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Abstract

The concept of a "polypill" is receiving growing attention to prevent cardiovascular disease. Yet similar if not overall higher benefits are achievable with regular exercise, a drug-free intervention for which our genome has been haped over evolution. Compared with drugs, exercise is available at low cost and relatively free of adverse effects. We summarize epidemiological evidence on the preventive/therapeutic benefits of exercise and on the main biological mediators involved.
Exercise is the Real Polypill
The concept of a “polypill” is receiving growing attention to prevent cardio-
vascular disease. Yet similar if not overall higher benefits are achievable with
regular exercise, a drug-free intervention for which our genome has been
haped over evolution. Compared with drugs, exercise is available at low cost
and relatively free of adverse effects. We summarize epidemiological evi-
dence on the preventive/therapeutic benefits of exercise and on the main
biological mediators involved.
Carmen Fiuza-Luces,
1,2
Nuria Garatachea,
3
Nathan A. Berger,
4
and
Alejandro Lucia
1,2
1
Universidad Europea Madrid, Madrid, Spain;
2
Instituto de
Investigación, Hospital 12 de Octubre, Madrid, Spain;
3
Facultad
de Ciencias de la Salud y del Deporte, Universidad de
Zaragoza, Huesca, Spain; and
4
Center for Science, Health and
Society, Case Western Reserve University, School of Medicine,
Cleveland, Ohio
alejandro.lucia@uem.es
An Evolutionary Perspective
Despite recent strong selection pressure (495), our
genetic makeup is largely shaped to support the
physical activity (PA) patterns of hunter-gatherer
societies living in the Paleolithic era, for which
food/fluid procurement (and thus survival) was
obligatorily linked to PA (71, 347). The energy ex-
penditure of hunter-gatherers during PA (1,000
1,500 kcal/day) can be reached with 3– 4 h/day of
moderate-to-vigorous PA (MVPA), e.g., brisk/very
brisk walking (71, 346). Yet technological improve-
ments over just 350 generations (agricultural fol-
lowed by industrial and, most recently, digital
revolution) have led to dramatic reductions in hu-
man PA levels (26, 475): 1/3 of adults worldwide
are currently inactive, and the endemic inactivity
trend starts in early life (166).
Physical inactivity in contemporary obesogenic
environments initiates maladaptations that cause
chronic disease and is becoming a major public
health problem (36). In contrast, regular PA has a
profound effect on the expression of a substantial
proportion of our genome (474), which has been
selected for optimizing aerobic metabolism to con-
serve energy in an environment of food scarcity
(40, 41), resulting in numerous beneficial adapta-
tions and decreased risk of chronic diseases, as
discussed below.
Epidemiological Evidence I:
Exercise Benefits–How Protective is
Exercise per se Against
Conventional Cardiovascular Risk
Factors Compared With Drugs?
The main outcome of regular PA
1
, achieving mod-
erate-to-high peak cardiorespiratory fitness (8
METs
2
), reduces the risk of cardiovascular events
and all-cause mortality (234). There is strong epi-
demiological evidence indicating that regular PA is
associated with reduced rates of all-cause mortal-
ity, cardiovascular disease (CVD), hypertension,
stroke, metabolic syndrome, Type 2 diabetes,
breast and colon cancer, depression, and falling
(see Ref. 255 for a review). Especially provocative
are recent findings showing a positive and negative
association between leisure time spent sitting or
doing PA, respectively, and mortality risk among
survivors of colorectal cancer (55). Furthermore,
the benefits of PA are such that a dose response is
usually observed in the general population. Higher
MVPA levels [450 min/wk, clearly above the min-
imum international recommendations of 150
min/wk of MVPA (515)] are associated with longer
life expectancy (317). And athletes, who are those
humans sustaining the highest possible PA levels,
live longer than their nonathletic counterparts
(415). Most epidemiological research up to date
has focused on exercise and CVD risk factors or
cardiovascular outcomes. For instance, the bene-
fits of regular exercise on all-cause mortality and
CVD are well above those of a nutritional interven-
tion, supplementation with marine-derived omega-3
polyunsaturated fatty acids (PUFAs), which has
gained considerable popularity owing to the po-
tential ability of omega-3 PUFAs to lower triglycer-
ide levels, prevent serious arrhythmias, or decrease
platelet aggregation and blood pressure (BP) (423).
These protective roles of omega-3 PUFAs are, however,
controversial since a recent meta-analysis showed that
omega-3 PUFAs are not significantly associated
with decreased risk of all-cause mortality and ma-
jor CVD outcomes (405).
Exercise training has a restoring/improving ef-
fect on endothelial function (103, 158, 500). This is
an important consideration because endothelial
dysfunction is a risk factor for CVD, whereas normal
or enhanced endothelial function has a protective
1
The terms “PA” (physical activity) and “exercise” are
used interchangeably in this review to make reading
more fluent.
2
1 MET equals an oxygen consumption of 3.5 ml·kg
1
·
min
1
.
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effect (158–160). In previously sedentary middle-
aged and older healthy men, regular aerobic exer-
cise can prevent the age-associated loss in
endothelium-dependent vasodilation (as assessed
by vasodilatory response to acetylcholine) and re-
store this variable to levels similar to those of
young adults (103). Exercise also reduces more
“traditional” CVD risk factors, albeit probably its
effects are modest compared with the impact of
medications, with the possible exception of (pre-)
diabetes. This is illustrated in the paragraphs be-
low, where we compare the effects of exercise in-
terventions alone to those of common drugs on
conventional CVD risk factors. There is scant bio-
medical literature containing direct comparison of
exercise to pharmacological intervention. There-
fore, the comparisons presented herein are based
on the results of recent meta-analyses (indepen-
dently searched by two authors, C. Fiuza-Luces
and N. Garatachea) of 1) randomized controlled
trials (RCTs) of drugs or drug combinations and
2) RCTs of exercise training alone.
Exercise vs. Drugs: Glucose Intolerance
A recent meta-analysis has reported that exercise
training is associated with an overall 0.67% decline
in glycosylated hemoglobin (HbA1c) levels [95%
confidence intervals (CI), 0.84 to 0.49] (479).
Separate analyses showed that each of aerobic
(0.73%; 95% CI, 1.06 to 0.40), resistance
(0.57%; 95% CI, 1.14 to 0.01), or combined
aerobic and resistance training modes were asso-
ciated with declines in HbA1c levels compared
with control participants (0.51%; 95% CI, 0.79
to 0.23). The overall reduction in HbA1c of
0.67% brought about by exercise compares rela-
tively well with the recently reported reductions
achieved by commonly used oral antidiabetic
medications such as metformin monotheraphy
and dipeptidyl peptidase inhibitors (sitagliptin,
saxagliptin, vildagliptin, linagliptin), which can
lower HbA1c levels by 1.12% (95% CI, 0.92 to
1.32) (182) and 0.76% (95% CI, 0.83 to 0.68),
respectively (362). On the other hand, a recent
meta-analysis has shown that non-drug approaches
(diet, exercise) are superior to drug interventions
in diabetes prevention [risk ratio of 0.52 (95% CI,
0.46 0.58) vs. 0.70 (95% CI, 0.58 0.85), respec-
tively (P 0.05)] (191).
Exercise vs. Drugs: Blood Lipids
A recent meta-analysis of RTCs (223) has shown a
significant decrease in triglycerides after exercise
interventions (6.0 mg/dl; 95% CI, 11.8 to 0.2)
but not in total cholesterol (0.9 mg/dl; 95% CI,
3.2 to 5.0), high-density lipoprotein (HDL) cho-
lesterol (1.0 mg/dl; 95% CI, 0.2 to 2.1), or low-
density lipoprotein (LDL) cholesterol (2.1 mg/dl;
95% CI, 1.5 to 5.7). Relative to baseline values,
changes were equivalent to 0.4%, 2.1%, 1.5%, and
5.7% for total cholesterol, HDL cholesterol, LDL
cholesterol, and triglycerides, respectively. Statins,
especially simvastatin and atorvastatin, are the
most widely prescribed cholesterol-lowering drugs
(113). A meta-analysis of 21 trials testing statin
regimens reported a weighted mean difference af-
ter 1 year of treatment of 1.07 mM (29%) for LDL
cholesterol (18). A more recent meta-analysis of
the effects of atorvastatin on blood lipids showed
decreases of 36–53% for LDL cholesterol (2).
Exercise vs. Drugs: Blood Pressure
A recent meta-analysis reported BP reductions
with aerobic exercise in healthy subjects [2.4
mmHg (95% CI, 4.2 to 0.6) for systolic BP (SBP)
and 1.6 mmHg (95% CI, 2.4 to 0.74) for diastolic
BP (DBP)] and in hypertensive people [6.9 mmHg
(95% CI, 9.1 to 4.6) for SBP and 4.9 mmHg
(95% CI, 6.5 to 3.3)] for DBP (73). Resistance
training, including either dynamic (72, 74, 222) or
static exercises (74, 221, 358), also has a BP-lower-
ing effect in people with normal pressure or pre-
hypertension, overall, 3.87 mmHg (95% CI, 6.19
to 1.54) for SBP and 3.6 mmHg (95% CI, 5.0 to
2.1) for DBP. Of note, it is difficult to compare the
effects of exercise and drugs since we are not aware
of a meta-analysis comparing the effects of BP-
lowering drugs vs. no drug administration. Never-
theless, the effects of exercise on BP are probably
of higher magnitude than those obtained with any
single BP-lowering drug, e.g., aliskiren, a renin in-
hibitor that induces an overall BP reduction of
0.18 mmHg (95% CI, 1.07 to 0.71) or angioten-
sin receptor blockers, which induce an overall BP
reduction of 0.15 mmHg (95% CI, 1.38 to 1.69)
(138). Exercise effects on BP are, however, likely to
be similar or slightly lower than those of drug com-
binations, as suggested by the fact that drug com-
binations are substantially more efficacious than
monotherapy in lowering BP. For instance, al-
iskiren combined with angiotensin receptor block-
ers would be superior to aliskiren monotherapy at
the maximum recommended dose on SBP (4.80
mmHg; 95% CI, 6.22 to 3.39) and DBP reduc-
tion (2.96 mmHg; 95% CI, 4.63 to 1.28). Sim-
ilar results can be found for aliskiren combined
with angiotensin receptor blockers vs. angiotensin
receptor blockers monotherapy (SBP: 4.43 mmHg,
95% CI: 5.91 to 2.96; DBP: 2.40 mmHg, 95% CI:
3.41 to 1.39) (531).
Exercise vs. Drugs: Thrombosis
Longitudinal studies have shown that increased
levels of PA reduce thrombosis-related cardiovas-
cular events, e.g., nonfatal myocardial infarctions,
strokes, and mortality, in people with (252, 376,
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504) or without a history of CVD (279, 330, 496). A
recent meta-analysis has concluded that moderate
exercise training after successful coronary stenting,
compared with control group, does not signifi-
cantly change the incidence of stent thrombosis
and major adverse cardiovascular events (death,
myocardial infarction, stroke) for up to 3 years
(1.8% vs. 2.0%, P 0.73; and 14.9% vs. 15.0%, P
0.97, respectively) but is effective in reducing un-
scheduled hospital visits for worsening angina
(20.2% vs. 27.2%, P 0.0001) (451). Comparisons
with drugs are also difficult here, but pharmaco-
logical interventions would seem to outweigh ex-
ercise benefits. For instance, in a meta-analysis
with 5,821 patients undergoing coronary stenting,
the use of cilostazol-based triple antiplatelet ther-
apy (TAT) was associated with a significant reduc-
tion in the risk of major adverse cardiovascular
events compared with dual antiplatelet therapy
(DAT) (9.2% vs. 13.4%; odds ratio of 0.59; 95% CI,
0.46 to 0.76) (142).
Thus, although regular exercise and cardiorespi-
ratory fitness are associated with a significant re-
duction in cardiac events (165, 329, 442), it seems
that the benefits of regular exercise go beyond
reducing traditional CVD risk factors. This is con-
sistent with classic (see Ref. 213 for a review) and
recent reports showing that high cardiorespiratory
fitness can reduce morbidity and mortality inde-
pendent of standard CVD risk factors (254, 354,
445). Notably, Mora et al. evaluated 27,055 appar-
ently healthy women and found that 59% of the
risk reduction for all forms of CVD associated with
higher levels of PA could be attributed to the effects
of exercise on known risk factors, with inflamma-
tory/hemostatic biomarkers (e.g., C-reactive pro-
tein, fibrinogen) making the largest contribution to
PA reduction of CVD, followed by BP, lipids, and
body mass index (319). So, where is the “risk factor
gap” explaining the remaining variance (40%) in
CVD risk reduction achieved by regular exercise?
Epidemiological Evidence II:
Exercise Attenuates Aging
Autonomic Dysfunction
Besides improving endothelial function (see above),
regular exercise contributes to attenuate aging au-
tonomic dysfunction; thus autonomic dysfunction
could be one of the missing or nonconventional
risk factors that is altered by exercise, as elegantly
hypothesized by Joyner and Green in a recent re-
view (213) and summarized below.
Aging is associated with marked increases in
sympathetic nervous system (SNS) activity to sev-
eral peripheral tissues, possibly to stimulate ther-
mogenesis to prevent increasing adiposity (436).
This tonic activation of the peripheral SNS has,
however, deleterious consequences on the struc-
ture and function of the cardiovascular system,
e.g., chronically reduced leg blood flow, increased
arterial BP, impaired baroreflex function, or hyper-
trophy of large arteries, which in turn can increase
CVD risk (436). Chronically augmented SNS-
mediated reductions in peripheral blood flow and
vascular conductance can also contribute to the
etiology of the metabolic syndrome, by increasing
glucose intolerance and insulin resistance (23,
270). Heart rate variability (HRV) is a noninvasive
measure of the autonomic nervous system func-
tion and a surrogate index for clinical outcome in
trials of CVD prevention (344), with high values
reflecting a survival advantage, whereas reduced
HRV is a marker of autonomic dysfunction that
may be associated with poorer cardiovascular
health and outcomes (412), including also a sub-
stantial increase in the incidence of coronary heart
disease, myocardial infarction, fatal coronary dis-
ease, and total mortality in diabetic individuals
(269). A recent study has shown that a simpler
marker of SNS, elevated resting heart rate, is a risk
factor for mortality (16% risk increase per 10 beats/
min) independent of conventional CVD risk factors
(208). Furthermore, high levels of sympathetic out-
flow in conjunction with endothelial dysfunction
may have a synergistic and detrimental effect in
terms of CVD risk (89). On the other hand, there is
evidence that exercise training can keep the auto-
nomic nervous system healthy, including in old
people.
Moderate aerobic exercise (brisk walking) for 3
mo attenuates age-related reductions in baroreflex
function, and there appears to be an exercise
“dose-response” with regard to the exercise bene-
fits, with endurance-trained older individuals
showing similar baroreflex function than their
moderately active younger peers (316). A recent
meta-analysis has shown that HRV increases with
exercise training (344), with this effect being re-
ported in middle-aged or old people who are either
healthy (106, 134, 374) or have myocardial infarc-
tion (51, 65, 108, 245, 262, 288, 289, 295, 359, 421),
chronic heart failure (227, 288, 375, 440), translu-
minal coronary angioplasty, coronary artery by-
pass grafting (197, 281, 464, 477), or diabetes (123,
277, 535). Although angiotensin II and nitric oxide
(NO
·
) may play a mediating role and more research
is needed, to date, it seems that exercise may in-
fluence HRV in humans via increasing vagal mod-
ulation and decreasing sympathetic tone (412).
Autonomic dysfunction can also contribute sig-
nificantly to the risk for sudden death due to ven-
tricular fibrillation, which is the leading cause of
death in most industrially developed countries
(33). Alterations in cardiac parasympathetic control are
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PHYSIOLOGY Volume 28 September 2013 www.physiologyonline.org332
indeed associated with an increased risk for sud-
den death (34, 56, 90, 413), and there is a particu-
larly strong association between reductions in HRV
or baroreceptor reflex sensitivity and increased in-
cidence of sudden cardiac death in patients recov-
ering from myocardial infarction (14, 31, 112, 187,
244, 246, 466). This provides evidence supporting the
probability that myocardial infarction reduces cardiac
parasympathetic regulation and enhances 2-adreno-
ceptor expression sensitivity, leading to intracellular
calcium dysregulation and arrhythmias (33). Thus not
only -adrenoceptor antagonists but also aerobic exer-
cise interventions, which favorably improve cardiac au-
tonomic balance by increasing parasympathetic or
decreasing sympathetic activity (114, 290, 353, 370,
450), could reduce the incidence of lethal ventricular
arrhythmias (32, 33). Evidence from canine models in-
dicates that exercise training improves cardiac para-
sympathetic regulation (as reflected by increased HRV),
restores a more normal -adrenoceptor balance (i.e.,
reducing 2-adrenoceptor sensitivity and expression),
and protects against ventricular fibrillation induced by
acute myocardial ischemia (see Ref. 33 for a review).
Epidemiological Evidence III in the
Context of the 21st Century’s
Medicine: Exercise Has
“Polypill-Like” Effects
Paradoxically, the pandemic spread of cardio-met-
abolic diseases has paralleled the ground-breaking
advances in pharmacology, and CVD remains the
leading cause of death worldwide (307). Further
complicating the problem, therapeutic strategies
designed to control several CVD risk factors simul-
taneously in people without evidence of CVD are
expensive and difficult to implement. The develop-
ment of fixed-dose drug combinations originally
designed for the treatment of myocardial infarc-
tion such as statins, diuretics, -blockers, angio-
tensin-converting enzyme (ACE) inhibitors, or
aspirin in one pill could help to potentially over-
come these limitations and is gaining attention as
a promising preventive strategy in the 21st century
(335, 422).
Wald and Law first described a combination pill
for CVD prevention (498), which they called a
“polypill” (499). In 2001, a World Health Organiza-
tion and Wellcome Trust meeting of experts con-
cluded that a fixed-dose polypill containing aspirin,
statin, and two BP-lowering agents may improve
adherence to treatment as well as substantially
reduce the cost of the drugs, particularly for low-
and middle-income countries (516). And, in 2003,
Wald and Law claimed that CVD could be reduced by
88% and strokes by 80% if all those over 55 years of
age were given a polypill containing three low-dose
BP-lowering medications: a statin, low-dose aspirin,
and folic acid (499). This controversial and provoc-
ative approach of “medicalizing” the population
has been followed by more targeted approaches.
For instance, a large clinical trial is being con-
ducted in five countries to investigate the effects of
a polypill (aspirin, an ACE inhibitor, and a statin)
on ischemic heart disease recurrence (137). Yet
polypill-like benefits are achievable with a drug-
free intervention, regular PA.
Elley et al. recently conducted a meta-analysis
(the only one we are aware of) on both the efficacy
and tolerability of polypills (115). They reviewed
data on six RCTs, including a total of 2,218 subjects
(1,116 in a polypill group and 1,102 in a compari-
son group) who were mostly middle-aged adults
(men/women, 5060 yr) with no previous CVD but
with 1 risk factors. The polypill consisted of one
to three antihypertensive drugs (calcium channel
blocker, thiazide, ACE inhibitor or angiotensin re-
ceptor blocker, or combinations of the above) and
one lipid-lowering medication (atorvastatin or
simvastatin) with or without aspirin for primary
CVD prevention, and treatment lasted 6 –56 wk. In
FIGURE 1, we compare the results of the above-
mentioned meta-analysis on important outcomes
related to CVD risk factors (BP, total and LDL cho-
lesterol), with those reported in two recent meta-
analyses of the effects of regular exercise in
middle-aged adults: a study by Pattyn et al. in 272
middle-aged men/women with the metabolic syn-
drome but with no other CVD (median age 52 yr,
82 sedentary controls, and 190 individuals exercis-
ing during 8–52 wk) (364) and a report by Corne-
lissen and Smart in 5,223 middle-aged men/
women without CVD (1,822 controls and 3,401
people who were exercise training for 4 –52 wk)
(75). Comparable and in fact slightly higher bene-
fits on total and LDL cholesterol can be obtained
with endurance exercise compared with polypills.
Whereas isometric exercise and polypills have an
overall similar BP-lowering effect, as FIGURE 1
shows, the other exercise modes have a more
modest effect. Of note, additional and important
health benefits of exercise interventions that are
unlikely to be achieved by polypills are signifi-
cant decreases and increases in adiposity and
cardiorespiratory fitness, respectively (364). Rates of
tolerability/adherence to the intervention also
seem to favor exercise interventions, with an aver-
age drop out from the exercise programs of 10%
(364), whereas those taking polypills are more
likely to discontinue medication compared with
placebo or one drug component (20% vs. 14%)
(115).
Despite provocative reports in the literature, e.g.,
orally active drugs such as the AMPK-activator 5-
amino-1--
D-ribofuranosyl-imidazole-4-carboxamide
(AICAR) can increase endurance without exercise
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training (331), it would be unrealistic to think that
the multi-systemic benefits of regular PA can be
replaced by ingesting daily an “exercise-like”
polypill (95, 155). Nonetheless, identification of the
bioactive molecules and biological mechanisms
that are candidates for mediating exercise benefits
through biological pathways that are largely dif-
ferent from those targeted by common drugs, is
of medical interest, since it might help to im-
prove our knowledge of the pathophysiology of
diseases of modern civilization as well as to max-
imize the efficacy of PA interventions by imple-
menting the best possible exercise dosage,
resulting in optimal circulating levels of “benefi-
cial” molecules.
Although describing in detail all the biological
mechanisms/mediators (including complex mo-
lecular-signaling pathways) that can potentially re-
spond and adapt to exercise stimuli is beyond our
scope, the intent of the subsequent part of this
review is to summarize the current body of knowl-
edge on the main biological mediators (ingredi-
ents) of the preventive/therapeutic effects of
regular PA against most prevalent chronic diseases,
cardiometabolic disorders, and cancer, and of its
anti-aging effects.
Skeletal-Muscle Manufactures the
Pill
Skeletal-muscle fibers can produce several hun-
dred secreted factors, including proteins, growth
factors, cytokines, and metallopeptidases (42,
178, 345, 407, 527), with such secretory capacity
increasing during muscle contractions (13, 94,
163, 190, 286, 357, 367), myogenesis (85, 87, 178),
and muscle remodeling (529), or after exercise
training (102, 345, 407). Muscle-derived molecules
exerting either paracrine or endocrine effects are
termed “myokines” (367) and are strong candi-
dates to make up a substantial fraction of the ex-
ercise polypill. Here, we focus on the main
myokines and their putative protective role against
disease phenotypes (see also FIGURE 2 and Table 1).
Myostatin, the first described secreted muscle
factor to fulfil the criteria of a myokine, is a potent
muscle-growth inhibitor (302) that acts via SMAD
signaling (398) or mammalian target-of-rapamycin
(mTOR) inhibition (12, 249, 271, 301, 403, 426,
476). Acute endurance (170, 278) or resistance
(228, 397) and chronic endurance exercise re-
duce myostatin expression (170, 184, 236, 237,
292). Although myostatin increases might con-
tribute to insulin resistance (184, 360), obesity
(185), muscle wasting (63, 70, 97, 154), or aging-
sarcopenia (523), its loss/inhibition decreases
adiposity (164, 303, 521, 530), induces browning
of the white adipose tissue [through AMPK-per-
oxisome proliferator-activated receptor- coacti-
vator 1 (PGC-1)-iriscin pathway] (443), and
ameliorates muscle weakness (29, 38, 241, 256,
272, 323, 328, 386, 448, 478, 497, 532).
IL-6 is probably the myokine prototype (366);
its release by working muscles explains the con-
sistently reported increase in blood IL-6 with
exercise (118, 183, 212, 220, 278, 369, 411, 457,
458). Muscle release of IL-6 increases with ex-
ercise intensity (356) and duration (125), with
muscle-mass recruitment (368), and when mus-
cle glycogen stores are low (220, 456), but de-
creases with muscle damage (285, 509) or with
carbohydrate ingestion (179, 248, 265–267, 339
341). Endogenous nitric oxide (NO
·
), interaction
between Ca
2
/nuclear factor of activated T-cell
(NFAT), and glycogen/p38 MAPK pathways are
putative upstream signals leading to muscle-
IL-6 secretion (368). More controversial are the
effects of chronic exercise on muscle-derived
IL-6 (81, 126), yet a training increase in the
sensitivity of its receptor IL-6R has been re-
ported (219). This myokine exerts its action lo-
cally (within muscles) or peripherally (in a
FIGURE 1. Comparison on the effects of the polypill vs. exercise interventions
on outcomes related to CVD risk using data from meta-analyses (see text for
more details)
Data of mean change in the outcomes are expressed in mean and 95% confidence intervals.
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hormone-like fashion) to mediate, among others,
important metabolic and anti-inflammatory/im-
mune modulatory effects. IL-6 has “leptin-like” ac-
tions: through AMPK activation in both skeletal-
muscle and adipose tissue (6, 61, 145, 224), it
increases glucose uptake (126) and intra-muscle
(50, 61, 373) or whole-body (486) lipid oxidation
(61, 214). Systemic low-level inflammation is a car-
dinal feature of aging, cardio-metabolic diseases,
and some types of cancer that can be attenuated by
the cumulative effect of regular exercise bouts,
during which the muscle can release myokines
such as IL-6; this creates a healthy milieu by in-
ducing the production of the anti-inflammatory
cytokines
IL-1Ra, IL-10, or sTNF-R, and inhibiting the pro-
inflammatory cytokine TNF- (122, 294, 312, 355,
356). Other potential roles of IL-6 are stimulation
of muscle growth (7, 441) and angiogenesis (172).
Another prototype of contraction-induced myo-
kine is IL-15, with resistance exercise stimulating
its secretion (338, 402). In addition to its local
anabolic/anti-catabolic effects (59, 60, 135, 338,
390, 391), IL-15 plays an anti-obesogenic effect
(337, 388), mainly by inhibiting lipid deposition
(8–10, 24, 59, 136, 389). Thus muscle-derived IL-15
is advocated as one of the mediators of the anti-
obesity effects of exercise (520). Although leukemia
inhibitory factor (LIF) can be released by many
tissues and have multiple effects, the functional
role of contraction-induced LIF (e.g., after resis-
tance exercise) would be restricted to skeletal muscles,
where it stimulates hypertrophy/regeneration, mainly
through satellite cell proliferation (47– 49, 161, 216,
217, 243, 418, 452, 453, 506). Contraction-induced
myokines IL-7 (174) and IL-8 (86, 278, 341) also work
mainly at the local level, where they modulate muscle
development (174) or promote angiogenesis through
FIGURE 2. Summary of the main myokines, their putative effects, and the molecular signals/pathways involved
AMPK, AMP-activated protein kinase; BDNF, brain-derived neurotrophic factor; CREB, cAMP response-element-binding protein; C-X-C R2, C-X-C
receptor 2; FFA, free-fatty acid; FGF21, fibroblast growth factor 21; Fndc5, fibronectin type III domain-containing 5 protein; Fstl1, follistatin-like 1;
IGF, insulin-like growth factor; IL-1ra, IL-1 receptor antagonist; Insl6, insulin-like 6; LIF, leukemia inhibitory factor; NO
·
, nitric oxide; NOS, nitric
oxide synthase; PGC-1, peroxisome proliferator-activated receptor- coactivator 1; PI3K, phosphatidylinositol 3-kinase; SIRT1, sirtuin 1; SPARC,
secreted protein acidic and rich in cysteine; sTNF-R, soluble TNF receptors; trkB, tropomyosin receptor kinase; UCP1, uncoupling protein 1.
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Table 1. The exercise “vademecum”: characteristics of the main myokines that are candidates to be ingredients of the exercise polypill (stem cells are also listed)
Name of Molecule or Cell Structure (If Molecule)
or Cell Type
Main Tissue(s) of Origin Main Type of
Exercise Probably
Maximizing its
Release/Secretion
Main Target Tissue(s)
Associated With
Exercise-Induced
Release/Secretion
Main Biological Effect(s)
Associated With
Exercise-Induced
Release/Secretion
Main Putative Health
Benefit(s) Associated
With Exercise-Induced
Released/Secretion
Potential Future
Medical
Application(s)/
Target Diseases
Dietary
Considerations
BDNF (brain-derived
neurotrophic factor)
Similar to other
neurothrophins; is
initially synthesized as
a precursor (pro-
BDNF, of 32 kDa),
which is subsequently
cleaved to generate
the mature BDNF
(mBDNF, 14 kDa)
Neuronal tissues: brain
(e.g., hippocampus)
and rest of central
nervous system
Moderate-intensity
aerobic exercise
Skeletal muscle 1 Muscle fat oxidation 1 Capillarization of
ischemic tissues
Enhancing
anti-depressant/
anxiolytic
treatment;
protection against
neurodegeneration
(including possibly
dementia)
Caloric restriction
might maximize
exercise effects
(at least in
diabetic murine
models)
Nonneuronal tissues:
vascular endothelial
cells, platelets,
lymphocytes,
eosinophils,
monocytes, pituitary
gland, working
skeletal muscle
(possibly mainly type
II fibers and satellite
cells or neurons within
muscle beds)
Brain 1 Neuroplasticity 1 Brain maintenance/
function and
promotes
neuroplasticity
Motoneurons 1 Motor unit
regeneration
1 Motor neuron
maintenance/repair
CAC [circulating angiogenic
cells including EPCs
(endothelial progenitor
cells)]
Any circulating
mononuclear cell
supporting vascular
repair and
re-endothelialization
Bone marrow Vigorous aerobic
exercise (e.g.,
bicycling,
running),
especially if
inducing
transient
ischemia in
cardiac patients
Damaged endothelium
(although actual CAC
engraftment remains
to be clearly shown in
humans)
1 Endothelial repair
and vasculogenesis
2 CVD risk Use of exercise
preconditioning to
increase the
efficacy of
regenerative
therapies with
stem-cells (by
increasing
circulating levels
of CAC), especially
in cardiovascular
medicine
Bone marrow-derived
stem/progenitor cells
(i.e., mainly EPCs)
Bloodstream and vessels
(but to a lower extent)
2 Disease progression
once CVD is already
established
Non bone marrow-
derived (pro-
angiogenic
macrophages and T-
cells, circulating cells
originating from the
vessel itself)
FGF21 (fibroblast growth
factor 21)
Member of the
fibroblast growth
factor (FGF) super
family
Mainly liver Not clearly known
yet (increased
secretion shown
with both
aerobic and
resistance
exercise)
Adipose tissue 2 Lipolysis 2 Lipotoxicity of
chronically elevated
FFA
Use of exercise in
obese people as a
coadjuvant
therapy to
decrease insulin
resistance and
diabetes risk
Skeletal muscle 2 FFA-induced insulin
resistance
Other tissues (pancreas,
adipose tissue,
thymus)
Fst1 [follistatin-like 1, also
known as TSC-36 (TGF-
beta-stimulated clone 36)]
Extracellular
glycoprotein that,
despite limited
homology, has been
grouped into the
follistatin family of
proteins
Myocardium Not known yet Skeletal muscle 1 Endothelial function
and revascularization
Coadjuvant in muscle
regeneration
To be determined
(yet likely muscle
atrophy
conditions)
Skeletal muscle
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Table 1. (continued)
Name of Molecule or Cell Structure (If Molecule)
or Cell Type
Main Tissue(s) of Origin Main Type of
Exercise Probably
Maximizing its
Release/Secretion
Main Target Tissue(s)
Associated With
Exercise-Induced
Release/Secretion
Main Biological Effect(s)
Associated With
Exercise-Induced
Release/Secretion
Main Putative Health
Benefit(s) Associated
With Exercise-Induced
Released/Secretion
Potential Future
Medical
Application(s)/Target
Diseases
Dietary
Considerations
IL-4 and IL-13 Share substantial
structure homology
and redundant
functions
Lymphocytes (TH2 CD4
helper cells),mast cells
and neutrophils
Intense strength
exercise
Skeletal muscle 1 Muscle growth 2 Muscle atrophy Muscle atrophy
Various origins (brain,
cancer cells, liver,
fibroblasts, and
muscle cells)
1 Muscle repair
following damage
(e.g., IL-4 co-injection
with transplanted
myoblasts might
be an approach to
enhance the
migration of
transplanted cells
for the treatment
of Duchenne
dystrophy)
Working muscles
IL-6 (also termed interferon,
beta 2)
Belongs to the IL-6
cytokine superfamily
(LIF, IL-11, CNF,
cardiotrophin-1,
oncostatin) that share
structural similarities
and the gp130
receptor subunit Low-
weight protein like all
cytokines (pro-
peptide of 212 amino
acids is cleaved into a
mature IL-6 peptide
(184 amino acids)
Working muscles [type I
and II fibers, satellite
cells (rodents)]
Immune cells
Adipocytes
Intense aerobic
exercise
involving large
muscle mass
but non-
damaging (e.g.,
running in
trained athletes
or brisk/very
brisk walking in
general)
Skeletal muscle
Adipose tissue
Pituitary gland-liver
Immune cells
1 Muscle lipolysis
1 Muscle growth
1 Adipocyte lipolysis
1 Liver-glucose release
to blood
2 Inflammation
Immunomodulation
Protection against
cardio-metabolic
diseases
2 Inflammation
Cardio-metabolic
diseases
Carbohydrate
ingestion during
exercise (e.g.,
brisk walking)
inhibits the
release of muscle-
IL-6 and, unless in
highly performing
athletes, is
probably not
necessary or
justified
IL-7 Predicted molecular
mass of 17 kDa and
25 kDa for non-
glycosylated and
glycosylated protein,
respectively
Lymphoid organs
(spleen)
Strength exercise Skeletal muscle Regulation of muscle
development
??
Epithelial cells
Skeletal muscle
IL-8 Belongs to the C-X-C
chemokine family,
low-molecular protein
of 8 kDa, which has
an amino acid
sequence Glu-Leu-
Arg preceding the
first conserved
cysteine amino acid
residue in the primary
protein structure
Monocytes and
macrophages
Probably
exhaustive
endurance
exercise (e.g.,
distance
running)
Skeletal muscle Muscle angiogenesis,
i.e., contributes to
the exercise training
effect on muscle
capillarization
? ? Like for IL-6, low
glycogen stores
increase muscle
secretion of this
myokine
Endothelial cells
Working skeletal muscle
IL-15 Belongs to the IL-2
superfamily (14–15
kDa, four-helix
configuration)
Working muscles (type I
and mainly type II
fibers)
Mainly strength
exercise
Skeletal muscle Promotes muscle
anabolism/inhibits
catabolism
Protection against
muscle wasting
caused by aging or
chronic disease
IL-15 and IL-15R are
potential
pharmacological
targets against:
muscle wasting
and its end-points
associated with
disease or aging
(sarcopenia and
cancer-cachexia)
Anti-obesogenic
effects are likely
independent of
diet
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Table 1. (continued)
Name of Molecule or Cell Structure (If Molecule)
or Cell Type
Main Tissue(s) of Origin Main Type of
Exercise Probably
Maximizing its
Release/Secretion
Main Target Tissue(s)
Associated With
Exercise-Induced
Release/Secretion
Main Biological Effect(s)
Associated With
Exercise-Induced
Release/Secretion
Main Putative Health
Benefit(s) Associated
With Exercise-Induced
Released/Secretion
Potential Future
Medical
Application(s)/Target
Diseases
Dietary
Considerations
Two IL-15 isoforms exist:
a long signaling
secreted peptide (48
amino acids) and a
short signaling
peptide (21 amino
acids)
Various origins (lymphoid
tissues, kidney, brain,
cardiac muscle, lung,
pancreas, testis, liver,
placenta, epithelial
cells, and activated
macrophages, and
maybe adipocytes)
Adipose tissue Anti-obesogenic (2
mainly visceral fat)
effect
Protection against
obesity
Obesity
(Skeletal muscle-adipose
tissue cross talk)
Insulin-sensitizing effect
Insl6 (insulin-like 6) Member of the insulin-
like/relaxin family
Male germ cells Unknown Skeletal muscle Muscle regenerative
factor (1 activation
of satellite cells in
injured muscles)
1 Muscle regeneration Strategies to
enhance Insl6-
mediated
signalling could be
a useful treatment
for skeletal muscle
myopathies or
trauma-induced
muscle injuries
Skeletal muscle
Iriscin 112-amino acid
glycoprotein that is
derived from the
cleavage and
secretion to
circulation of the type
I membrane protein
Fndc5 (209 amino
acids)
Working skeletal-muscle
(muscle is the main
tissue where FNDC5
gene is expressed)
To be clearly
determined
White adipose tissue “Browning” of white
adipose tissue
through 1 UCP1 and
thus 1
thermogenesis
Protection against
diabetes and obesity
Exercise as a
coadjuvant for
anti-obesogenic/
and anti-diabetic
therapies
targeting iriscin
Muscle-related tissues
(e.g., pericardium,
heart)
To a minor extent,
kidney, liver, lung, or
adipose tissue
LIF (leukemia inhibiting
factor)
Belongs to the IL-6
cytokine superfamily
Working muscles (type I
fibers, satellite cells)
Mainly strength
exercise
Skeletal muscle Mainly local (autocrine/
paracrine effect): 1
Muscle growth
(satellite cell
proliferation)
Protection against
muscle wasting
Muscle wasting
Long-chain four -helix
bundle protein, which is
highly glycosylated (38–
67 kDa, which can be
deglycosylated to 20
kDa)
Central nervous system
(hypothalamus,
hippocampus,
amygdala, cerebellum,
cerebral cortex, and
basal forebrain nuclei)
1 Muscle regeneration
MSCs (mesenchymal stem
cells)
Mononuclear cell
population that, when
cultured ex vivo,
adheres to plastic with
a fibroblast-like
morphology. In vivo
characteristics include
adherence to plastic,
specific surface antigen
expression pattern and
differentiation potential
Bone marrow Eccentric exercise
inducing muscle
damage
Skeletal muscle Tissue repair and
vasculogenesis in
damaged skeletal
muscle
1 Muscle repair
(complementing the
effects of muscle
satellite cells)
Muscle atrophy
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Table 1. (continued)
Name of Molecule or Cell Structure (If Molecule)
or Cell Type
Main Tissue(s) of Origin Main Type of
Exercise Probably
Maximizing its
Release/Secretion
Main Target Tissue(s)
Associated With
Exercise-Induced
Release/Secretion
Main Biological Effect(s)
Associated With
Exercise-Induced
Release/Secretion
Main Putative Health
Benefit(s) Associated
With Exercise-Induced
Released/Secretion
Potential Future
Medical
Application(s)/Target
Diseases
Dietary
Considerations
Adipose tissue Vigorous aerobic
exercise
inducing no
muscle damage
but transient
myocardial
ischemia in case
of CVD patients
Myocardium? Same effect in damages
in myocardium?
1 Myocardium repair? Peripheral arterial
disease
Others sources: dental
pulp, cord blood, and
a variety of MSCs
(mMSCs) residing in
skeletal muscles
Note: tissue
engraftment of
exercise-released
nonresident MSCs
remains to be
demonstrated in
humans
Same as with CAC:
use of exercise to
increase the
efficacy of
regenerative
therapies with
stem cells (by
increasing
circulating levels
of MSCs)
Myonectin [also termed
CTRP5 (C1q/TNF-related
protein 5)]
340-amino acid-protein.
Tends to form
heteromeric
complexes with other
proteins of the CTRP
family, possibly to
expand its function
Skeletal muscle
(especially in type I
fibers, at least in
animals)
Remains to be
determined in
humans
Liver 1 FFA uptake in liver
and adipocytes
Control of whole body
metabolism (muscle-
liver-adipose tissue
cross talk)
?
Adipose tissue
Musclin (also termed
osteocrin)
20-kDa protein, contains
a region homologous
to members of the
natriuretic peptide
family, i.e., it can
share related
functions or receptors
Skeletal muscle (mainly
type II fibers)
Remains to be
determined
whether
exercise actually
induces musclin
expression in
humans
Skeletal muscle 2 Glucose uptake in
muscle
? ? Musclin expression
increases with
obesity and with
feeding
Non-muscle sources
(osteocytes,
osteoblasts)
Myostatin [also termed,
GDF8 (growth
differentiation factor 8)]
378-amino acid protein,
belongs to the TGB
family
Skeletal muscle Acute endurance
and resistance
exercise
decrease
myostatin
expression, but
decreased
expression has
been more
consistently
shown with
aerobic training
than with
resistance
training
Skeletal muscle Main effects associated
to myostatin
inhibition which can
be partly achieved by
exercise are: 1
Muscle growth 2
Adiposity 1 Insulin
sensitivity
Attenuation of disease/
age muscle wasting
Use of exercise as a
coadjuvant of
myostatin-
inhibition
therapies for
muscle wasting
Adipose tissue? Obesity/diabetes
prevention
NO
·
(nitric oxide) Contracting muscles
(with the main NOS
isozyme expressed in
muscles being
nNOS)
Vigorous aerobic
exercise (e.g.,
bicycling)
Skeletal muscles 1 Glucose uptake 1 Glucose control in
Type 2 diabetes
Therapeutics that
mimic the muscle-
NO pathway (e.g.,
Type 2 diabetes)?
Duchenne muscular
dystrophy? (Disease
associated with
decreased nNOS)
1 Myogenesis and
muscle repair
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Table 1. (continued)
Name of Molecule or Cell Structure (If Molecule)
or Cell Type
Main Tissue(s) of Origin Main Type of
Exercise Probably
Maximizing its
Release/Secretion
Main Target Tissue(s)
Associated With
Exercise-Induced
Release/Secretion
Main Biological Effect(s)
Associated With
Exercise-Induced
Release/Secretion
Main Putative Health
Benefit(s) Associated
With Exercise-Induced
Released/Secretion
Potential Future
Medical
Application(s)/Target
Diseases
Dietary
Considerations
NSCs (neural stem cells, also
termed neural progenitor
cells)
Stem cells that, at least
in embryonic state,
can differentiate into
neurons, astrocytes,
and oligodendrocytes
Central nervous system Aerobic exercise
(only shown in
rodent models)
Central nervous system Increased neurogenesis 1 Neural plasticity Using exercise as a
co-adjuvant
therapy against
aging
neuro-degeneration
1 Brain function
(included cognitive
capacity)
NT4 (neurotrophin-4, also
known as NT4/5)
Member of the nerve
growth factor family,
which also includes
BDNF. The mature
peptide has a
predicted molecular
mass of
approximately 14
kDa, and is 130
amino acid in length
Working muscles (type I
fibers)
? Motoneurons Growth and remodeling
of adult motoneuron
innervation
1 Neuromuscular
performance
Using exercise to
attenuate age loss
of neuromuscular
performance or as
a coadjuvant
treatment against
neuromuscular
disorders?
S100A8-S100A9 complex
(calprotectin)
S100 family proteins
MRP-8 (S100A8) and
MRP-14 (S100A9) are
small (10–14 kDa)
calcium-binding
proteins that form a
heterodimer
Neutrophils, monocytes,
acute-phase
macrophages
Exhausting
endurance
exercise (e.g.,
marathon
running)
Remains to be clearly
elucidated
Among other effects
(including cytokine-
like action), anti-
tumor effect
1 Protection against
cancer (e.g., colon)?
Using exercise as a
coadjuvant
treatment against
colon cancer (not
only for
prevention)
Secretory epithelia
Working muscles
SPARC [secreted protein
acidic and rich in cysteine,
also known as basement
membrane protein
(BM)-40]
Multifunctional
nonstructural,
matricellular
glycoprotein (43 kDa)
associated with the
extracellular matrix
that is expressed
abundantly in basal
lamina
Skeletal muscles
(progenitors cells,
fibers, endothelial
cells)
Strength exercise? Regulation of glucose
metabolism
Prevents tumorigenesis
of colon cancer
Same as above
Tumors (ovarian,
colorectal,
melanomas)
Inhibits proliferation of
colon cancer cells
Adipocytes, fibroblasts,
endothelial cells,
cardiac myocytes (at
low levels), -smooth
muscle actin-positive
myofibroblasts, CD45-
positive leukocytes
Visfatin [also known as
NAMPT (nicotinamide
phosphoribosyltransferase)
or PBEF (pre-B cell
enhancing factor)]
Multifunctional protein.
Polypeptide of 491
amino acids with a
molecular mass of 52
kDa
Ubiquitous expression in
human tissues,
including adipose and
skeletal muscle tissue
(i.e., it is both an
adipokine and a
myokine)
Endurance
exercise
Skeletal muscle and
adipose tissue
AMPK activation ¡1
SIRT1 ¡ PGC-1
Might mediate major
exercise-induced
health/anti-aging
effects involving
SIRT1-pathways: anti-
oxidant defense,
macromolecular
damage repair, or
mitochondriogenesis
Exercise as a major
component of
anti-aging
medicine
Liver It provides NAD
Bone marrow
Lymphocytes
Beta-cells and human
islets
Heart
AMPK, adenosine monophosphate-activated protein kinase; CVD, cardiovascular disease; FFA, free-fatty acids; Fndc5, fibronectin type III domain-containing 5 protein; IL-15R,
interleukin-15 receptor; NOS, nitric oxide synthase; PPAR-, peroxisome proliferator-activated receptor ; SIRT1, sirtuin 1; TGB, transforming growth factor; UCP1: uncoupling protein
1. Research is growing fast in the field since the original paper by Asahara et al. (15) where the term endothelial progenitor cell (EPC) was first introduced, and caution is needed
with nomenclature. The difficulty of identifying cells with a unique EPC phenotype (based on cell membrane antigens) as originally defined by Asahara et al. and the fact that a variety
of hematopoietic cells (including stem and progenitors) participate in initiating and modulating neo-angiogenesis make the issue complicated and the term EPC too restrictive (see
Ref. 181 for a review). As such, the broader term circulating angiogenic cells (CAC) is being used in the literature instead of EPC.
REVIEWS
PHYSIOLOGY Volume 28 September 2013 www.physiologyonline.org340
C-X-C receptor 2 receptor signaling (131). IL-4 and
IL-13, which share a substantial fraction of their
sequence structure and biological roles, are up-
regulated by resistance training (385), with IL-4
mediating NFATc2-induced muscle growth (192)
and myotube maturation (247) and IL-3 stimulat-
ing additional recruitment of reserve cells during
IGF-I-induced hypertrophy (204).
Among all neurotrophins (molecules that stimu-
late neuronal survival, differentiation, or growth),
brain-derived neurotrophic factor (BDNF) is the
most affected by exercise (231). Circulating BDNF
increases with aerobic exercise (121, 147, 409, 437,
465, 510), especially with high-intensity exercise
(121, 431, 510), and rapidly decreases to basal lev-
els shortly after exertion (431), suggesting its clear-
ance is mediated by target-tissue uptake (284). Less
clear is its response to acute resistance exercise
(76, 146, 429) or resistance exercise training (66,
146, 263, 429, 435, 437, 524, 534). Several tissues,
such as contracting muscles (111, 152, 293) or
platelets (465), can express BDNF. Yet the main
origin of exercise-induced blood BDNF is likely the
brain before this molecule crosses the blood-brain
barrier (284). Increased BDNF transcripts in exer-
cised rodents’ brains are well documented, provid-
ing mechanistic support for a beneficial exercise
effect in cognitive function (4, 5, 30, 153, 193, 275,
315, 333, 334, 352, 396, 417, 425, 460, 488, 507), e.g.,
through the downstream signals tropomyosin re-
ceptor kinase (trkB), cAMP response-element-
binding protein (CREB), or synapsin I (488).
Exercise-induced BDNF in rodents is also likely to
contribute to the anticancer effect of PA (57).
Muscle-produced BDNF could act locally, enhanc-
ing muscle lipid oxidation via AMPK-activation
(293), whereas exercise-induced BDNF coming
from different sources might improve depression
(526) or anxiety symptoms through MAPK signal-
ing pathways (110), maintain brain function and
promote neuroplasticity (78, 153), or enhance the
efficacy of antidepressant treatment (416). BDNF
can also help maintain/repair motoneurons (327)
like other muscle-derived neurotrophins such as
neurotrophin 4 (133, 162) or could regulate satel-
lite-cell function/regeneration (69, 326).
Secreted protein acidic and rich in cysteine
(SPARC), is a matricellular protein that regulates
cell proliferation/migration and is implicated in
numerous biological processes (45). It was recently
identified as a myokine (13, 345) whose expression
increases with resistance training (345). SPARC,
which is in fact a potential target in cancer immu-
notherapy (198), might mediate the preventive ef-
fects of exercise on colon cancer by suppressing
the formation of aberrant crypt foci, probably
through stimulation of apoptosis via caspase-3
and -8 (13). Circulating (117, 318, 324, 365) and
muscle-transcript levels of S100A8-S100A9 com-
plex (calprotectin) increase with acute endurance
exercise (324). Potential beneficial effects (yet to be
demonstrated) of muscle-derived calprotectin might
also be cancer protection for its ability to induce
apoptosis in certain tumor lines (528), including
colon cancer lines (143), or to inhibit matrix met-
alloproteinases associated with cancer invasion
and metastasis (200).
Although there is controversy (473), recent re-
search has identified a novel PGC-1-induced
myokine called iriscin (43). In white adipocytes,
iriscin induces expression of uncoupling protein 1
and other brown adipose tissue-associated genes
[partly via increased peroxisome proliferator-
activated receptor (PPAR-)] and thus increases
thermogenesis and switching of these cells toward
a brown, fat-like phenotype (43). These provoca-
tive findings have led to the postulation that iriscin
may be a therapeutic agent against cardiometa-
bolic disorders and a major component of the ex-
ercise polypill (420). Iriscin is linked with improved
aerobic fitness in cardiac patients (253), muscle
mass, and metabolic factors in healthy people
(195), and neurogenesis in animal models (171).
IGF-phosphatidylinositol 3-kinase (PI3K)-Akt signal-
ing plays a central role in muscle regeneration (88,
372), inducing myokines with an essentially local
action: insulin-like 6, which activates satellite cell
activation (529); follistatin-like 1, which promotes
endothelial function and revascularization in re-
sponse to ischemic insult through endothelial NO
·
synthase (eNOS) signaling (357); and VEGF, which
stimulates angiogenesis (463). The Akt pathway
also upregulates muscle fibroblast growth factor 21
(FGF21) (201), an insulin-regulated myokine (188)
that is released to the blood during exercise (84),
although there exists controversy on the effects of
regular exercise in its basal levels (83, 287, 522). By
inhibiting lipolysis in adipocytes, exercise-released
FGF21 could play a protective role against lipotox-
icity, i.e., ectopic deposition of lipids in the liver or
muscle (84).
Other myokines and their putative roles (await-
ing more human research) include myonectin, a
metabolic regulator that stimulates uptake of free-
fatty acids in liver and adipocytes (439); musclin
(343, 525), an inhibitor of muscle-glucose uptake
(274); and visfatin (503), a NAD biosynthetic en-
zyme whose expression and circulating levels in-
crease (77) and decrease, respectively, with exercise
training (93). By virtue of its activating effect on
NAD-dependent sirtuin 1 (SIRT1), visfatin
might mediate major exercise-induced health/
anti-aging effects involving SIRT1-pathways
(235): anti-oxidant defense, macromolecular
damage repair, or mitochondriogenesis. Of note,
visfatin is also an adipokine with rather different
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PHYSIOLOGY Volume 28 September 2013 www.physiologyonline.org 341
functions, i.e., pro-inflammatory (410) and anti-
apoptotic effects (91, 268).
Exercise and Regenerative
Medicine
Pluripotent stem cells (SCs) able to differentiate
into many cell types are proposed as a valuable
therapeutic source, notably in ischemic tissues
with low self-repair capacity. Because using em-
bryonic SCs has ethical and immune-related limi-
tations (401), researchers have explored other
means of obtaining SCs, e.g., isolating them from
extracorporeal sources (placenta, umbilical cord)
or reprogramming of mature cells. Yet another
strategy is stimulating adult SC proliferation and
migration from their home tissue (e.g., bone mar-
row) to target damaged tissue for subsequent en-
graftment and cell regeneration by applying
specific physiological stimuli, of which exercise is a
good example (284) (FIGURE 3).
Together with macrophage-mediated reverse
cholesterol transport
3
the capacity for vessel wall
regeneration and angiogenesis is the main mech-
anism responsible for maintaining cardiovascular
health (321). The lower CVD risk associated with
regular exercise is largely mediated by an improve-
ment in such capacity (511). Endothelial regener-
ation and neovascularization not only depends on
cells residing within the vessel wall but also on
circulating SCs coming from other sources, notably
the bone marrow. A specific SC subset, originally
identified as endothelial progenitor cells (15) or now
more broadly referred to as circulating angiogenic cells
3
Although there is some recent controversy (305), reg-
ular exercise seems to stimulate macrophage-reverse
cholesterol transport RCT in vitro (351) and in vivo (408),
with exercise-triggered activation of peroxisome prolif-
erator-activated receptor gamma (abbreviated as PPAR
or NR1C, according to the unified nomenclature system
for the nuclear receptor superfamily) within these cells
being advocated as a putative involved mechanism (52,
472).
FIGURE 3. Summary of the main types of stem cells associated with exercise, their main putative effects, and the molecular
signals/pathways involved
Ang, angiopoietin; CAC, circulating angiogenic cells; C-X-C R4, C-X-C motif receptor 4; GH, growth hormone; HGF, hepatocyte growth factor;
HIF-1, hypoxia-inducible factor 1-; JAK-2, janus kinease-2; mMSC, muscle-derived mesenchymal stem cells; SC, stem cell; SCF, stem cell
factor.
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PHYSIOLOGY Volume 28 September 2013 www.physiologyonline.org342
(CAC), target the vascular endothelium, where they
can engraft and promote repair and angiogenesis
(82, 505). Low CAC counts/function is correlated
with risk of CVD (19) or diabetes complications
(308) and decreases with senescence (480, 508),
whereas high CAC (see below) represents a link
between regular exercise and decreased CVD risk
(250), with such exercise benefits starting early in
life (501). CAC increases could also provide mech-
anistic support for the training-induced improve-
ment in myocardial perfusion and lower disease
progression in CVD patients (167, 173, 336, 434);
they also could complement the exercise benefits
in endothelial NO
·
production and thus in vascular
tone regulation, with regular bouts of exercise-
increased laminar flow increasing the expression/
activation (through phosphorylation via Akt) of
eNOS while attenuating NO
·
degradation into re-
active oxygen species (ROS) or reactive nitrogen
species (RNS) (144).
Circulating CAC increase with acute exercise in
healthy individuals (39, 157, 313, 322, 485), people
at risk for CVD (399), and CVD patients (3), al-
though this effect is blunted with age (276, 471).
Intense exercise, especially if inducing transient
myocardial ischemia, seems the most potent stim-
ulus for CAC release and subsequent vasculogen-
esis in CVD patients (3). Acute exercise also
appears to reverse CAC dysfunction in CVD pa-
tients (483, 484). Regular exercise increases CAC
number (250, 282, 424) or function in people with
CVD (44, 141, 459, 484), metabolic syndrome (120),
peripheral artery disease (430), or obesity/over-
weight (68), and in the elderly (519). However, this
effect has not been corroborated in some healthy
cohorts (394, 471, 512), and data from animal stud-
ies showing actual CAC engraftment in injured
tissues (92) remains to be validated in humans.
Postulated biological mediators of exercise-
induced CAC proliferation and release to the
bloodstream are reduced CAC apoptosis (250), ox-
idative stress (511), thrombin (276), VEGF (3, 250),
stimulation of PI3K/Akt-dependent hypoxia-in-
duced factor-1 (92) or C-X-C motif receptor 4-ja-
nus kinase-2 signaling pathways (519), IL-6 (39),
pro-angiogenic factors (hepatocyte growth factor,
angiopoietin 1 and 2 or stem cell factor) (39),
endothelial-derived NO
·
(512) or maybe NO
·
pro-
duced locally in the bone marrow (511), and NO
·
/
oxidative stress interaction (314, 511). Increases in
NO
·
produced inside CAC might mediate the im-
provement in the function of these cells with exer-
cise (206).
Research on another type of SC, mesenchymal
stem cells (MSCs) (129), has grown fast in the last
decade (139). Regardless of their origin (mainly, but
not only, bone marrow and adipose tissue), they repre-
sent pluripotent progenitors of mesoderm- or even
non-mesoderm-derived tissues with a wide variety
of therapeutic potential (graft vs. host or Crohn’s
disease, wound healing or as vehicles of anticancer
genes) (139, 536). Intense exercise, whether induc-
ing (395) or not inducing eccentric muscle damage,
is a potent stimulus for MSC release to the blood-
stream (280, 432). Vigorous exertion also increases
the migratory capacity of MSCs, an effect poten-
tially mediated by the myokine IL-6 (432). Similar
to what occurs with CAC, intense exercise-inducing
transient ischemia can increase circulating MSCs
in CVD patients (280), which is a potentially
promising finding because, together with the few
cardiac-resident SCs, MSCs have the potential to
repair damaged myocardium (518). However, ac-
tual engraftment of migratory MSCs in damaged
tissue (muscle, myocardium) remains to be dem-
onstrated.
SCs can also reside within the perivascular niche
of a variety of tissues, directly repairing injury or
indirectly facilitating regeneration by excreting cy-
tokines/growth factors that can stimulate other
resident SCs (58, 304). This seems to be the case for
skeletal muscles, where not only satellite cells but
also a variety of resident MSCs (mMSCs) can repair
damage (16, 100, 325, 419, 482). Proliferation of
mMSCs is stimulated by the muscle protein 7
integrin or by eccentric exercise (482), and these
cells can secrete angiogenic factors (VEGF, gran-
ulocyte-macrophage colony-stimulating factor),
contributing to vessel remodeling in skeletal
muscles following eccentric damage (196).
Proliferation of neural SCs might also contribute
to improve brain regenerative capacity and cogni-
tive ability, with some rodent models showing
training increases in hippocampal (242, 514) or
periventricular progenitors (35). Current candidate
neutrophins mediating exercise-induced neuro-
genesis are above-mentioned BDNF (231, 533),
growth hormone (35), or VEGF (79, 116).
The ROS Paradox
As first reported 35 years ago (105), acute exercise
generates ROS (see Ref. 384 for a review) and does
so in an intensity- (209, 387, 428) and duration-
dependent manner (37). Exercise-generated ROS
come from many sources (384) and include hydro-
gen peroxide (H
2
O
2
) (28, 297, 487, 492), superoxide
anion (O
2
·) (22, 296, 400), or hydroxyl radicals
(OH
) (104, 124, 348, 381) (FIGURE 4). However,
strong evidence showing that regular exercise up-
regulates endogenous antioxidants not only in
muscles (1, 27, 80, 148, 149, 156, 169, 177, 180, 189,
207, 211, 225, 251, 259, 260, 264, 296, 297, 299, 309,
349, 377–379, 381, 404, 428, 446, 470, 490, 493, 494),
where the effect can be evident after just five con-
secutive training days (493, 494), but also in liver
REVIEWS
PHYSIOLOGY Volume 28 September 2013 www.physiologyonline.org 343
(194, 211, 491), blood (17, 21, 46, 53, 62, 64, 96, 98,
107, 127, 128, 140, 151, 215, 229, 232, 238, 239, 258,
264, 291, 306, 311, 342, 350, 404, 406, 433, 438, 444,
449, 461, 467, 469, 470), or other tissues (brain,
heart, kidney, stomach, intestine, vessels) (27, 96,
132, 186, 264, 332, 404, 468, 490) has changed the
old view of exercise as a potential source of harm-
ful oxidative damage. In fact, muscle-derived ROS
occurring during prolonged inactivity contribute to
disuse muscle atrophy (382, 383), whereas the
same stimulus coming from working fibers is re-
quired for training adaptations to occur (149, 150,
168, 404). This apparent paradox could be ex-
plained by the hormesis theory (54, 210, 392, 393):
chemicals and toxic substances that are deleterious at
high doses can have a low-dose beneficial effect.
Thus increases in ROS elicited by moderate-inten-
sity exercise could lead to beneficial adaptations,
especially increased muscle oxidative capacity (109,
202). Yet, if ROS levels are increased many-fold
above basal levels and antioxidant defense capac-
ity, muscle atrophy can occur, e.g., Duchenne
muscular dystrophy (383, 393). A second potential
factor is differences in the ROS origin between
contracting and resting muscle fibers, with mito-
chondria being the primary source in the latter
(218) but not in the former (380).
ROS might play an important signaling role in angio-
genesis (67), improved vascular distensibility (261),
PGC-1 upregulation (404, 447), PGC-1/nuclear
FIGURE 4. Summary of exercise-generated ROS, their main putative effects, and the molecular signals/pathways involved
CAT, catalase; GCS, -glutamylcysteine synthetase; GPx, glutathione peroxidase; H
2
O
2
, hydrogen peroxide; HO-1, heme oxygenase-1; HSP: heat
shock proteins; NADPH, nicotinamide adenine dinucleotide phosphate; O
2
·, superoxide anion radical; SOD, super oxide dismutase.
REVIEWS
PHYSIOLOGY Volume 28 September 2013 www.physiologyonline.org344
respiratory factor 1-stimulated mitochondriogen-
esis (199, 371, 517), upregulation of cytoprotective
“stress proteins” (heme oxygenase 1, heat shock
proteins like HSP60 and HSP70) in muscle (25, 101,
119, 273, 298, 363, 454, 455), or skeletal muscle
hypertrophy (203, 427). An important signaling link
between contraction-induced ROS production and
exercise adaptations involves the redox regulation
of NF-B, a family of transcriptional activators
controlling the expression of genes involved in in-
flammation, cell growth, stress responses, or apop-
tosis (109, 210, 240, 310, 481). Other pathways are
MAPK, PI3K/Akt, or p53 activation (11, 203, 361).
Interestingly, despite its popularity among west-
erners for its hypothetical anti-disease/rejuvenating
effects, antioxidant supplementation does not mimic,
and in fact can reverse, beneficial exercise adapta-
tions (127, 148, 149, 226, 404).
Skeletal muscle also generates RNS including
NO
·
(20, 99, 233, 462, 502) or nitrite ion (NO
2
)
(489), which at high doses may cause nitrosative
stress and tissue damage but at low doses has
beneficial regulatory effects in vasodilation, glu-
cose uptake, or immune function (300).
Autophagy
Autophagy, a cellular quality control mechanism of
degradation and recycling of damaged macromol-
ecules and organelles, is gaining attention for its
potential involvement in longevity promotion
(414) and defense against chronic diseases (320). It
could also mediate some of the exercise benefits
(FIGURE 5), as suggested by recent data from ro-
dent models.
In normal mice, acute exercise increases au-
tophagy activity in skeletal/cardiac muscles and
tissues involved in glucose/energy homeostasis
(pancreas, liver, adipose tissue), whereas transgenic
mice deficient in stimulus-induced autophagy show
decreased endurance and altered glucose metabo-
lism (175). Exercise also induces autophagy in
mouse brain, supporting its potential to promote
elimination of damaging proteins causing aging
FIGURE 5. Exercise and autophagy
FoxO3a, FOXO transcription factor; mTOR, mammalian target-of-rapamycin.
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PHYSIOLOGY Volume 28 September 2013 www.physiologyonline.org 345
neurodegeneration (176). Chronic exercise in-
creases autophagy activity and reduces apoptosis
in aging muscle (230, 283) by modulating IGF-I,
Akt/mTOR, and Akt/FoxO3a signaling, thereby
preventing loss of muscle mass/strength (283).
Others, however, found the protective effect of
chronic exercise on diabetes-induced muscle atro-
phy was probably due to decreased muscle au-
tophagy (257). Taken together, these apparently
controversial data would suggest an optimal bal-
ance is obtained in the trained muscle between
“healthy” autophagy-induced turnover of dam-
aged cellular components (which attenuates/pre-
vents muscle atrophy), and “excessive” autophagy-
mediated protein degradation (which eventually
leads to muscle atrophy).
Data is still scarce in humans, yet recent prelim-
inary reports suggest upregulation of muscle mark-
ers of autophagy after strenuous acute endurance
(205) or resistance exercise (130), or after a com-
bined weight loss and moderate-intensity exercise
program in old obese women (513).
Summary and Perspective
There is strong epidemiological evidence on the
beneficial effects of regular exercise, which are
likely to go well beyond reducing CVD risk factors.
Furthermore, exercise benefits can overcome those
of common drugs when one considers that the
exercise polypill combines preventive, multi-sys-
temic effects with little adverse consequences and
at lower cost. Exercise, and especially the contract-
ing muscle, is indeed a source of numerous drug-
like molecules with beneficial effects across all
ages. Furthermore, regular exercise is probably the
lifestyle intervention with the most profound up-
regulating effect on hundreds of genes involved in
tissue maintenance and homeostasis, implying a
complex cross talk between muscles and other tis-
sues. Progress in proteomics and other techniques
is allowing identification of a myriad of novel myo-
kines and also is unraveling the fact that many
molecules can have a quite different effect depend-
ing on their tissue of origin, as well as on the
metabolic state (rest vs. exercise) during which
they are secreted to the bloodstream.
Identification of exercise adaptations is helping
to improve our understanding of the pathophysi-
ology of chronic diseases and changing old views,
which could help investigate new therapeutic tar-
gets and approaches. For instance, ROS signals are
increasingly viewed as mediators of the health-
promoting, lifespan-extending capabilities of exer-
cise, even questioning the classic Harman’s Free
Radical Theory of Aging. With regard to aging, the
“oldest old” are the most rapidly growing population
segment among westerners. As opposed to exer-
cise, no drug intervention has proven efficient to
maintain muscle fitness, a key factor to ensure
independent living throughout all stages of life.
No conflicts of interest, financial or otherwise, are de-
clared by the author(s).
Author contributions: C.F.-L. and A.L. conception and
design of research; C.F.-L., N.G., and A.L. drafted manu-
script; C.F.-L., N.G., N.B., and A.L. edited and revised
manuscript; C.F.-L., N.G., N.B., and A.L. approved final
version of manuscript; N.G. and A.L. prepared figures.
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