao Lee*
INTRODUCTION:Exercise provides a vast array
of health benefits. The increased metabolic
activity of contracting skeletal muscle elicits
an integrated response involving multiple
tissues and signaling pathways to cope with
increased energy and oxygen demands. A co-
ordinated effort to promote endurance is me-
diated by a switch from glycolytic to oxidative
metabolism favoring fatty acids
as the energy source. This meta-
bolic fueling strategy is met with
specialized muscle fibers that
exhibit distinct energy substrate
preferences and mitochondrial
oxidative capacity. These adaptive
changes—such as increased car-
diorespiratory capacity, enhanced
muscle oxidative metabolism,
and improved whole-body glucose
homeostasis—promote metabolic
fitness. However, the mechanisms
that mediate these adaptive re-
sponses remain unclear.
RATIONALE:In the early 1960s, la-
bile blood and lymph factors were
found to mediate some of the
metabolic effects of exercise. Re-
cent studies further support the
notion that communication be-
tween resident immune cells
and their host tissues is impor-
tant for regulating the metabolic
setpoint and thereby maintain-
ing tissue function. We found
that endurance exercise increased
circulating levels of the cytokine
interleukin-13 (IL-13) in mice and
humans. Endurance exercise also
led to the expansion of type 2 in-
nate lymphoid cells (ILC2s), one of the primary
IL-13–producing cell types within mouse muscle.
This implicated a role for IL-13 in the control of
the adaptive responses elicited by exercise. We
used several molecular and bioenergetic assays
and generated three genetic models to deter-
mine the role of IL-13 signaling in the metabolic
reprogramming of skeletal muscle in response
to endurance exercise training.
RESULTS:Relative to wild-type control animals,
Il13-deficient mice showed reduced running
capacity on a treadmill. RNA sequencing of
skeletal muscle from control andIl13-deficient
mice was performed to examine the role of
IL-13 in exercise physiology. IL-13 did not have
an appreciable effect on metabolic gene ex-
pression in resting muscles. However, endurancetraining increased a network of mitochon-
drial and fatty acid oxidation genes in mus-
cle of control animals, which was lost in mice
lackingIl13.Il13-deficient muscle showed
defective fatty acid utilization after a single
bout of exercise and failed to increase mito-
chondrial biogenesis after endurance training.
Furthermore, endurance training in control
animals led to increased numbers of muscleoxidative fibers and improvements in mito-
chondrial respiration, endurance capacity, and
glucose tolerance. All of these metabolic bene-
fits of exercise training required intact IL-13
signaling.
We found that IL-13 acts directly on skeletal
muscle through its receptor IL-13Ra1, lead-
ing to the activation of Stat3. Stat3 phos-
phorylation was elevated
in muscle after both a
single session and endur-
ance training—an effect
lost inIl13-deficient mice.
In C2C12 myotubes, IL-13
treatment increased mito-
chondrial respiration that was dependent
onIl13ra1andStat3. The IL-13–Stat3 axis
controlled the metabolic program elicited by
exercise training partly through a coordi-
nated transcriptional regulation with two
nuclear receptors and mitochondrial regu-
lators, ERRaand ERRg. Mice specifically
lackingIl13ra1orStat3in skeletal muscle
displayed reductions in muscle
fatty acid oxidation and endur-
ance capacity. By contrast, in-
creasing levels of IL-13 in skeletal
muscle recapitulated the meta-
bolic reprogramming induced by
endurance exercise in a Stat3-
dependent manner, leading to
improvements in systemic glu-
cose homeostasis and running
capacity.CONCLUSION:IL-13 signaling
appears to be activated immedi-
ately after exercise and stabilized
by endurance training, with the
effects of modulating substrate
utilization and mediating mito-
chondrial biogenesis, respectively.
As such, it fits the criteria of a
humoral factor that regulates
exercise-induced metabolic ef-
fects. IL-13 exerts direct effects
on skeletal muscle to increase
transcriptional programs encod-
ing fatty acid oxidation and
mitochondrial electron trans-
port chain complexes through
IL-13Ra1 and the downstream
effector Stat3. This adaptive
response, an interplay of the
immune and metabolic path-
ways, primes muscle for sustained phys-
ical activity. These observations highlight
the importance of immune signaling in the
maintenance of tissue metabolic fitness.
▪RESEARCH
488 1 MAY 2020•VOL 368 ISSUE 6490 sciencemag.org SCIENCE
The list of author affiliations is available in the full article online.
*Corresponding author. Email: [email protected]
Cite this article as N. H. Knudsenet al.,Science 368 ,
eaat3987 (2020). DOI: 10.1126/science.aat3987IL-13IIL-13L- 13
IL-13RIL-13RIL- 13 R__ 11
Stat3Stat 3Metabolic conditioningMetabolic conditioning
Mitochondrial Mitochondrial
biogenesisbiogenesis
Endurance Endurance
capacitycapacityGlucose Glucose
tolerancetoleranceFatty acid Fatty acid
oxidationoxidationEndurance exerciseEEndurance exercisendurance exerciseStat3Metabolic conditioning
Mitochondrial
biogenesis
Endurance
capacityGlucose
toleranceFatty acid
oxidationIL-13 mediates muscle metabolic programming to support endurance exercise
via IL-13Ra1 and Stat3.Image shows gastrocnemius muscle cross section
stained for myosin heavy chain (MyHC) isoforms to determine muscle fiber type
composition. Blue, green, and red indicate MyHC I-, IIa-, and IIb-positive muscle
fibers, respectively. Type I and type IIa muscles contain more oxidative fibers
and are characterized by high endurance, whereas type IIb muscle fibers are
glycolytic and prone to fatigue.ON OUR WEBSITE◥Read the full article
at https://dx.doi.
org/10.1126/
science.aat3987
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