SCIENCE sciencemag.org
cle glycogen stores and showed reduced
performance in endurance exercise. Even
after several weeks of training, they were
unable to up-regulate the expression of
genes necessary for muscle oxidative me-
tabolism and to improve performance.
Delivering IL-13 to mouse skeletal muscle
in vivo conferred an endurance training–
like effect, which translated into increased
exercise performance and a mild improve-
ment in the ability of muscle to take up
glucose from circulation. It remains to be
determined how the IL-13–mediated break
on glycolysis is removed to allow exercise
at higher intensity.
Mechanistically, Knudsen et al. demon-
strate that signal transducer and activator
of transcription 3 (STAT3) is essential for
the effects of IL-13 on skeletal muscle me-
tabolism and performance. STAT3 is a ubiq-
uitously expressed transcription factor that
activates gene programs associated with cell
survival, proliferation, and growth in re-
sponse to a variety of cytokines and growth
factors, most notably IL-6. STAT3 has im-
portant regulatory functions in a plethora
of physiological and pathophysiological
processes, including embryonic develop-
ment, wound healing, cancer, and immunity
( 8 ). In skeletal muscle, the effects of STAT3
activation are complex and context depen-
dent. Heightened STAT3 activation has been
implicated in the development of cancer ca-
chexia (muscle wasting in cancer patients)
and in the pathophysiology of various mus-
cular diseases ( 9 ). Activation of STAT3 in
fibro-adipogenic progenitors contributes to
mouse skeletal muscle atrophy and fibrosis
induced by experimental denervation ( 10 ),
whereas transient pharmacological inhibi-
tion of STAT3 improves muscle regeneration
in old and dystrophic mice by expanding
the pool of satellite cells ( 11 ). Thus, STAT3
inhibition (widely pursued in clinical tri-
als as a therapy for various types of cancer)
has emerged as a potential therapeutic ap-
proach for muscular diseases.
Despite its negative effects on skeletal
muscle function, STAT3 is transiently ac-
tivated in muscle fibers by resistance exer-
cise, suggesting a potential role for STAT3
signaling in the physiological adaptation
to exercise. Furthermore, Knudsen et al.
showed that, in mice, STAT3 is activated by
endurance exercise and that STAT3 signal-
ing in skeletal muscle fibers is necessary
for the beneficial effects of IL-13 on exer-
cise performance and glucose homeostasis.
These findings change the view of STAT3,
which to date was mostly considered del-
eterious to skeletal muscle function. This
positive role of STAT3 in muscle metabo-
lism should be taken into consideration
when devising potential therapies that in-
hibit STAT3 signaling in skeletal muscle.
In the quest for health-promoting strat-
egies, exercise training and maintaining
muscle metabolic fitness are some of the
best tools available. The identification of
IL-13 as an exerkine that promotes muscle
oxidative metabolism could be the founda-
tion for future therapies to help patients
with metabolic dysregulation. It will be
interesting to follow how the biological ef-
fects of IL-13 fit within the larger picture of
systemic adaptations to exercise. jREFERENCES AND NOTES- C. Handschin, B. M. Spiegelman, Nature 454 , 463
(2008). - N. Knudsen et al., Science 368 , eaat3987 (2020).
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eaaf9794 (2017). - M. Messing, S. C. Jan-Abu, K. McNagny, Int. J. Mol. Sci. 21 ,
E1350 (2020). - J. Hawley, Aust. J. Nutr. Diet 58 , S19 (2001).
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E2265 (2018). - L. Madaro et al., Nat. Cell Biol. 20 , 917 (2018).
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10.1126/science.abb4116NEUROSCIENCEDampening
light sensitivity
An inhibitory signal
from the retina limits the
response to light
By Jennifer Ding and Wei WeiI
n the eyes of vertebrates, the retina de-
tects incoming photons of visible light
and transforms them through intricate
neural circuits into multiple channels
of visual information that are then con-
veyed to the brain. Each channel is rep-
resented by the spiking activity of a specific
type of retinal ganglion cell (RGC) whose
axons project to one or more brain regions
to support a multitude of visual functions
( 1 ). Like many other long-range projection
neurons in the brain, RGCs provide excit-
atory inputs to their targets in the brain us-
ing the neurotransmitter glutamate ( 2 ). On
page 527 of this issue, Sonoda et al. ( 3 ) de-
scribe an inhibitory channel from the eye to
the brain by way of a subset of intrinsically
photosensitive RGCs (ipRGCs) that release
g-aminobutyric acid (GABA) in mice. The
authors report that the inhibitory inputs
from these GABAergic ipRGCs are involved
in curbing the sensitivity of certain non–im-
age-forming behaviors and renders them re-
silient to minor perturbations in light level.
The excitatory glutamatergic signaling
of RGCs is unequivocally established by
anatomical, physiological, and molecular
characterizations of the retina and retino-
recipient structures in the brain, such as the
dorsal lateral geniculate nucleus (dLGN)
and the superior colliculus (SC) ( 4 – 6 ).
Curiously, earlier immunohistochemical
studies indicated that a small number of
RGCs in several mammalian species express
markers of GABAergic neurotransmission,
such as GABA and the GABA synthesis en-
zyme glutamate decarboxylase (GAD) ( 7 – 9 ).
However, the function of these apparent
GABAergic RGCs is unknown.
Sonoda et al. revisit this puzzle in the
mouse by leveraging the powerful toolset
of circuit analysis available for this model
organism. Using a transgenic mouse line in
which GABAergic neurons are selectively
labeled, they found that GAD-expressing
cells are a small subset of ipRGCs (~10%)Department of Neurobiology, University of Chicago,
Chicago, IL, USA. Email: [email protected]Enduring prolonged
activity takes regular
exercise and the release of
“exerkines” from muscles.1 MAY 2020 • VOL 368 ISSUE 6490 471