Redox Signaling in Widespread Health Beneﬁts of Exercise
Ruy A. Louzada,
Leonardo P. Matta,
Joao Pedro Werneck-de-Castro,
Denise P. Carvalho,
and Rodrigo S. Fortunato
Signiﬁcance: Exercise-induced reactive oxygen species (ROS) production activates multiple intracellular
signaling pathways through genomic and nongenomic mechanisms that are responsible for the beneﬁcial effects
of exercise in muscle. Beyond the positive effect of exercise on skeletal muscle cells, other tissues such as white
and brown adipose, liver, central nervous system, endothelial, heart, and endocrine organ tissues are also
responsive to exercise.
Recent Advances: Crosstalk between different cells is essential to achieve homeostasis and to promote the
beneﬁts of exercise through paracrine or endocrine signaling. This crosstalk can be mediated by different
effectors that include the secretion of metabolites of muscle contraction, myokines, and exosomes. During the
past 20 years, it has been demonstrated that contracting muscle cells produce and secrete different classes of
myokines, which functionally link muscle with nearly all other cell types.
Critical Issues: The redox signaling behind this exercise-induced crosstalk is now being decoded. Many of
these widespread beneﬁcial effects of exercise require not only a complex ROS-dependent intramuscular
signaling cascade but simultaneously, an integrated network with many remote tissues.
Future Directions: Strong evidence suggests that the powerful beneﬁcial effect of regular physical activity for
preventing (or treating) a large range of disorders might also rely on ROS-mediated signaling. Within a
contracting muscle, ROS signaling may control exosomes and myokines secretion. In remote tissues, exercise
generates regular and synchronized ROS waves, creating a transient pro-oxidative environment in many cells.
These new concepts integrate exercise, ROS-mediated signaling, and the widespread health beneﬁts of exercise.
Antioxid. Redox Signal. 00, 000–000.
Keywords: ROS, exercise, myokines, redox signaling
Reactive oxygen species (ROS), such as superoxide
), hydroxyl (OH
), and the nonfree radical species,
, are small radical or nonradical molecules derived from
molecular oxygen (O
) (142). Superoxide and nitric oxide
seem to be the primary free radicals generated by different
sources in contracting skeletal muscle during and immedi-
ately after exercise (84, 129, 130). ROS have a critical role as
signaling molecules that are necessary for skeletal muscle
force development and to achieve the adaptive responses to
physical exercise (64, 133). A more detailed description of
how physical exercise increases skeletal muscle ROS gen-
eration and the role of ROS-mediated signaling for muscular
exercise adaptations has been extensively reviewed by others
(63, 84, 129, 130).
In 1961, the term ‘‘exercise factors’’ was used to deﬁne a
group of factors delivered by contracting muscles that were
able to lower glycemia (62). Nowadays, metabolites, lipid
peroxidation products, extracellular ROS, myokines, and
exosomes are the main suggested mechanisms through which
muscle cells communicate with remote cells. These factors
Institut of Biophysics Carlos Chagas Filho, Federal University of Rio de Janeiro, Rio de Janeiro, Brazil.
´Paris-Sud, Orsay, UMR 8200 CNRS and Institut Gustave Roussy, Villejuif, France.
Division of Endocrinology, Diabetes and Metabolism, Miller School of Medicine, University of Miami, Miami, Florida, USA.
ANTIOXIDANTS & REDOX SIGNALING
Volume 00, Number 00, 2020
ªMary Ann Liebert, Inc.
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that are modulated by exercise, in a chronic perspective, are
directly related to the beneﬁts of physical exercise under
different physiological and pathophysiological conditions. In
this review, we will focus on the effects of physical exercise
beyond skeletal muscle, providing an overview about the
communication between contracting muscles and remote
tissues through ROS-mediated mechanisms.
Hypothetical Model of ROS Waves
The ROS waves hypothesis is based on the ability of
physical exercise to increase ROS production in contracting
muscles and its later spread to remote tissues. A hypothetical
model is proposed in Figure 1 to summarize the probable
mechanisms through which contracting skeletal muscle
communicates with remote tissues, leading to changes in
redox-mediated signaling pathways that operate the wide-
spread health beneﬁcial effects of exercise. A ﬁrst phase of
ROS waves after exercise occurs in contracting muscle and
promotes multiple post-translational modiﬁcations of ami-
noacids in many kinases and phosphatases (e.g., AMPK,
CaMK, PTEN, PPIA, etc.) that are crucial for the local
stimulus of muscular glucose uptake, mitochondrial biogen-
esis, and antioxidant capacity. Further, skeletal muscles also
produce ROS in the extracellular milieu that leads to macro-
molecules oxidation, such as lipid peroxidation. Interestingly,
lipid peroxidation products can act as signaling molecules.
Myokines and exosomes might be released from skeletal
muscle in response to intracellular ROS stimulated by phys-
ical exercise. Once in blood circulation, these mediators
change the function of remote tissues during and after exercise
periods. Further, the second phase of ROS waves might
stimulate many similar redox-sensible signaling pathways in
noncontracting tissues that promote widespread responses to
physical exercise (Fig. 1B).
In 1978, Dillard et al. found that expired pentane, an index
of lipid peroxidation, increased during aerobic physical ex-
ercise (42). One year later, Brady et al. demonstrated that
lipid peroxidation levels were higher in the skeletal muscle
and liver of rats immediately after swimming (22). Probably,
this was the ﬁrst indirect demonstration of the ability of
physical exercise to increase ROS generation, but the tissue
involved in their production was only revealed 3 years later.
Davies et al. showed by using electron paramagnetic resonance
that skeletal muscle and liver ROS production are increased
immediately after exhaustive exercise (36). Nowadays, it is
well known that skeletal muscle contractile activity leads to
ROS generation, which is related to biomolecule oxidation, not
only in skeletal muscle but also in other tissues (114, 130).
Electrical stimulation of the hind limb muscle in adult mice
was found to increase malonaldehyde levels in serum and liver
and decrease liver glutathione and protein thiol content (34),
suggesting that the ROS generated by skeletal muscle could
oxidize extracellular molecules also in noncontracting tissues,
such as the liver. In humans, the venous concentration of ox-
idized glutathione was foundto increase after physical exercise
in an intensity-dependent manner (35, 114).
The redox communication between contracting muscle
and remote tissues can be mediated by several mechanisms:
(i) lactate conversion to pyruvate in almost every cell, which
increases NADH levels; (ii) purines released by contracting
muscle that serve as substrates for xanthine oxidase; (iii)
myokines; (iv) ROS gradient reaching adjacent cells; (v) lipid
peroxidation products; and (vi) exosomes secretion. The
oxidative environment induced in remote tissues by physical
exercise is probably related to protein modiﬁcation in their
cysteine residues, which cause structural and functional
FIG. 1. Exercise-induced ROS waves illustration. (A)
Contracting muscle creates an oxidative environment through
consecutive ROS spikes. The ﬁrst ROS wave is produced
mainly by skeletal muscle Nox2, induces activation of ROS-
mediated signaling pathways, and promotes correct folding of
newly born proteins. Skeletal muscle releases signals to re-
mote tissues in many ways during muscle contraction. For
example, metabolites released by skeletal muscle can be ta-
ken up and metabolized in remote tissues, an event that can
stimulate ROS production. Moreover, myokines can also
control the production of ROS in remote tissues. Products of
lipid peroxidation (HODE and HNE) produced during skel-
etal muscle contraction are capable of binding to nuclear
receptors in remote cells in which these compounds can then
regulate gene expression. Finally, exosomes released by the
muscles undergoing contraction might stimulate signaling
pathways in remote tissues. ROS production in remote tissues
after contraction is proposed as a second ROS wave. (B) First
and second ROS waves induced by physical exercise in a
temporal perspective. During skeletal muscle contraction, the
ﬁrst ROS wave within skeletal muscle occurs during exercise
and can spread to remote tissues. At the end of exercise,
contracting muscle causes a decrease in ROS production,
whereas remote tissues present the second ROS wave, leading
to activation of ROS-mediated signaling pathways. 13-
HODE, 13-hydroxyoctadecadienoic acid; 4-HNE, 4-hydro-
xynonenal; Nox2, NADPH oxidase 2; ROS, reactive oxygen
species. Color images are available online.
2 LOUZADA ET AL.
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modiﬁcations (Fig. 1) and increased oxidation markers that
are detected after exercise in noncontracting tissues. More-
over, several myokines released during physical exercise
control the expression of genes in an ROS-dependent man-
ner, as well as the activity of transcription factors, such as
peroxisome proliferator-activated receptor gamma coacti-
vator 1-alpha (PGC-1a), nuclear factor erythroid 2-related
factor 2 (Nrf2), and nuclear factor-kappa B (33, 90, 123, 142).
Adaptations and Beneﬁts of Redox Signaling
Due to Exercise
The expression of PGC-1aduring physical exercise is
dependent on a tightly, ﬁne-tuned redox-mediated signal
(87), and boosting PGC-1ahas been related to protection
against several pathological conditions, such as sarcopenia,
insulin resistance, and cancer-induced cachexia (68). PGC-
1ais responsible for many of the beneﬁcial effects of
exercise in muscle due to its ability to orchestrate the tran-
scription of both nuclear and mitochondrial DNA, promoting
a balanced expression of mitochondrial proteins and anti-
oxidant defenses against exacerbated ROS production. Im-
portantly, an accumulation of PGC-1aafter each bout of
exercise is indispensable to achieve these beneﬁcial effects
(47, 53, 70).
Many of the intracellular actors involved in obtaining the
beneﬁcial effects of exercise contain redox sensible regions
that are directly affected by ROS. The crucial requirement of
optimal ROS signaling is clearly observed by the effect of
antioxidants in hampering many important adaptations that
are related to endurance training, such as an increase in ex-
ercise capacity (21, 64), mitochondrial biogenesis (153),
muscular glucose uptake, improvement in insulin sensitivity
(133), and the increase of lean mass after resistance training
Several chronic exercise adaptations are dependent on
ROS produced by skeletal muscle in response to an acute
exercise session. Transient increases in ROS induced through
bouts of acute exercise stimulate Nrf2 activation. Nrf2 is the
master regulator of antioxidant defenses, a transcription
factor that regulates the expression of more than 200 cyto-
protective genes (44). Regular aerobic exercise in rodent
models has consistently been shown to activate Nrf2 sig-
naling in multiple tissues, including skeletal muscle (111),
kidney (122), brain (162), liver (135), and myocardium (145),
which leads to the upregulation of endogenous antioxidant
defenses and an overall greater ability to counteract the
damaging effects of oxidative stress.
Regarding protein quality control, exercise might be im-
portant to the correct folding of proteins, due to the creation
of an oxidative redox potential needed to oxidize the free
sulfhydryl groups of cysteine leading to disulﬁde bonds for-
mation that stabilize the protein conformation (Fig. 1) (166).
Antioxidant administration before exercise (64, 133) pre-
vents some of the most important exercise responses, prob-
ably by maintaining the intracellular environment in an
inappropriate reduced state. This reduced state may impair
the correct folding of born proteins (166). Loss of protein
folding regulation leads to an accumulation of unfolded or
misfolded proteins inside the endoplasmic reticulum (ER)
lumen and drives ER stress (ERS), which accentuates the
progression of many diseases, including Alzheimer’s. Unlike
almost all other cellular locations that have reducing redox
potentials, the typical ER has the oxidative redox potential
that is necessary to form disulﬁde bonds. It has been reported
that the ER of insulin-resistant rodents contains much higher
proportions of unfolded polypeptides and fewer disulphide
bonds than normal endoplasmic reticula, which is associated
with the loss of protein folding regulation (116).
Interestingly, exercise reduces negative outcomes in Alz-
heimer’s disease, including the accumulation of misfolded
proteins (159). The unfolded protein response (UPR) is in-
duced within contracting muscle cells and plays an important
role in cell protection from stress, mainly through an essential
chaperoning system (50). Exercise seems to improve many
ERS-related pathologies, such as diabetes mellitus, neurode-
generative diseases, sarcopenia, or cardiovascular alterations
(81, 91, 169) and PGC-1a, the redox sensible master gene
involved in the beneﬁcial effects of exercise, interacts with
ATF6a to regulate the UPR in muscle (169). Many proteins
included in the axis that regulates UPR activation (e.g.,
PERK, eIF2a, ATF4, CHOP, IRE1, XBP1, BiP, and ATF-6)
are regulated in both muscle and remote tissues after ex-
ercise training. For example, exercise training upregulates
ER chaperones, such as binding immunoglobulin protein
(BiP) in mouse muscle (39, 110), liver (31), and brain (89,
96). In summary, both acute and chronic exercise seems to
activate UPR signaling to alleviate ERS-related patholo-
A tight regulation of UPR is also crucial to the correct
folding of tumor suppressor proteins (79, 166). An exercise-
mediated control of tumor suppressor proteins has been
proposed to be one plausible mechanism for the lower inci-
dence of cancer in regular physically active individuals (113,
166). Indeed, a tumor suppressor protein might be delivered
from contracting muscle or synthetized directly in different
tissues by ROS-mediated signaling that is induced by phys-
ical exercise (Fig. 1A). Another possible mechanism is re-
lated to decreased insulin resistance in trained individuals,
since insulin resistance seem to be positively related to tumor
development (3). Once again, notably, such hypotheses ﬁt
well with the association of being actively healthy and the
lower incidence of cancer (83).
Lipid Peroxidation as a Mediator of Crosstalk
Between Different Tissues
Over the past three decades, an extensive body of literature
has shown the role of lipid peroxidation, not only in the
pathophysiology of diseases but also in cell biology and
human health (9). Lipid peroxidation is a process in which
oxidants attack lipids containing carbon–carbon double
bond(s) and involve hydrogen abstraction from a carbon,
with oxygen insertion resulting in lipid peroxyl radicals and
hydroperoxides (27). Increased ROS production can lead to
membrane lipid peroxidation and different cell fate, de-
pending on the cellular metabolic state and repair ability (9).
Products of lipid peroxidation (at low rates) can mediate
cell to cell communication during exercise. NADPH oxidase
2 (NOX2) is expressed at the sarcolemma of skeletal muscle,
and it seems to be the main source of ROS during contractile
activities that produce superoxide in the extracellular me-
dium (74, 77, 138). It is believed that superoxide is rapidly
converted into H
, which is more stable and membrane
REDOX SIGNALING IN WIDESPREAD EFFECTS OF EXERCISE 3
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permeable, acting as a signaling molecule. However, super-
oxide production near the sarcolema might increase the
oxidation of extracellular lipids/lipoproteins, converting
linonelic acid into 13-hydroxyoctadecadienoic acid (13-
HODE) and cholesterol into oxysterol, which is able to
activate transcription factors such as peroxisome proliferator-
activated receptor gamma and liver X receptor alpha,
respectively (41). Apart from this, 4-Hydroxynonenal (4-HNE)
is another product of lipid peroxidation that can activate
transcription factors. It was demonstrated that 4-HNE acti-
vates Nrf2, increasing mitochondriogenesis and antioxidant
defense (95). Interestingly, Nrf2 is activated after physical
exercise in several tissues, including the brain, kidney, and
testis (44). Once products of lipid peroxidation are increased
in the blood after physical exercise (66), it is possible that
they can communicate with skeletal muscle and with other
distant cells in the body (Fig. 2).
Metabolites Acting as Communicating Molecules
Through ROS-Dependent Mechanisms
A growing body of evidence suggests that different me-
tabolites produced during muscle contraction are secreted
during physical exercise. Interestingly, these metabolic
products can act like chemical mediators between cells (20).
Lactate is a very well-known metabolite produced by glucose
oxidation during muscle contraction that has been suggested
as a candidate molecule to communicate muscle with remote
cells. Formerly, it was believed that lactate was a waste
product of glycolysis, even referred to be the cause of fa-
tiguing muscle during physical exercise (24). The role of
lactate has changed from a possibly bad intermediate mole-
cule in muscle physiology to an important messenger mole-
cule during physical exercise (1). Nowadays, many
physiological functions are attributed to lactate, such as
slowing muscular fatigue (117), increasing force production
(92), and serving as a high-energy rich carbon skeleton for
many crucial biochemical processes within cells (24, 140).
The biochemical aspect of lactate production and its
physiological role were extensively reviewed by Brooks (24).
In brief, there are three main proposed functions for lactate,
as follows: (i) as an energy source, (ii) a major gluconeogenic
precursor after exercise, mainly due to a shuttle between the
skeletal muscle and the liver (the Cori cycle), and (iii) a
‘‘lactormone,’’ able to mediate autocrine, paracrine, and
endocrine communication (24). New information regarding a
shuttle between contracting muscle and microbiota has just
become available, which suggests that intestinal microbiota
are able to metabolize lactate and, thus, inﬂuence the exercise
capacity (143). Besides, a potential mechanism showing that
lactate might be able to stimulate ROS-mediated signaling
has also been proposed (Fig. 3).
FIG. 2. Lipid peroxidation
as a mediator of skeletal
muscle-remote tissue cross-
talk. NADPH oxidase is pro-
posed as the main source of
ROS during contractile activity
and due to its transmembrane
location, ROS production is
very close to the phospholipids
of the membrane. Circulating
lipids and membrane phos-
pholipids can be attacked by
extracellular-produced ROS to
form lipid peroxidation inter-
mediates that can interact with
nuclear receptors in remote
tissues and modulate gene ex-
pression. Color images are
4 LOUZADA ET AL.
Intracellular lactate levels increase during physical ex-
ercise in an intensity dependent way. Lactate can cross the
sarcolemma and reach blood circulation through mono-
carboxylate transporters ( MCTs). Serum lactate can be
uptaken by a wide range of cells such as contracting skel-
etal muscles themselves (16), heart (59), brain (132), liver
(48), kidney (112), astrocytes, or neurons (126). It is be-
lieved that slow-twitch skeletal muscle ﬁbers and liver are
the most important tissues for the removal of lactate from
blood (Fig. 3) (60), and the expression of MCTs is crucial
for the uptake of lactate from circulation. Moreover,
functional mitochondria are fundamental for lactate to be
oxidized (12, 24).
As proposed by Hashimoto and Brooks, lactate may act as
a communicating mediator called ‘‘lactormone’’ that couples
contracting muscle to other tissues (69). Supporting this hy-
pothesis, intraperitoneal l-lactate administration was found
to increase mitochondrial content in diverse mouse tissues
such as liver and brain (46), as well as PGC-1aand un-
coupling protein 3 expression in gastrocnemius (90). Because
these events are also observed after physical exercise, the
transitory increase in blood lactate during physical exercise
can contribute to the widespread health adaptations that occur
in remote tissues. Recently, it was demonstrated that lactate
was able to upregulate transforming growth factor beta2
(TGF-b2) in white adipose tissue. Further, TGF-b2 was se-
creted by adipose tissue in response to physical exercise,
which is related to the improvement of glucose tolerance.
Interestingly, the administration of a lactate-lowering agent
dichloroacetate during exercise training decreased circulat-
ing TGF-b2 levels and reduced exercise-stimulated im-
provements in glucose tolerance (154).
A hypothetical model is proposed in Figure 1, which shows
the probable redox-mediated mechanisms through which
contracting skeletal muscle communicates with remote tis-
sues. ROS might be involved in lactate action in different
tissues. Indeed, lactate increases the expression of genes in-
volved in lactate transport and mitochondrial oxidation in an
ROS-dependent manner (69), although the source of ROS has
not been deﬁned. Recently, it has been shown that lactate-
mediated increase in PGC1-aexpression was blunted by
N-acetyl cysteine pretreatment in skeletal muscle (90, 115).
Figure 3 illustrates the hypothetical sources of ROS that can
be activated by lactate: mitochondria, xanthine oxidase, and
NAD(P)H oxidase. During lactate oxidation, NADH is gen-
erated, increasing mitochondrial oxidative phosphorylation,
FIG. 3. Crosstalk between muscle and other tissues. Skeletal muscle contraction increases glucose oxidation rates in an
exercise intensity-dependent manner and stimulates the conversion of pyruvate into lactate via LDH. Lactate is mainly
produced by fast-twitch muscles during exercise and is released in muscles undergoing contraction to the blood circulation
through speciﬁc transporters (such as MCT). Once in circulation, lactate can be taken up by many tissues, such as liver,
WAT, brain, heart, and kidney. In the liver, lactate is converted into pyruvate by PDH, causes an increase in the levels of
, and stimulates several intracellular metabolic pathways. Robust ATP hydrolysis produces ADP, which is con-
verted into ATP and AMP by AK. AMP deamination yields hypoxanthine, which is released into the circulation. Xanthine
oxidase converts hypoxanthine into urate and also produces superoxide, leading to redox-mediated signaling in the liver.
Urate is a potent antioxidant molecule that is released into the circulation. The proposed crosstalk between muscle and liver
involves spatially and temporally synchronized ROS production and ROS scavenging to ensure that correct ROS-mediated
signaling occurs within the whole body during and after exercise. In the left panel, intestinal NADH-dependent ROS
production is proposed as a mechanism that may use NADH derived from lactate oxidation by NAD(P)H oxidase to produce
ROS in a microbiota-dependent way. ADP, adenosine diphosphate; AK, adenylate kinase; AMP, adenosine monophosphate;
ATP, adenosine triphosphate; LDH, lactate dehydrogenase; MCT, monocarboxylate transporter; PDH, pyruvate dehydro-
genase; WAT, white adipose tissue. Color images are available online.
REDOX SIGNALING IN WIDESPREAD EFFECTS OF EXERCISE 5
which can increase ROS production. Another potential
mechanism may be the use of NADH derived from lactate
oxidation by NAD(P)H oxidase to produce ROS. This hy-
pothesis is supported by experiments in Drosophila in which
lactate stimulates intestinal NADH-dependent ROS produc-
tion (82). A dysbiosis marked by overgrowth of Lactobacillus
plantarum in the ﬂy gut increases lactate production and
promotes over-proliferation of intestinal stem cells. Using
this model, the authors proposed that lactate is a key element
for communication between microbes and intestinal cells,
and that NADH produced by oxidation of lactate derived
from bacteria could be a substrate for NAD(P)H oxidase to
increase ROS production (82). In this context, it would be
interesting to test whether the same process occurs after ex-
Lactate also seems to exert a free radical scavenger func-
tion, able to act as an antioxidant in some speciﬁc conditions
as heart ischemia, since the perfusion with a lactate solution
protects the tissue from oxidative damage (65). These newly
proposed functions of lactate, acting as a free radical scav-
enger and as a signaling molecule, are illustrated in Figure 3.
A purine cycle also intermediates the crosstalk between
contracting muscle and liver. Mostly in the liver, inosine and
hypoxanthine derived from the muscle can be converted into
uric acid by xanthine oxidase (71). This cycle might be a
potential mechanism by which exercise promotes (paradox-
ically) a pro-oxidant effect due to xanthine oxidase in the
liver, and an increase of urate, a powerful antioxidant in
circulation (114). In fact, increased plasma total antioxidant
capacity has been observed after high-intensity exercise (71).
The circulating urate can be taken up by different cells and,
after a recovery period after exercise, converted into allantoin
(73). During this process, there is a scavenger of the hydroxyl
radical, hydroperoxide, and lipid peroxidation (37). Inter-
estingly, urate is taken up preferentially by the contracting
muscle, and not by the resting ones (72). Although the
mechanism is not well understood, urate might be useful for
protecting the contracting muscle from oxidative damage
once its exogenous administration reduces exercise-induced
oxidative stress (165).
Based on this intimate co-operation between muscle and
liver, we propose synchronized and tightly regulated ROS-
mediated signaling in remote tissues that might be dependent
on the products of muscle contraction and liver processing.
This crosstalk is a well-organized network that synchronizes
contracting muscle and other remote tissues to ensure optimal
redox-mediated signaling during exercise and recovery (as
illustrated in the hypothetical schema in Fig. 1). For example,
lactate is produced and released into blood circulation,
reaching multiple different tissues, then altering the metab-
olism, and ﬁnally promoting an ROS-mediated signaling.
Simultaneously, intense ATP hydrolyses, mostly found dur-
ing intense exercise, promote the release of inositol and
hypoxanthine, which mostly reaches its peak after exercise.
Once in the liver, urate is produced from hypoxanthine and
released into circulating blood, delivering a potent antioxi-
dant and probably counteracting the peaks of ROS produc-
tion. This hypothetical possibility elaborates the ﬁne-tuning
process required for the exchange of purines and lactates that
are derived from contracting muscle and is dictated by the
intensity of exercise. When this fascinating and natural
communication is perturbed, a disaccord in redox-mediated
signaling can lead to impaired function in many tissues and
blunt the widespread health beneﬁts of exercise.
Gradient as a Chemoattracting Agent
Supporting Skeletal Muscle Regeneration
In skeletal muscle, cooperation between immune and
muscular cells is observed during muscular regeneration. The
recruitment of neutrophils and monocytes from blood cir-
culation is mediated by chemoattracting molecules that are
secreted by many cells (e.g., endothelial cells, satellites cells,
and immune-resident cells) at the lesion site. Multiple factors
such as C-C motif ligand 2/monocyte chemoattractant
protein-1 (MCP1) and tumor necrosis factor alpha are known
to attract monocytes and to differentiate them into macro-
phages, respectively (128), orchestrating the process of
myogenesis (32, 94, 137). H
gradient also serves as a
chemoattracting agent. In the zebraﬁsh model, an H
gradient generated by the DUOX enzyme (after tissue injury)
recruits leucocytes to the site of the lesion to promote wound
healing (118). Moreover, H
production seems to be cru-
cial to promote progenitor cell proliferation during acute
kidney lesions (33). In these two examples, the inhibition of
generation abolished the regenerative process. In
mammals, the role of DUOX1 in the recruitment of immune
cells was demonstrated in lung inﬂammatory response, which
was found to be crucial to the regenerative process (30, 67).
Thus, one can speculate that exercise-induced H
ation in skeletal muscle cells could create a gradient to attract
supportive cells to participate in exercise responses.
After eccentric exercise, there is a peak in pro-
macrophages inﬁltration at 48 h (100,
102) that switches to anti-inﬂammatory CD163
phages after 72 h (57, 131). Given that ROS are produced and
released into the blood from skeletal muscle (11, 34, 84), one
can hypothesize that these molecules participate in the re-
cruitment of immune cells to support cellular regeneration
after damaging exercise. In fact, DUOX1 is expressed in
muscular progenitor cells and its expression declines during
myogenesis (139), suggesting that DUOX1 could be a source
of ROS from satellite muscular progenitor cells to commu-
nicate to other cells through an H
gradient, as observed
during zebraﬁsh and mammalian lung and kidney injury.
Myokines and Its ROS-Dependent Regulation:
Communicating the Contracting Muscle
to the Whole Body
After contractile activity, skeletal muscle cells increase the
production and release of several molecules such as cytokines
or other small proteins (*5–20 kDa) and proteoglycan pep-
tides that show autocrine, paracrine, and/or endocrine effects.
Several well-known cytokines (e.g., IL-6, IL-8, IL-10, IL-15,
etc.) have been shown to be secreted by skeletal muscle
during physical exercise and, as a result, they are referred to
as myokines (123). Myokines are involved in exercise-
associated metabolic changes and not only in muscle but also
in other tissues such as heart, adipose tissue, liver, pancreas
bone, and brain. Myokines play important roles in metabolic
changes that are induced by physical exercise. They also
participate in tissue regeneration and repair, immunomodula-
tion. and cell differentiation (124). The interconnections be-
tween contracting muscle and practically all cells are complex
6 LOUZADA ET AL.
and not a completely deciphered system. Currently, several
myokines have been described to be stimulated by physical
exercise, including IL-6 (121), Irisin (19), IL-15 (146), FGF21
(156), LIF (23), and MCP1 (28). Interestingly,the PGC-1aand
Akt/mTOR pathways seem to be involved in myokine secre-
tion, and both of them are redox-sensitive intracellular path-
ways (Fig. 4). The most well-studied myokines are IL-6 and
Skeletal muscle IL-6 secretion increases after a single bout
of physical exercise (124), which induces liver glucose out-
put (52). IL-6 secretion during physical exercise is not related
to tissue damage or pro-inﬂammatory processes (124, 142,
150), and it seems to be regulated by intracellular calcium
levels (167). It was demonstrated that the administration of a
cocktail of antioxidants containing Vitamins A, C, and E
(161) or Vitamin C and E (54) before a single bout of physical
exercise attenuated IL-6 secretion in humans. L-NAME, a
nitric oxide synthase (NOS) inhibitor, also attenuated the
increase in IL-6 mRNA levels in response to exercise (151).
In addition, it has been suggested that NOX enzymes are
involved in IL-6 secretion by skeletal muscle during physical
exercise, since apocynin, an NOX inhibitor, attenuated this
phenomenon, which also occurred in a gp91phox knockout
IL-6, secreted by contracting skeletal muscle during re-
sistance training, seems to activate satellite cells through
the activation of STAT3, which is crucial for hypertrophy
(144). It has not been investigated whether this action is
dependent on ROS-mediated signaling; however, ROS can
stimulate STAT3 via a modiﬁcation on its Tyr 7055 and
Cys 253 (147). Further, IL-6 stimulates ROS production in
plenty of different cell types (163), so it is possible that
ROS can act as an intermediate in the effect of IL-6 in
remote tissues during exercise. For instance, increased in-
sulin sensitivity and fatty acid oxidation that is stimulated
by IL-6 (26) might, in part, be dependent on the activation
of AMP-activated protein kinase (AMPK) by ROS (157).
Also, the stimulus of muscle glucose uptake after exercise
might be through a similar mechanism (61). The interplay
ferent tissues (88).
Irisin was ﬁrst described as a myokine with the ability to
induce a browning phenotype in white adipose tissue, raising
basal metabolic rates (Fig. 5) (19). Several studies showed
that irisin promotes widespread effects in remote tissues,
preventing oxidative stress and tissue damage. Nrf2 activates
a well-known antioxidant pathway that protects against var-
ious pathological conditions (43, 97, 99), and its activation
seems to correlate with the antiﬁbrotic and antioxidative ef-
fects of irisin (33, 45, 171). For instance, irisin treatment
protects hepatocytes in vitro from overproduction of ROS
that is induced by H
(13). Moreover, irisin mediates part
of the protective effect of dexmedetomidine in livers under
intestinal ischemia/reperfusion damages via decreasing in-
ﬂammasome markers and ROS production (51). In addition,
irisin is known to decrease several pro-inﬂammatory cyto-
kines and increase antioxidant defenses (e.g., SOD and GPX)
in hepatocytes through Nrf2 upregulation (45). In endothelial
cells, irisin stimulates angiogenesis via AKT/mTOR/S6K1/
Nrf2 signaling, which reduces the higher ROS content in-
duced by oxidized LDL (Fig. 5) (171).
A major role of oxidative stress in ﬁbrosis development is
caused by over-activated Smad-3 signaling (18) that leads to
exacerbated ROS production (14). Mechanistically, irisin-
induced Nrf2 activation in cardiac cells suppresses the ROS
generation that is induced by angiotensin II, which is triggered
by TGF-b1 in ﬁbroblasts (33). Moreover, irisin was found to
prevent heart remodeling (98) and reduce blood pressure of
spontaneously hypertensive rats through endothelial cells
oxidative stress reduction via AMPK and NO signaling (56).
In a type 2 diabetes mice model,irisin ameliorated endothelial
function by reducing the overproduction of superoxide and
peroxynitrite (172). However, in endothelial cells, irisin also
reverted the oxidative stress induced by advanced glycation
end products by decreasing endothelial NOS activity and
therefore, preventing the endothelial damage that is secondary
to inﬂammasome overactivation (40).
In macrophages, irisin was found to increase proliferation
and phagocytosis ability (105) and protected these cells
against oxidative stress damage via upregulation of antioxi-
dant defenses, even under LPS stimulation (106). Given the
undeniable implication of macrophages in the development
and progression of many diseases, a direct action of exercise-
induced irisin on macrophages could contribute to the
widespread beneﬁcial effects of exercise. Some of these ef-
fects are illustrated in Figure 5.
Previous studies have suggested that myokines mediate the
beneﬁcial effects of exercise in brain function (Fig. 5). Under
an ischemia/reperfusion stroke, brain cells experiment a
glucose/oxygen deprivation that triggers an intense ROS
FIG. 4. Myokines and ROS dependence. The most studied myokines are illustrated and their ROS dependence is
highlighted. IL-6, IL-8, and IL-15 are regulated by ROS. The control of several myokines relies on the activation of human
PGC-1aand AKT/mTOR signaling, but their dependence on redox signaling has not yet been completely investigated.
AKT/mTOR, protein kinase B/mechanistic target of rapamycin; IL, interleukin; PGC-1a, peroxisome proliferator-activated
receptor gamma coactivator 1-alpha. Color images are available online.
REDOX SIGNALING IN WIDESPREAD EFFECTS OF EXERCISE 7
production that can lead to an irreversible injury. Using
in vitro model, irisin protected neuron cells from oxidative
stress via decreasing the higher ROS production and in-
ﬂammation through increased SOD expression, consequently
protecting neurons from stroke-induced apoptosis (127).
In 1944, one of the ﬁrst reports suggested that exercise
reduced tumor growth and progression in mice (136). Since
then, there are several evidences showing that a healthy
lifestyle hinders the development of several types of cancer
and regular exercise can protect from a large range of dis-
eases (49, 119, 134). However, the precise mechanisms are
still unclear. Regarding the effect of exercise on tumor
growth, there are many conﬂicting results that have been
obtained from rodent experiments. Recent studies have
shown that exercise may decrease tumor growth if tumor-
bearing mice were trained 4 weeks before inoculation with
B16 melanoma cells (125), whereas another study suggested
avoiding free access to exercise because they observed in-
creased tumor growth and decreased lifespan in a model of
intramuscular tumor inoculation (8). Despite the gap of
knowledge about the mechanisms of actions involved in this
process, regular exercise has been recommended as a sup-
plementary therapy for cancer patients (83). Based on exist-
ing evidence, some public health organizations have issued
physical activity guidelines also for cancer prevention. Re-
garding the large number of studies conducted on physical
activity and cancer prevention, most of them have an in-
complete description of physical activity (such as type, in-
tensity, duration, and metabolic responses).
Mechanistically, an antiproliferative effect of serum col-
lected from mice after moderate exercise intensity (50% of
maximal exercise capacity), but not from mice submitted to
high-intensity swimming exercise (50% and 80% of maximal
capacity, respectively), conﬁrms the idea that a mix of
myokines are secreted that are able to affect tumor cells,
reducing tumor growth (2). However, another study showed
that high-intensity training (corresponding to 85% of VO
max) was able to promote a reduction in tumor mass (10). By
screening 28 potential candidate molecules upregulated in
serum after swimming exercise, Oncostatin M has emerged
as a candidate for reducing mammary cancer cells growth
(78). Another candidate able to prevent the initiation of a
tumor was the ‘‘Secreted Protein Acidic and Rich in Cy-
steine’’ (SPARC). The level of circulating SPARC increased
in mice and humans after a single bout of exercise. Low-
intensity exercise induces SPARC expression and secretion
that reduces the formation of aberrant crypt foci and prevents
the onset of colon cancer (6). SPARC expression seems to be
induced by low and moderate exercise programs (149) and is
mainly secreted by slow-twitch ﬁbers instead of fast-twitch
ﬁbers after resistance exercise (Fig. 5) (148). Apart from its
possible direct action as an antitumor molecule, SPARC also
FIG. 5. Crosstalk between
skeletal muscle and other
tissues. The regular practice
of physical exercise promotes
widespread health beneﬁts
that can prevent and treat
many diseases. Most of the
desirable effects of physical
exercise are mediated by
myokines that can facilitate
communication of contract-
ing muscles with remote tis-
sues. The mechanism of
action of many myokines re-
lies directly or indirectly on
redox signaling. Color ima-
ges are available online.
8 LOUZADA ET AL.
seems to mimic some of the beneﬁcial effects of exercise on
glucose metabolism via AMPK activation (5).
Therefore, myokines secreted by the muscles may mediate
the beneﬁcial effects of exercise on tumor development.
Although it is a promising and innovative theme, the effects
of contracting muscle myokines (e.g., IL-6, Irisin, FGF21,
Oncostatin M, SPARC, etc.) on tumor growth and progres-
sion using xenograph and inoculated rodent models are still
Extracellular Vesicles Released After Exercise
and Physiological Perspectives
Other important products secreted by skeletal muscle
during contraction are extracellular vesicles that include
exosomes and microvesicles (also known as shedding vesi-
cles, ectosome). Exosomes are complex 20–100-nm vesicles
formed by the inward budding of endosomal membranes to
form large multivesicular bodies. These vesicles are released
out of the cell when the multivesicular body fuses with the
plasma membrane. The exosome is characterized by soluble
and membrane-bound proteins, lipids, metabolites, DNA,
and RNA (mRNA, miRNAs, and other small regulatory
RNAs) that are involved in a protective lipid bilayer that can
modify signaling pathways and protein expression in remote
Physical exercise considerably increases the metabolic
demands of the body. and the vesicle trafﬁcking of metabolic
mediators might be a tool through which tissues can share
resources during this physiological situation. Using quanti-
tative proteomic techniques and intravital imaging experi-
ments, Whitham et al. demonstrated that skeletal muscle
contraction stimulates extracellular vesicle release and pro-
vides the means for tissue crosstalk during exercise (168).
Although the temporal aspects of exosome and small vesicle
biogenesis and transport in exercise are unknown, it has been
demonstrated that the release of exosomes is associated with
increases in the levels of intracellular calcium (141). Because
motor neuron stimulation of skeletal muscle ﬁbers leads to a
rapid release of Ca
from the sarcoplasmic reticulum (109),
it is plausible that a transient Ca
increase during skeletal
muscle contraction is likely involved in exosome release.
ROS seems to be involved in the secretion of extracellular
vesicles since pro-oxidant conditions seem to induce their
release (15). In addition, NADPH oxidase and NOS-2 in-
hibitors reduced the production and release of neutrophil
microvesicles (158). Further, tumor and senescent cells have
altered redox balances with elevated ROS levels, which is
related to the higher number of microvesicles secreted by
these cells (29, 80). From an exercise perspective, more re-
search is necessary to elucidate the relationship between in-
creases in ROS production during skeletal muscle contraction
and microvesicle release (Fig. 1). However, some evidence
suggests that disrupted ROS-mediated signaling caused by
NAD(P)H oxidase inhibition (75), or aging, through exac-
erbated ROS generation (107), can affect the nature of exo-
somes (e.g., heat shock proteins [HSPs] expression),
delivering and potentially hampering the widespread bene-
ﬁcial effect of exercise.
HSPs, for example, can be transferred between two cells
(170) and participate in the maintenance of protein homeo-
stasis (155). Previous studies suggested that Hsp70 secretion
is mediated by ATP-binding cassette transporter (ABCA1)
transmembrane transporters (4). Further, three other mecha-
nisms can also be related to Hsp70 release, such as: (i) cell
lysis with consequent release of cytoplasmic content; (ii) cell
surface blebbing and Hsp70 release in microvesicles to the
extracellular ﬂuid; and (iii) through endolysosomes (58, 103,
104). HSPs are molecular chaperones that facilitate protein
folding and maintain protein structure and function during
cellular stress. HSPs are involved in a wide range of cellular
processes that are perturbed by oxidative stress, such as
protein folding, apoptosis, and inﬂammation (85, 86). As
recently discussed (108), the intercellular communication via
exosomes might compensate for the imbalance in HSP levels
in almost every cell (155). For example, differentiated neu-
rons seem to be dependent on a transfer of HSP from other
cells to maintain their cytoprotection against stress (101). It
has been demonstrated that intercellular HSP transfer occurs
by exosomes after exercise (93, 164), raising the idea that this
intercellular communication is critical to ensure an integrated
stress response across different tissues (160a). The exosomes
secreted after acute exercise have higher levels of HSPs (55,
168). On the contrary, muscle denervation alters the content
of exosomes (38), suggesting a crucial role for contractile
activity on exosome content and secretion.
Alzheimer’s is a neurodegenerative disease in which there
is a prevalent protein folding disorder in the brain, and the
HSP response in some neurons becomes reduced (25). It has
been extensively demonstrated that HSP is involved in pro-
tein homeostasis in the brain, and an accumulation of mis-
folded proteins (b-amyloid peptides) contributes to the
progression of this neurodegenerative disease (7). Interest-
ingly, an increase in HSP70 expression improves cognition
function and reduces amyloid-bpeptide levels in Alzhei-
mer’s model mice (152). Based on the mechanisms men-
tioned earlier, it is tempting to suggest that HSP transfer
through exosomes, which follows exercise, could retard or
even prevent the development of brain diseases; and this
hypothesis is illustrated in Figure 5.
The widespread beneﬁcial effects of physical exercise are
mediated by multiple soluble factors that interfere with a
variety of signaling pathways, and the decoding of these
pathways is a challenge for basic and translational research.
Fascinatingly, optimal ROS-mediated signaling is necessary
to achieve the beneﬁcial effects of exercise. In a common
way, exercise-secreted mediators seem to operate via PGC-
1aand Nrf2, two redox sensible pathways that promote
healthier conditions globally.
Recently, attention has focused on the mechanisms of
action of new myokines. Many exercise responses and ad-
aptations may be dictated by the (un)balance of ‘‘cytokines
cocktail,’’ deﬁned as a net balance between deleterious
hampering molecules and beneﬁt enhancing molecules. Un-
derstanding how aging and obesity blunt some of these ex-
ercise adaptations and proposing a multiple and combined
therapeutic strategy that will optimize the beneﬁcial effect of
exercise in many diseases is a critical issue in exercise bi-
ology. In addition, the ROS-rich environment that is created
after exercise is not exclusively restricted to contracting
muscle. Understanding the processes by which the beneﬁcial
REDOX SIGNALING IN WIDESPREAD EFFECTS OF EXERCISE 9
effects of exercise occurs is, therefore, a prerequisite to de-
ﬁning how lack of exercise contributes to a poor quality of
life and high incidence of disease. Therefore, further studies
designed to decipher the mechanism of action of myokines
are indispensable to understand the redox code that underlies
the beneﬁcial effects of exercise and, thus, will expand the
therapeutic strategies for many diseases.
All authors listed have made a substantial, direct, and in-
tellectual contribution to the work, and approved it for pub-
lication. R.A.L., J.B., and L.P.M. wrote the article; D.P.C.,
C.D., and J.P.W-.d.-C. revised the article; and R.A.L. and
R.S.F. designed the outline of the article and wrote the article.
The authors would like to thank Sapiens scientiﬁc illus-
trations for the design of the ﬁgures.
The study was supported by research grants from CNPq,
Fundac¸ao Carlos Chagas Filho de Amparo a Pesquisa do
Estado do Rio de Janeiro (FAPERJ), and Coordenac¸a
Aperfeic¸oamento de Pessoal de Nı
´vel Superior (CAPES).
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Address correspondence to:
Dr. Ruy A. Louzada
Institut of Biophysics Carlos Chagas Filho
Federal University of Rio de Janeiro
Rio de Janeiro 21941-590
Date of ﬁrst submission to ARS Central, November 11, 2019;
date of ﬁnal revised submission, February 29, 2020; date of
acceptance, March 9, 2020.
13-HODE ¼13-hydroxyoctadecadienoic acid
AK ¼adenylate kinase
AKT/mTOR ¼protein kinase B/mechanistic target
AMP ¼adenosine monophosphate
AMPK ¼AMP-activated protein kinase
ATP ¼adenosine triphosphate
BiP ¼binding immunoglobulin protein
/calmodulin-dependent protein kinases
DUOX ¼dual oxidase
ER ¼endoplasmic reticulum
ERS ¼endoplasmic reticulum stress
FGF21 ¼ﬁbroblast growth factor 21
GLUT4 ¼glucose transporter 4
HSPs ¼heat shock proteins
LIF ¼leukemia inhibitory factor
LDH ¼lactate dehydrogenase
L-NAME ¼N(G)-nitro-l-arginine methyl ester
MAPK ¼mitogen-activated protein kinase
MCP1 ¼monocyte chemoattractant protein 1
MCT ¼monocarboxylate transporter
NADH ¼nicotinamide adenine dinucleotides
NOX ¼NADPH oxidase
Nrf2 ¼nuclear factor erythroid 2-related factor 2
PDK4 ¼pyruvate dehydrogenase kinase 4
PGC-1a¼peroxisome proliferator-activated receptor
gamma coactivator 1-alpha
ROS ¼reactive oxygen species
SPARC ¼secreted protein acidic and rich
TGF-b¼transforming growth factor beta
16 LOUZADA ET AL.