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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,
Nuria Garatachea,
Nathan A. Berger,
Alejandro Lucia
Universidad Europea Madrid, Madrid, Spain;
Instituto de
Investigación, Hospital 12 de Octubre, Madrid, Spain;
de Ciencias de la Salud y del Deporte, Universidad de
Zaragoza, Huesca, Spain; and
Center for Science, Health and
Society, Case Western Reserve University, School of Medicine,
Cleveland, Ohio
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
, achieving mod-
erate-to-high peak cardiorespiratory fitness (8
), 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
The terms “PA” (physical activity) and “exercise” are
used interchangeably in this review to make reading
more fluent.
1 MET equals an oxygen consumption of 3.5 ml·kg
PHYSIOLOGY 28: 330–358, 2013; doi:10.1152/physiol.00019.2013
1548-9213/13 ©2013 Int. Union Physiol. Sci./Am. Physiol. Soc.330
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,
PHYSIOLOGY Volume 28 September 2013 331
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
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
) 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
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%)
Despite provocative reports in the literature, e.g.,
orally active drugs such as the AMPK-activator 5-
(AICAR) can increase endurance without exercise
PHYSIOLOGY Volume 28 September 2013 333
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
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
/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.
PHYSIOLOGY Volume 28 September 2013 www.physiologyonline.org334
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
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.
PHYSIOLOGY Volume 28 September 2013 335
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
Main Target Tissue(s)
Associated With
Main Biological Effect(s)
Associated With
Main Putative Health
Benefit(s) Associated
With Exercise-Induced
Potential Future
Target Diseases
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
aerobic exercise
Skeletal muscle 1 Muscle fat oxidation 1 Capillarization of
ischemic tissues
protection against
(including possibly
Caloric restriction
might maximize
exercise effects
(at least in
diabetic murine
Nonneuronal tissues:
vascular endothelial
cells, platelets,
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
Motoneurons 1 Motor unit
1 Motor neuron
CAC [circulating angiogenic
cells including EPCs
(endothelial progenitor
Any circulating
mononuclear cell
supporting vascular
repair and
Bone marrow Vigorous aerobic
exercise (e.g.,
especially if
ischemia in
cardiac patients
Damaged endothelium
(although actual CAC
engraftment remains
to be clearly shown in
1 Endothelial repair
and vasculogenesis
2 CVD risk Use of exercise
preconditioning to
increase the
efficacy of
therapies with
stem-cells (by
circulating levels
of CAC), especially
in cardiovascular
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
Non bone marrow-
derived (pro-
macrophages and T-
cells, circulating cells
originating from the
vessel itself)
FGF21 (fibroblast growth
factor 21)
Member of the
fibroblast growth
factor (FGF) super
Mainly liver Not clearly known
yet (increased
secretion shown
with both
aerobic and
Adipose tissue 2 Lipolysis 2 Lipotoxicity of
chronically elevated
Use of exercise in
obese people as a
therapy to
decrease insulin
resistance and
diabetes risk
Skeletal muscle 2 FFA-induced insulin
Other tissues (pancreas,
adipose tissue,
Fst1 [follistatin-like 1, also
known as TSC-36 (TGF-
beta-stimulated clone 36)]
glycoprotein that,
despite limited
homology, has been
grouped into the
follistatin family of
Myocardium Not known yet Skeletal muscle 1 Endothelial function
and revascularization
Coadjuvant in muscle
To be determined
(yet likely muscle
Skeletal muscle
PHYSIOLOGY Volume 28 September 2013 www.physiologyonline.org336
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
Main Target Tissue(s)
Associated With
Main Biological Effect(s)
Associated With
Main Putative Health
Benefit(s) Associated
With Exercise-Induced
Potential Future
IL-4 and IL-13 Share substantial
structure homology
and redundant
Lymphocytes (TH2 CD4
helper cells),mast cells
and neutrophils
Intense strength
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
Working muscles
IL-6 (also termed interferon,
beta 2)
Belongs to the IL-6
cytokine superfamily
(LIF, IL-11, CNF,
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
Intense aerobic
involving large
muscle mass
but non-
damaging (e.g.,
running in
trained athletes
or brisk/very
brisk walking in
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
Protection against
2 Inflammation
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
IL-7 Predicted molecular
mass of 17 kDa and
25 kDa for non-
glycosylated and
glycosylated protein,
Lymphoid organs
Strength exercise Skeletal muscle Regulation of muscle
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
exercise (e.g.,
Skeletal muscle Muscle angiogenesis,
i.e., contributes to
the exercise training
effect on muscle
? ? Like for IL-6, low
glycogen stores
increase muscle
secretion of this
Endothelial cells
Working skeletal muscle
IL-15 Belongs to the IL-2
superfamily (14–15
kDa, four-helix
Working muscles (type I
and mainly type II
Mainly strength
Skeletal muscle Promotes muscle
Protection against
muscle wasting
caused by aging or
chronic disease
IL-15 and IL-15R are
targets against:
muscle wasting
and its end-points
associated with
disease or aging
(sarcopenia and
effects are likely
independent of
PHYSIOLOGY Volume 28 September 2013 337
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
Main Target Tissue(s)
Associated With
Main Biological Effect(s)
Associated With
Main Putative Health
Benefit(s) Associated
With Exercise-Induced
Potential Future
Two IL-15 isoforms exist:
a long signaling
secreted peptide (48
amino acids) and a
short signaling
peptide (21 amino
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)
Protection against
(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-
signalling could be
a useful treatment
for skeletal muscle
myopathies or
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
Working skeletal-muscle
(muscle is the main
tissue where FNDC5
gene is expressed)
To be clearly
White adipose tissue “Browning” of white
adipose tissue
through 1 UCP1 and
thus 1
Protection against
diabetes and obesity
Exercise as a
coadjuvant for
and anti-diabetic
targeting iriscin
Muscle-related tissues
(e.g., pericardium,
To a minor extent,
kidney, liver, lung, or
adipose tissue
LIF (leukemia inhibiting
Belongs to the IL-6
cytokine superfamily
Working muscles (type I
fibers, satellite cells)
Mainly strength
Skeletal muscle Mainly local (autocrine/
paracrine effect): 1
Muscle growth
(satellite cell
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
Central nervous system
amygdala, cerebellum,
cerebral cortex, and
basal forebrain nuclei)
1 Muscle regeneration
MSCs (mesenchymal stem
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
Skeletal muscle Tissue repair and
vasculogenesis in
damaged skeletal
1 Muscle repair
(complementing the
effects of muscle
satellite cells)
Muscle atrophy
PHYSIOLOGY Volume 28 September 2013 www.physiologyonline.org338
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
Main Target Tissue(s)
Associated With
Main Biological Effect(s)
Associated With
Main Putative Health
Benefit(s) Associated
With Exercise-Induced
Potential Future
Adipose tissue Vigorous aerobic
inducing no
muscle damage
but transient
ischemia in case
of CVD patients
Myocardium? Same effect in damages
in myocardium?
1 Myocardium repair? Peripheral arterial
Others sources: dental
pulp, cord blood, and
a variety of MSCs
(mMSCs) residing in
skeletal muscles
Note: tissue
engraftment of
nonresident MSCs
remains to be
demonstrated in
Same as with CAC:
use of exercise to
increase the
efficacy of
therapies with
stem cells (by
circulating levels
of MSCs)
Myonectin [also termed
CTRP5 (C1q/TNF-related
protein 5)]
340-amino acid-protein.
Tends to form
complexes with other
proteins of the CTRP
family, possibly to
expand its function
Skeletal muscle
(especially in type I
fibers, at least in
Remains to be
determined in
Liver 1 FFA uptake in liver
and adipocytes
Control of whole body
metabolism (muscle-
liver-adipose tissue
cross talk)
Adipose tissue
Musclin (also termed
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
exercise actually
induces musclin
expression in
Skeletal muscle 2 Glucose uptake in
? ? Musclin expression
increases with
obesity and with
Non-muscle sources
Myostatin [also termed,
GDF8 (growth
differentiation factor 8)]
378-amino acid protein,
belongs to the TGB
Skeletal muscle Acute endurance
and resistance
expression, but
expression has
been more
shown with
aerobic training
than with
Skeletal muscle Main effects associated
to myostatin
inhibition which can
be partly achieved by
exercise are: 1
Muscle growth 2
Adiposity 1 Insulin
Attenuation of disease/
age muscle wasting
Use of exercise as a
coadjuvant of
therapies for
muscle wasting
Adipose tissue? Obesity/diabetes
(nitric oxide) Contracting muscles
(with the main NOS
isozyme expressed in
muscles being
Vigorous aerobic
exercise (e.g.,
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
PHYSIOLOGY Volume 28 September 2013 339
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
Main Target Tissue(s)
Associated With
Main Biological Effect(s)
Associated With
Main Putative Health
Benefit(s) Associated
With Exercise-Induced
Potential Future
NSCs (neural stem cells, also
termed neural progenitor
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
therapy against
1 Brain function
(included cognitive
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
? Motoneurons Growth and remodeling
of adult motoneuron
1 Neuromuscular
Using exercise to
attenuate age loss
of neuromuscular
performance or as
a coadjuvant
treatment against
S100A8-S100A9 complex
S100 family proteins
MRP-8 (S100A8) and
MRP-14 (S100A9) are
small (10–14 kDa)
proteins that form a
Neutrophils, monocytes,
exercise (e.g.,
Remains to be clearly
Among other effects
(including cytokine-
like action), anti-
tumor effect
1 Protection against
cancer (e.g., colon)?
Using exercise as a
treatment against
colon cancer (not
only for
Secretory epithelia
Working muscles
SPARC [secreted protein
acidic and rich in cysteine,
also known as basement
membrane protein
glycoprotein (43 kDa)
associated with the
extracellular matrix
that is expressed
abundantly in basal
Skeletal muscles
(progenitors cells,
fibers, endothelial
Strength exercise? Regulation of glucose
Prevents tumorigenesis
of colon cancer
Same as above
Tumors (ovarian,
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
or PBEF (pre-B cell
enhancing factor)]
Multifunctional protein.
Polypeptide of 491
amino acids with a
molecular mass of 52
Ubiquitous expression in
human tissues,
including adipose and
skeletal muscle tissue
(i.e., it is both an
adipokine and a
Skeletal muscle and
adipose tissue
AMPK activation ¡1
Might mediate major
effects involving
SIRT1-pathways: anti-
oxidant defense,
damage repair, or
Exercise as a major
component of
Liver It provides NAD
Bone marrow
Beta-cells and human
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.
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
PHYSIOLOGY Volume 28 September 2013 341
functions, i.e., pro-inflammatory (410) and anti-
apoptotic effects (91, 268).
Exercise and Regenerative
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
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
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,
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
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
duced locally in the bone marrow (511), and NO
oxidative stress interaction (314, 511). Increases in
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-
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
) (28, 297, 487, 492), superoxide
anion (O
·) (22, 296, 400), or hydroxyl radicals
) (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
PHYSIOLOGY Volume 28 September 2013 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
, hydrogen peroxide; HO-1, heme oxygenase-1; HSP: heat
shock proteins; NADPH, nicotinamide adenine dinucleotide phosphate; O
·, superoxide anion radical; SOD, super oxide dismutase.
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
(20, 99, 233, 462, 502) or nitrite ion (NO
(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, 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.
PHYSIOLOGY Volume 28 September 2013 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.
1. Abruzzo PM, Esposito F, Marchionni C, di Tullio S, Belia S,
Fulle S, Veicsteinas A, Marini M. Moderate exercise training
induces ROS-related adaptations to skeletal muscles. Int J
Sports Med. In press.
2. Adams SP, Tsang M, Wright JM. Lipid lowering efficacy of
atorvastatin. Cochrane Database Syst Rev 12: CD008226,
3. Adams V, Lenk K, Linke A, Lenz D, Erbs S, Sandri M, Tarnok
A, Gielen S, Emmrich F, Schuler G, Hambrecht R. Increase of
circulating endothelial progenitor cells in patients with coro-
nary artery disease after exercise-induced ischemia. Arterio-
scler Thromb Vasc Biol 24: 684690, 2004.
4. Adlard PA, Perreau VM, Engesser-Cesar C, Cotman CW. The
timecourse of induction of brain-derived neurotrophic factor
mRNA and protein in the rat hippocampus following volun-
tary exercise. Neurosci Lett 363: 43–48, 2004.
5. Aguiar AS Jr, Speck AE, Prediger RD, Kapczinski F, Pinho RA.
Downhill training upregulates mice hippocampal and striatal
brain-derived neurotrophic factor levels. J Neural Transm
115: 1251–1255, 2008.
6. Al-Khalili L, Bouzakri K, Glund S, Lonnqvist F, Koistinen HA,
Krook A. Signaling specificity of interleukin-6 action on glu-
cose and lipid metabolism in skeletal muscle. Mol Endocrinol
20: 3364–3375, 2006.
7. Al-Shanti N, Saini A, Faulkner SH, Stewart CE. Beneficial
synergistic interactions of TNF-alpha and IL-6 in C2 skeletal
myoblasts–potential cross-talk with IGF system. Growth Fac-
tors 26: 61–73, 2008.
8. Almendro V, Busquets S, Ametller E, Carbo N, Figueras M,
Fuster G, Argiles JM, Lopez-Soriano FJ. Effects of interleu-
kin-15 on lipid oxidation: disposal of an oral [
load. Biochim Biophys Acta 1761: 37–42, 2006.
9. Almendro V, Fuster G, Ametller E, Costelli P, Pilla F, Bus-
quets S, Figueras M, Argiles JM, Lopez-Soriano FJ. Interleu-
kin-15 increases calcineurin expression in 3T3–L1 cells:
possible involvement on in vivo adipocyte differentiation. Int
J Mol Med 24: 453–458, 2009.
10. Alvarez B, Carbo N, Lopez-Soriano J, Drivdahl RH, Busquets
S, Lopez-Soriano FJ, Argiles JM, Quinn LS. Effects of inter-
leukin-15 (IL-15) on adipose tissue mass in rodent obesity
models: evidence for direct IL-15 action on adipose tissue.
Biochim Biophys Acta 1570: 33–37, 2002.
11. Allen RG, Tresini M. Oxidative stress and gene regulation.
Free Radic Biol Med 28: 463–499, 2000.
12. Amirouche A, Durieux AC, Banzet S, Koulmann N, Bonnefoy
R, Mouret C, Bigard X, Peinnequin A, Freyssenet D. Down-
regulation of Akt/mammalian target of rapamycin signaling
pathway in response to myostatin overexpression in skeletal
muscle. Endocrinology 150: 286–294, 2009.
13. Aoi W, Naito Y, Takagi T, Tanimura Y, Takanami Y, Kawai Y,
Sakuma K, Hang LP, Mizushima K, Hirai Y, Koyama R, Wada
S, Higashi A, Kokura S, Ichikawa H, Yoshikawa T. A novel
myokine, secreted protein acidic and rich in cysteine
(SPARC), suppresses colon tumorigenesis via regular exer-
cise. Gut 62: 882–889, 2013.
14. Appel ML, Berger RD, Saul JP, Smith JM, Cohen RJ. Beat to
beat variability in cardiovascular variables: noise or music? J
Am Coll Cardiol 14: 1139–1148, 1989.
15. Asahara T, Murohara T, Sullivan A, Silver M, van der Zee R, Li
T, Witzenbichler B, Schatteman G, Isner JM. Isolation of
putative progenitor endothelial cells for angiogenesis. Sci-
ence 275: 964–967, 1997.
PHYSIOLOGY Volume 28 September 2013 www.physiologyonline.org346
16. Asakura A, Seale P, Girgis-Gabardo A, Rudnicki
MA. Myogenic specification of side population
cells in skeletal muscle. J Cell Biol 159: 123–134,
17. Azizbeigi K, Azarbayjani MA, Peeri M, Agha-
Alinejad H, Stannard S. The effect of progressive
resistance training on oxidative stress and eryth-
rocyte antioxidant enzymes activity in untrained
men. Int J Sport Nutr Exerc Metab 23: 230–238,
18. Baigent C, Blackwell L, Emberson J, Holland LE,
Reith C, Bhala N, Peto R, Barnes EH, Keech A,
Simes J, Collins R. Efficacy and safety of more
intensive lowering of LDL cholesterol: a meta-
analysis of data from 170,000 participants in 26
randomised trials. Lancet 376: 1670–1681, 2010.
19. Bakogiannis C, Tousoulis D, Androulakis E, Bria-
soulis A, Papageorgiou N, Vogiatzi G, Kampoli
AM, Charakida M, Siasos G, Latsios G, Antonia-
des C, Stefanadis C. Circulating endothelial pro-
genitor cells as biomarkers for prediction of
cardiovascular outcomes. Curr Med Chem 19:
2597–2604, 2012.
20. Balon TW, Nadler JL. Nitric oxide release is pres-
ent from incubated skeletal muscle preparations.
J Appl Physiol 77: 2519–2521, 1994.
21. Banfi G, Malavazos A, Iorio E, Dolci A, Doneda L,
Verna R, Corsi MM. Plasma oxidative stress bio-
markers, nitric oxide and heat shock protein 70 in
trained elite soccer players. Eur J Appl Physiol
96: 483–486, 2006.
22. Barclay JK, Reading SA, Murrant CL, Woodley
NE. Inotropic effects on mammalian skeletal
muscle change with contraction frequency. Can J
Physiol Pharmacol 81: 753–758, 2003.
23. Baron AD, Laakso M, Brechtel G, Hoit B, Watt C,
Edelman SV. Reduced postprandial skeletal mus-
cle blood flow contributes to glucose intolerance
in human obesity. J Clin Endocrinol Metab 70:
1525–1533, 1990.
24. Barra NG, Reid S, MacKenzie R, Werstuck G,
Trigatti BL, Richards C, Holloway AC, Ashkar AA.
Interleukin-15 contributes to the regulation of
murine adipose tissue and human adipocytes.
Obesity (Silver Spring) 18: 1601–1607, 2010.
25. Barreiro E, Comtois AS, Mohammed S, Lands LC,
Hussain SN. Role of heme oxygenases in sepsis-
induced diaphragmatic contractile dysfunction
and oxidative stress. Am J Physiol Lung Cell Mol
Physiol 283: L476–L484, 2002.
26. Bassett DR. Physical activity of Canadian and
American children: a focus on youth in Amish,
Mennonite, and modern cultures. Appl Physiol
Nutr Metab 33: 831–835, 2008.
27. Bayod S, Del Valle J, Lalanza JF, Sanchez-Roige
S, de Luxan-Delgado B, Coto-Montes A, Canudas
AM, Camins A, Escorihuela RM, Pallas M. Long-
term physical exercise induces changes in sirtuin
1 pathway and oxidative parameters in adult rat
tissues. Exp Gerontol 47: 925–935, 2012.
28. Bejma J, Ramires P, Ji LL. Free radical generation
and oxidative stress with ageing and exercise:
differential effects in the myocardium and liver.
Acta Physiol Scand 169: 343–351, 2000.
29. Benny Klimek ME, Aydogdu T, Link MJ, Pons M,
Koniaris LG, Zimmers TA. Acute inhibition of myosta-
tin-family proteins preserves skeletal muscle in mouse
models of cancer cachexia. Biochem Biophys Res
Commun 391: 1548–1554, 2010.
30. Berchtold NC, Chinn G, Chou M, Kesslak JP,
Cotman CW. Exercise primes a molecular mem-
ory for brain-derived neurotrophic factor protein
induction in the rat hippocampus. Neuroscience
133: 853–861, 2005.
31. Bigger JTJ. The predictive value of RR variability
and baroreflex sensitivity in coronary heart dis-
ease. Cardiac Electrophysiol Rev 1/2: 198–204,
32. Billman GE. Aerobic exercise conditioning: a non-
pharmacological antiarrhythmic intervention. J
Appl Physiol 92: 446454, 2002.
33. Billman GE. Cardiac autonomic neural remodel-
ing and susceptibility to sudden cardiac death:
effect of endurance exercise training. Am J
Physiol Heart Circ Physiol 297: H1171–H1193,
34. Billman GE. A comprehensive review and analysis
of 25 years of data from an in vivo canine model
of sudden cardiac death: implications for future
anti-arrhythmic drug development. Pharmacol
Ther 111: 808835, 2006.
35. Blackmore DG, Golmohammadi MG, Large B,
Waters MJ, Rietze RL. Exercise increases neural
stem cell number in a growth hormone-depen-
dent manner, augmenting the regenerative re-
sponse in aged mice. Stem Cells 27: 2044 –2052,
36. Blair SN. Physical inactivity: the biggest public
health problem of the 21st century. Br J Sports
Med 43: 1–2, 2009.
37. Bloomer RJ, Davis PG, Consitt LA, Wideman L.
Plasma protein carbonyl response to increasing
exercise duration in aerobically trained men and
women. Int J Sports Med 28: 21–25, 2007.
38. Bogdanovich S, Krag TO, Barton ER, Morris LD,
Whittemore LA, Ahima RS, Khurana TS. Func-
tional improvement of dystrophic muscle by
myostatin blockade. Nature 420: 418 421, 2002.
39. Bonsignore MR, Morici G, Riccioni R, Huertas A,
Petrucci E, Veca M, Mariani G, Bonanno A, Chi-
menti L, Gioia M, Palange P, Testa U. Hemopoi-
etic and angiogenetic progenitors in healthy
athletes: different responses to endurance and
maximal exercise. J Appl Physiol 109: 6067,
40. Booth FW, Laye MJ, Lees SJ, Rector RS, Thyfault
JP. Reduced physical activity and risk of chronic
disease: the biology behind the consequences.
Eur J Appl Physiol 102: 381–390, 2008.
41. Booth FW, Lees SJ. Fundamental questions
about genes, inactivity, and chronic diseases.
Physiol Genomics 28: 146–157, 2007.
42. Bortoluzzi S, Scannapieco P, Cestaro A, Danieli
GA, Schiaffino S. Computational reconstruction
of the human skeletal muscle secretome. Pro-
teins 62: 776–792, 2006.
43. Bostrom P, Wu J, Jedrychowski MP, Korde A, Ye
L, Lo JC, Rasbach KA, Bostrom EA, Choi JH,
Long JZ, Kajimura S, Zingaretti MC, Vind BF, Tu
H, Cinti S, Hojlund K, Gygi SP, Spiegelman BM. A
PGC1-alpha-dependent myokine that drives
brown-fat-like development of white fat and
thermogenesis. Nature 481: 463–468, 2012.
44. Brehm M, Picard F, Ebner P, Turan G, Bolke E,
Kostering M, Schuller P, Fleissner T, Ilousis D,
Augusta K, Peiper M, Schannwell C, Strauer BE.
Effects of exercise training on mobilization and
functional activity of blood-derived progenitor
cells in patients with acute myocardial infarction.
Eur J Med Res 14: 393–405, 2009.
45. Brekken RA, Sage EH. SPARC, a matricellular
protein: at the crossroads of cell-matrix commu-
nication. Matrix Biol 19: 816827, 2001.
46. Brites FD, Evelson PA, Christiansen MG, Nicol
MF, Basilico MJ, Wikinski RW, Llesuy SF. Soccer
players under regular training show oxidative
stress but an improved plasma antioxidant sta-
tus. Clin Sci (Lond) 96: 381–385, 1999.
47. Broholm C, Laye MJ, Brandt C, Vadalasetty R,
Pilegaard H, Pedersen BK, Scheele C. LIF is a
contraction-induced myokine stimulating human
myocyte proliferation. J Appl Physiol 111: 251–
259, 2011.
48. Broholm C, Mortensen OH, Nielsen S, Akerstrom
T, Zankari A, Dahl B, Pedersen BK. Exercise in-
duces expression of leukaemia inhibitory factor
in human skeletal muscle. J Physiol 586: 2195–
2201, 2008.
49. Broholm C, Pedersen BK. Leukaemia inhibitory
factor: an exercise-induced myokine. Exerc Im-
munol Rev 16: 77–85, 2010.
50. Bruce CR, Dyck DJ. Cytokine regulation of skel-
etal muscle fatty acid metabolism: effect of inter-
leukin-6 and tumor necrosis factor-alpha. Am J
Physiol Endocrinol Metab 287: E616 –E621, 2004.
51. Bryniarski L, Kawecka-Jaszcz K, Bacior B, Gro-
decki J, Rajzer M. Effect of exercise rehabilitation
on heart rate variability in hypertensives after
myocardial infarction. J Hypertens 15: 1739
1743, 1997.
52. Butcher LR, Thomas A, Backx K, Roberts A,
Webb R, Morris K. Low-intensity exercise exerts
beneficial effects on plasma lipids via PPAR-
gamma. Med Sci Sports Exerc 40: 1263–1270,
53. Cakir-Atabek H, Demir S, PinarbaSili RD, Gunduz
N. Effects of different resistance training inten-
sity on indices of oxidative stress. J Strength
Cond Res 24: 2491–2497, 2010.
54. Calabrese LH, Nieman DC. Exercise, immunity,
infection. J Am Osteopath Assoc 96: 166 –176,
55. Campbell PT, Patel AV, Newton CC, Jacobs EJ,
Gapstur SM. Associations of recreational physical
activity and leisure time spent sitting with colo-
rectal cancer survival. J Clin Oncol 31: 876 885,
56. Cao JM, Chen LS, KenKnight BH, Ohara T, Lee
MH, Tsai J, Lai WW, Karagueuzian HS, Wolf PL,
Fishbein MC, Chen PS. Nerve sprouting and sud-
den cardiac death. Circ Res 86: 816821, 2000.
57. Cao L, Liu X, Lin EJ, Wang C, Choi EY, Riban V,
Lin B, During MJ. Environmental and genetic ac-
tivation of a brain-adipocyte BDNF/leptin axis
causes cancer remission and inhibition. Cell 142:
52–64, 2010.
58. Caplan AI. Why are MSCs therapeutic? New da-
ta: new insight. J Pathol 217: 318–324, 2009.
59. Carbo N, Lopez-Soriano J, Costelli P, Alvarez B,
Busquets S, Baccino FM, Quinn LS, Lopez-So-
riano FJ, Argiles JM. Interleukin-15 mediates re-
ciprocal regulation of adipose and muscle mass:
a potential role in body weight control. Biochim
Biophys Acta 1526: 17–24, 2001.
60. Carbo N, Lopez-Soriano J, Costelli P, Busquets S,
Alvarez B, Baccino FM, Quinn LS, Lopez-Soriano
FJ, Argiles JM. Interleukin-15 antagonizes mus-
cle protein waste in tumour-bearing rats. Br J
Cancer 83: 526–531, 2000.
61. Carey AL, Steinberg GR, Macaulay SL, Thomas
WG, Holmes AG, Ramm G, Prelovsek O, Hohnen-
Behrens C, Watt MJ, James DE, Kemp BE, Pe-
dersen BK, Febbraio MA. Interleukin-6 increases
insulin-stimulated glucose disposal in humans
and glucose uptake and fatty acid oxidation in
vitro via AMP-activated protein kinase. Diabetes
55: 2688–2697, 2006.
62. Carlsohn A, Rohn S, Bittmann F, Raila J, Mayer F,
Schweigert FJ. Exercise increases the plasma an-
tioxidant capacity of adolescent athletes. Ann
Nutr Metab 53: 96–103, 2008.
63. Carlson CJ, Booth FW, Gordon SE. Skeletal mus-
cle myostatin mRNA expression is fiber-type spe-
cific and increases during hindlimb unloading.
Am J Physiol Regul Integr Comp Physiol 277:
R601–R606, 1999.
PHYSIOLOGY Volume 28 September 2013 347
64. Cases N, Aguilo A, Tauler P, Sureda A, Llompart
I, Pons A, Tur JA. Differential response of plasma
and immune cell’s vitamin E levels to physical
activity and antioxidant vitamin supplementa-
tion. Eur J Clin Nutr 59: 781–788, 2005.
65. Casolo G, Balli E, Taddei T, Amuhasi J, Gori C.
Decreased spontaneous heart rate variability in
congestive heart failure. Am J Cardiol 64: 1162–
1167, 1989.
66. Castellano V, White LJ. Serum brain-derived neu-
rotrophic factor response to aerobic exercise in
multiple sclerosis. J Neurol Sci 269: 85–91, 2008.
67. Castier Y, Brandes RP, Leseche G, Tedgui A,
Lehoux S. p47phox-dependent NADPH oxidase
regulates flow-induced vascular remodeling. Circ
Res 97: 533–540, 2005.
68. Cesari F, Sofi F, Gori AM, Corsani I, Capalbo A,
Caporale R, Abbate R, Gensini GF, Casini A.
Physical activity and circulating endothelial pro-
genitor cells: an intervention study. Eur J Clin
Invest 42: 927–932, 2012.
69. Clow C, Jasmin BJ. Brain-derived neurotrophic
factor regulates satellite cell differentiation and
skeltal muscle regeneration. Mol Biol Cell 21:
2182–2190, 2010.
70. Constantin D, McCullough J, Mahajan RP, Green-
haff PL. Novel events in the molecular regulation
of muscle mass in critically ill patients. J Physiol
589: 3883–3895, 2011.
71. Cordain L, Gotshall RW, Eaton SB, Eaton SB, 3rd.
Physical activity, energy expenditure and fitness:
an evolutionary perspective. Int J Sports Med 19:
328–335, 1998.
72. Cornelissen VA, Fagard RH. Effect of resistance
training on resting blood pressure: a meta-anal-
ysis of randomized controlled trials. J Hypertens
23: 251–259, 2005.
73. Cornelissen VA, Fagard RH. Effects of endurance
training on blood pressure, blood pressure-reg-
ulating mechanisms, and cardiovascular risk fac-
tors. Hypertension 46: 667–675, 2005.
74. Cornelissen VA, Fagard RH, Coeckelberghs E,
Vanhees L. Impact of resistance training on blood
pressure and other cardiovascular risk factors: a
meta-analysis of randomized, controlled trials.
Hypertension 58: 950–958, 2011.
75. Cornelissen VA, Smart NA. Exercise training for
blood pressure: a systematic review and meta-
analysis. J Am Heart Assoc 2: e004473, 2013.
76. Correia PR, Pansani A, Machado F, Andrade M,
Silva AC, Scorza FA, Cavalheiro EA, Arida RM.
Acute strength exercise and the involvement of
small or large muscle mass on plasma brain-de-
rived neurotrophic factor levels. Clinics 65: 1123–
1126, 2010.
77. Costford SR, Bajpeyi S, Pasarica M, Albarado DC,
Thomas SC, Xie H, Church TS, Jubrias SA, Conley
KE, Smith SR. Skeletal muscle NAMPT is induced
by exercise in humans. Am J Physiol Endocrinol
Metab 298: E117–E126, 2010.
78. Cotman CW, Berchtold NC. Exercise: a behav-
ioral intervention to enhance brain health and
plasticity. Trends Neurosci 25: 295–301, 2002.
79. Cotman CW, Berchtold NC, Christie LA. Exercise
builds brain health: key roles of growth factor
cascades and inflammation. Trends Neurosci 30:
464472, 2007.
80. Criswell D, Powers S, Dodd S, Lawler J, Edwards
W, Renshler K, Grinton S. High intensity training-
induced changes in skeletal muscle antioxidant
enzyme activity. Med Sci Sports Exerc 25: 1135–
1140, 1993.
81. Croft L, Bartlett JD, MacLaren DP, Reilly T, Evans
L, Mattey DL, Nixon NB, Drust B, Morton JP.
High-intensity interval training attenuates the ex-
ercise-induced increase in plasma IL-6 in re-
sponse to acute exercise. Appl Physiol Nutr
Metab 34: 1098–1107, 2009.
82. Crosby JR, Kaminski WE, Schatteman G, Martin
PJ, Raines EW, Seifert RA, Bowen-Pope DF. En-
dothelial cells of hematopoietic origin make a
significant contribution to adult blood vessel for-
mation. Circ Res 87: 728–730, 2000.
83. Cuevas-Ramos D, Almeda-Valdes P, Gomez-
Perez FJ, Meza-Arana CE, Cruz-Bautista I,
Arellano-Campos O, Navarrete-Lopez M, Agui-
lar-Salinas CA. Daily physical activity, fasting glu-
cose, uric acid, and body mass index are
independent factors associated with serum fibro-
blast growth factor 21 levels. Eur J Endocrinol
163: 469477, 2010.
84. Cuevas-Ramos D, Almeda-Valdes P, Meza-Arana
CE, Brito-Cordova G, Gomez-Perez FJ, Mehta R,
Oseguera-Moguel J, Aguilar-Salinas CA. Exercise
increases serum fibroblast growth factor 21
(FGF21) levels. PLos One 7: e38022, 2012.
85. Chan CY, Masui O, Krakovska O, Belozerov VE,
Voisin S, Ghanny S, Chen J, Moyez D, Zhu P,
Evans KR, McDermott JC, Siu KW. Identification
of differentially regulated secretome compo-
nents during skeletal myogenesis. Mol Cell Pro-
teomic 10: M110004804, 2011.
86. Chan MH, Carey AL, Watt MJ, Febbraio MA.
Cytokine gene expression in human skeletal mus-
cle during concentric contraction: evidence that
IL-8, like IL-6, is influenced by glycogen availabil-
ity. Am J Physiol Regul Integr Comp Physiol 287:
R322–R327, 2004.
87. Chan XC, McDermott JC, Siu KW. Identification
of secreted proteins during skeletal muscle de-
velopment. J Proteome Res 6: 698–710, 2007.
88. Charge SB, Rudnicki MA. Cellular and molecular
regulation of muscle regeneration. Physiol Rev
84: 209–238, 2004.
89. Charkoudian N, Joyner MJ, Barnes SA, Johnson
CP, Eisenach JH, Dietz NM, Wallin BG. Relation-
ship between muscle sympathetic nerve activity
and systemic hemodynamics during nitric oxide
synthase inhibition in humans. Am J Physiol Heart
Circ Physiol 291: H1378–H1383, 2006.
90. Chen PS, Chen LS, Cao JM, Sharifi B, Karagueu-
zian HS, Fishbein MC. Sympathetic nerve sprout-
ing, electrical remodeling and the mechanisms of
sudden cardiac death. Cardiovasc Res 50: 409
416, 2001.
91. Cheng Q, Dong W, Qian L, Wu J, Peng Y. Visfatin
inhibits apoptosis of pancreatic beta-cell line,
MIN6, via the mitogen-activated protein kinase/
phosphoinositide 3-kinase pathway. Mol Endocri-
nol 47: 13–21, 2011.
92. Cheng XW, Kuzuya M, Kim W, Song H, Hu L,
Inoue A, Nakamura K, Di Q, Sasaki T, Tsuzuki
M, Shi GP, Okumura K, Murohara T. Exercise
training stimulates ischemia-induced neovascu-
larization via phosphatidylinositol 3-kinase/
Akt-dependent hypoxia-induced factor-1 alpha
reactivation in mice of advanced age. Circula-
tion 122: 707–716, 2010.
93. Choi KM, Kim JH, Cho GJ, Baik SH, Park HS, Kim
SM. Effect of exercise training on plasma visfatin
and eotaxin levels. Eur J Endocrinol 157: 437–
442, 2007.
94. Choi S, Liu X, Li P, Akimoto T, Lee SY, Zhang M,
Yan Z. Transcriptional profiling in mouse skeletal
muscle following a single bout of voluntary run-
ning: evidence of increased cell proliferation. J
Appl Physiol 99: 2406–2415, 2005.
95. Church TS, Blair SN. When will we treat physical
activity as a legitimate medical therapy...even
though it does not come in a pill? Br J Sports
Med 43: 8081, 2009.
96. da Rocha RF, de Oliveira MR, Pasquali MA, An-
drades ME, Oliveira MW, Behr GA, Moreira JC.
Vascular redox imbalance in rats submitted to
chronic exercise. Cell Biochem Funct 28: 190
196, 2010.
97. Dasarathy S, Dodig M, Muc SM, Kalhan SC, Mc-
Cullough AJ. Skeletal muscle atrophy is associ-
ated with an increased expression of myostatin
and impaired satellite cell function in the porta-
caval anastamosis rat. Am J Physiol Gastrointest
Liver Physiol 287: G1124–G1130, 2004.
98. Dekany M, Nemeskeri V, Gyore I, Harbula I,
Malomsoki J, Pucsok J. Antioxidant status of in-
terval-trained athletes in various sports. Int J
Sports Med 27: 112–116, 2006.
99. Delp MD, Laughlin MH. Time course of en-
hanced endothelium-mediated dilation in aorta
of trained rats. Med Sci Sports Exerc 29: 1454
1461, 1997.
100. Dellavalle A, Sampaolesi M, Tonlorenzi R, Taglia-
fico E, Sacchetti B, Perani L, Innocenzi A, Galvez
BG, Messina G, Morosetti R, Li S, Belicchi M,
Peretti G, Chamberlain JS, Wright WE, Torrente
Y, Ferrari S, Bianco P, Cossu G. Pericytes of hu-
man skeletal muscle are myogenic precursors
distinct from satellite cells. Nat Cell Biol 9: 255–
267, 2007.
101. Demirel HA, Hamilton KL, Shanely RA, Tumer N,
Koroly MJ, Powers SK. Age and attenuation of
exercise-induced myocardial HSP72 accumula-
tion. Am J Physiol Heart Circ Physiol 285:
H1609–H1615, 2003.
102. Dennis RA, Zhu H, Kortebein PM, Bush HM, Har-
vey JF, Sullivan DH, Peterson CA. Muscle expres-
sion of genes associated with inflammation,
growth, and remodeling is strongly correlated in
older adults with resistance training outcomes.
Physiol Genomics 38: 169–175, 2009.
103. DeSouza CA, Shapiro LF, Clevenger CM, Di-
nenno FA, Monahan KD, Tanaka H, Seals DR.
Regular aerobic exercise prevents and restores
age-related declines in endothelium-dependent
vasodilation in healthy men. Circulation 102:
1351–1357, 2000.
104. Diaz PT, She ZW, Davis WB, Clanton TL. Hy-
droxylation of salicylate by the in vitro dia-
phragm: evidence for hydroxyl radical
production during fatigue. J Appl Physiol 75:
540–545, 1993.
105. Dillard CJ, Litov RE, Savin WM, Dumelin EE, Tap-
pel AL. Effects of exercise, vitamin E, and ozone
on pulmonary function and lipid peroxidation. J
Appl Physiol 45: 927–932, 1978.
106. Dixon EM, Kamath MV, McCartney N, Fallen EL.
Neural regulation of heart rate variability in en-
durance athletes and sedentary controls. Cardio-
vasc Res 26: 713–719, 1992.
107. Djordjevic D, Cubrilo D, Macura M, Barudzic N,
Djuric D, Jakovljevic V. The influence of training
status on oxidative stress in young male handball
players. Mol Cell Biochem 351: 251–259, 2011.
108. Drexler H, Coats AJ. Explaining fatigue in congestive
heart failure. Annu Rev Med 47: 241–256, 1996.
109. Droge W. Free radicals in the physiological con-
trol of cell function. Physiol Rev 82: 47–95, 2002.
110. Duman CH, Schlesinger L, Russell DS, Duman RS.
Voluntary exercise produces antidepressant and
anxiolytic behavioral effects in mice. Brain Res
1199: 148–158, 2008.
111. Dupont-Versteegden EE, Houle JD, Dennis RA,
Zhang J, Knox M, Wagoner G, Peterson CA. Ex-
ercise-induced gene expression in soleus muscle
is dependent on time after spinal cord injury in
rats. Muscle Nerve 29: 73–81, 2004.
112. Eckberg DL. Sympathovagal balance: a critical
appraisal. Circulation 98: 2643–2644, 1998.
PHYSIOLOGY Volume 28 September 2013 www.physiologyonline.org348
113. Edwards JE, Moore RA. Statins in hypercholes-
terolaemia: a dose-specific meta-analysis of lipid
changes in randomised, double blind trials. BMC
Fam Pract 4: 18, 2003.
114. Ekblom B, Kilbom A, Soltysiak J. Physical train-
ing, bradycardia, and autonomic nervous system.
Scand J Clin Lab Invest 32: 251–256, 1973.
115. Elley CR, Gupta AK, Webster R, Selak V, Jun M,
Patel A, Rodgers A, Thom S. The efficacy and
tolerability of ‘polypills’: meta-analysis of ran-
domised controlled trials. PLos One 7: e52145,
116. Fabel K, Fabel K, Tam B, Kaufer D, Baiker A,
Simmons N, Kuo CJ, Palmer TD. VEGF is neces-
sary for exercise-induced adult hippocampal neu-
rogenesis. Eur J Neurosci 18: 2803–2812, 2003.
117. Fagerhol MK, Nielsen HG, Vetlesen A, Sandvik K,
Lyberg T. Increase in plasma calprotectin during
long-distance running. Scand J Clin Lab Invest
65: 211–220, 2005.
118. Farmawati A, Kitajima Y, Nedachi T, Sato M, Kan-
zaki M, Nagatomi R. Characterization of contrac-
tion-induced IL-6 up-regulation using contractile
C2C12 myotubes. Endocr J 60: 137–147, 2013.
119. Febbraio MA, Koukoulas I. HSP72 gene expres-
sion progressively increases in human skeletal
muscle during prolonged, exhaustive exercise. J
Appl Physiol 89: 1055–1060, 2000.
120. Fernandez JM, Rosado-Alvarez D, Da Silva
Grigoletto M.E, Rangel-Zuniga OA, Landaeta-
Diaz LL, Caballero-Villarraso J, Lopez-Miranda
J, Perez-Jimenez F, Fuentes-Jimenez F. Mod-
erate-to-high-intensity training and a hypocal-
oric Mediterranean diet enhance endothelial
progenitor cells and fitness in subjects with the
metabolic syndrome. Clin Sci (Lond) 123: 361–
373, 2012.
121. Ferris LT, Williams JS, Shen CL. The effect of
acute exercise on serum brain-derived neu-
rotrophic factor levels and cognitive function.
Med Sci Sports Exerc 39: 728–734, 2007.
122. Fiers W. Tumor necrosis factor. Characterization
at the molecular, cellular and in vivo level. FEBS
Lett 285: 199–212, 1991.
123. Figueroa A, Baynard T, Fernhall B, Carhart R,
Kanaley JA. Endurance training improves post-
exercise cardiac autonomic modulation in obese
women with and without Type 2 diabetes. Eur J
Appl Physiol 100: 437–444, 2007.
124. Finaud J, Lac G, Filaire E. Oxidative stress: rela-
tionship with exercise and training. Sports Med
36: 327–358, 2006.
125. Fischer CP. Interleukin-6 in acute exercise and
training: what is the biological relevance? Exerc
Immunol Rev 12: 6–33, 2006.
126. Fischer CP, Plomgaard P, Hansen AK, Pilegaard
H, Saltin B, Pedersen BK. Endurance training re-
duces the contraction-induced interleukin-6
mRNA expression in human skeletal muscle. Am
J Physiol Endocrinol Metab 287: E1189–E1194,
127. Fisher G, Schwartz DD, Quindry J, Barberio MD,
Foster EB, Jones KW, Pascoe DD. Lymphocyte
enzymatic antioxidant responses to oxidative
stress following high-intensity interval exercise. J
Appl Physiol 110: 730–737, 2011.
128. Franzoni F, Ghiadoni L, Galetta F, Plantinga Y,
Lubrano V, Huang Y, Salvetti G, Regoli F, Taddei
S, Santoro G, Salvetti A. Physical activity, plasma
antioxidant capacity, and endothelium-depen-
dent vasodilation in young and older men. Am J
Hypertens 18: 510–516, 2005.
129. Friedenstein AJ, Chailakhjan RK, Lalykina KS. The
development of fibroblast colonies in monolayer
cultures of guinea-pig bone marrow and spleen
cells. Cell Tissue Kinet 3: 393–403, 1970.
130. Fry CS, Drummond MJ, Glynn EL, Dickinson JM,
Gundermann DM, Timmerman KL, Walker DK,
Volpi E, Rasmussen BB. Skeletal muscle au-
tophagy and protein breakdown following resis-
tance exercise are similar in younger and older
adults. J Gerontol A Biol Sci Med Sci 68: 599
607, 2013.
131. Frydelund-Larsen L, Penkowa M, Akerstrom T,
Zankari A, Nielsen S, Pedersen BK. Exercise in-
duces interleukin-8 receptor (CXCR2) expression
in human skeletal muscle. Exp Physiol 92: 233–
240, 2007.
132. Fukai T, Siegfried MR, Ushio-Fukai M, Cheng Y,
Kojda G, Harrison DG. Regulation of the vascular
extracellular superoxide dismutase by nitric ox-
ide and exercise training. J Clin Invest 105: 1631–
1639, 2000.
133. Funakoshi H, Belluardo N, Arenas E, Yamamoto
Y, Casabona A, Persson H, Ibanez CF. Muscle-
derived neurotrophin-4 as an activity-dependent
trophic signal for adult motor neurons. Science
268: 1495–1499, 1995.
134. Furlan R, Piazza S, Dell’Orto S, Gentile E, Cerutti
S, Pagani M, Malliani A. Early and late effects of
exercise and athletic training on neural mecha-
nisms controlling heart rate. Cardiovasc Res 27:
482–488, 1993.
135. Furmanczyk PS, Quinn LS. Interleukin-15 in-
creases myosin accretion in human skeletal myo-
genic cultures. Cell Biol Int 27: 845–851, 2003.
136. Fuster G, Almendro V, Fontes-Oliveira CC, To-
ledo M, Costelli P, Busquets S, Lopez-Soriano FJ,
Argiles JM. Interleukin-15 affects differentiation
and apoptosis in adipocytes: implications in obe-
sity. Lipids 46: 1033–1042, 2011.
137. Fuster V, Sanz G. Fixed-dose compounds and the
secondary prevention of ischemic heart disease.
Rev Esp Cardiol 64, Suppl 2: 3–9, 2011.
138. Gao D, Ning N, Niu X, Wei J, Sun P, Hao Aliskiren
vs G. angiotensin receptor blockers in hyperten-
sion: meta-analysis of randomized controlled tri-
als. Am J Hypertens 24: 613–621, 2011.
139. Garcia-Gomez I, Elvira G, Zapata AG, Lamana
ML, Ramirez M, Castro JG, Arranz MG, Vicente
A, Bueren J, Garcia-Olmo D. Mesenchymal stem
cells: biological properties and clinical applica-
tions. Expert Opin Biol Ther 10: 1453–1468,
140. Garcia-Lopez D, Cuevas MJ, Almar M, Lima E, De
Paz JA, Gonzalez-Gallego J. Effects of eccentric
exercise on NF-kappaB activation in blood mono-
nuclear cells. Med Sci Sports Exerc 39: 653–664,
141. Gatta L, Armani A, Iellamo F, Consoli C, Molinari
F, Caminiti G, Volterrani M, Rosano GM. Effects
of a short-term exercise training on serum factors
involved in ventricular remodelling in chronic
heart failure patients. Int J Cardiol 155: 409 413,
142. Geng DF, Liu M, Jin DM, Wu W, Deng J, Wang
JF. Cilostazol-based triple antiplatelet therapy
compared to dual antiplatelet therapy in patients
with coronary stent implantation: a meta-analysis
of 5,821 patients. Cardiology 122: 148 –157,
143. Ghavami S, Kerkhoff C, Los M, Hashemi M, Sorg
C, Karami-Tehrani F. Mechanism of apoptosis in-
duced by S100A8/A9 in colon cancer cell lines:
the role of ROS and the effect of metal ions. J
Leukoc Biol 76: 169–175, 2004.
144. Gielen S, Sandri M, Erbs S, Adams V. Exercise-
induced modulation of endothelial nitric oxide
production. Curr Pharm Biotechnol 12: 1375–
1384, 2011.
145. Glund S, Deshmukh A, Long YC, Moller T, Koisti-
nen HA, Caidahl K, Zierath JR, Krook A. Interleu-
kin-6 directly increases glucose metabolism in
resting human skeletal muscle. Diabetes 56:
1630–1637, 2007.
146. Goekint M, De Pauw K, Roelands B, Njemini R,
Bautmans I, Mets T, Meeusen R. Strength train-
ing does not influence serum brain-derived neu-
rotrophic factor. Eur J Appl Physiol 110: 285–
293, 2010.
147. Gold SM, Schulz KH, Hartmann S, Mladek M,
Lang UE, Hellweg R, Reer R, Braumann KM,
Heesen C. Basal serum levels and reactivity of
nerve growth factor and brain-derived neu-
rotrophic factor to standardized acute exercise in
multiple sclerosis and controls. J Neuroimmunol
138: 99–105, 2003.
148. Gomez-Cabrera MC, Borras C, Pallardo FV, Sas-
tre J, Ji LL, Vina J. Decreasing xanthine oxidase-
mediated oxidative stress prevents useful
cellular adaptations to exercise in rats. J Physiol
567: 113–120, 2005.
149. Gomez-Cabrera MC, Domenech E, Romagnoli M, Ar-
duini A, Borras C, Pallardo FV, Sastre J, Vina J. Oral
administration of vitamin C decreases muscle mito-
chondrial biogenesis and hampers training-induced
adaptations in endurance performance. Am J Clin
Nutr 87: 142–149, 2008.
150. Gomez-Cabrera MC, Domenech E, Vina J. Mod-
erate exercise is an antioxidant: upregulation of
antioxidant genes by training. Free Radic Biol
Med 44: 126–131, 2008.
151. Gomez-Cabrera MC, Martinez A, Santangelo G,
Pallardo FV, Sastre J, Vina J. Oxidative stress in
marathon runners: interest of antioxidant supple-
mentation. Br J Nutr 96, Suppl 1: S31–S33, 2006.
152. Gomez-Pinilla F, Ying Z, Opazo P, Roy RR, Edg-
erton VR. Differential regulation by exercise of
BDNF and NT-3 in rat spinal cord and skeletal
muscle. Eur J Neurosci 13: 1078–1084, 2001.
153. Gomez-Pinilla F, Ying Z, Roy RR, Molteni R,
Edgerton VR. Voluntary exercise induces a
BDNF-mediated mechanism that promotes
neuroplasticity. J Neurophysiol 88: 2187–2195,
154. Gonzalez-Cadavid NF, Taylor WE, Yarasheski K,
Sinha-Hikim I, Ma K, Ezzat S, Shen R, Lalani R, Asa
S, Mamita M, Nair G, Arver S, Bhasin S. Organi-
zation of the human myostatin gene and expres-
sion in healthy men and HIV-infected men with
muscle wasting. Proc Natl Acad Sci USA 95:
14938–14943, 1998.
155. Goodyear LJ. The exercise pill: too good to be
true? N Engl J Med 359: 1842–1844, 2008.
156. Gore M, Fiebig R, Hollander J, Leeuwenburgh C,
Ohno H, Ji LL. Endurance training alters antioxi-
dant enzyme gene expression in rat skeletal mus-
cle. Can J Physiol Pharmacol 76: 1139 –1145,
157. Goussetis E, Spiropoulos A, Tsironi M, Skenderi
K, Margeli A, Graphakos S, Baltopoulos P, Papas-
sotiriou I. Spartathlon, a 246 kilometer foot race:
effects of acute inflammation induced by pro-
longed exercise on circulating progenitor repar-
ative cells. Blood Cells Mol Dis 42: 294 –299,
158. Green DJ, Maiorana A, O’Driscoll G, Taylor R.
Effect of exercise training on endothelium-de-
rived nitric oxide function in humans. J Physiol
561: 1–25, 2004.
159. Green DJ, O’Driscoll G, Joyner MJ, Cable NT.
Exercise and cardiovascular risk reduction: time
to update the rationale for exercise? J Appl
Physiol 105: 766–768, 2008.
160. Green DJ, Walsh JH, Maiorana A, Best MJ, Taylor
RR, O’Driscoll JG. Exercise-induced improve-
ment in endothelial dysfunction is not mediated
by changes in CV risk factors: pooled analysis of
diverse patient populations. Am J Physiol Heart
Circ Physiol 285: H2679–H2687, 2003.
PHYSIOLOGY Volume 28 September 2013 349
161. Gregorevic P, Williams DA, Lynch GS. Effects of
leukemia inhibitory factor on rat skeletal muscles
are modulated by clenbuterol. Muscle Nerve 25:
194–201, 2002.
162. Griesbeck O, Parsadanian AS, Sendtner M, Thoe-
nen H. Expression of neurotrophins in skeletal
muscle: quantitative comparison and significance
for motoneuron survival and maintenance of
function. J Neurosci Res 42: 21–33, 1995.
163. Guelfi KJ, Casey TM, Giles JJ, Fournier PA, Ar-
thur PG. A proteomic analysis of the acute ef-
fects of high-intensity exercise on skeletal muscle
proteins in fasted rats. Clin Exp Pharmacol
Physiol 33: 952–957, 2006.
164. Guo T, Jou W, Chanturiya T, Portas J, Gavrilova
O, McPherron AC. Myostatin inhibition in muscle,
but not adipose tissue, decreases fat mass and
improves insulin sensitivity. PLos One 4: e4937,
165. Hakim AA, Curb JD, Petrovitch H, Rodriguez BL,
Yano K, Ross GW, White LR, Abbott RD. Effects
of walking on coronary heart disease in elderly
men: the Honolulu Heart Program. Circulation
100: 9–13, 1999.
166. Hallal PC, Andersen LB, Bull FC, Guthold R,
Haskell W, Ekelund U, and Lancet Physical Activ-
ity Series Working G. Global physical activity lev-
els: surveillance progress, pitfalls, and prospects.
Lancet 380: 247–257, 2012.
167. Hambrecht R, Walther C, Mobius-Winkler S,
Gielen S, Linke A, Conradi K, Erbs S, Kluge R,
Kendziorra K, Sabri O, Sick P, Schuler G. Percu-
taneous coronary angioplasty compared with ex-
ercise training in patients with stable coronary
artery disease: a randomized trial. Circulation
109: 1371–1378, 2004.
168. Hamilton KL, Staib JL, Phillips T, Hess A, Lennon
SL, Powers SK. Exercise, antioxidants, and
HSP72: protection against myocardial ischemia/
reperfusion. Free Radic Biol Med 34: 800809,
169. Hammeren J, Powers S, Lawler J, Criswell D,
Martin D, Lowenthal D, Pollock M. Exercise train-
ing-induced alterations in skeletal muscle oxida-
tive and antioxidant enzyme activity in senescent
rats. Int J Sports Med 13: 412–416, 1992.
170. Harber MP, Crane JD, Dickinson JM, Jemiolo B,
Raue U, Trappe TA, Trappe SW. Protein synthesis
and the expression of growth-related genes are
altered by running in human vastus lateralis and
soleus muscles. Am J Physiol Regul Integr Comp
Physiol 296: R708–R714, 2009.
171. Hashemi MS, Ghaedi K, Salamian A, Karbalaie K,
Emadi-Baygi M, Tanhaei S, Nasr-Esfahani MH,
Baharvand H. Fndc5 knockdown significantly de-
creased neural differentiation rate of mouse em-
bryonic stem cells. Neuroscience 231: 296–304,
172. Hashizume M, Hayakawa N, Suzuki M, Mihara M.
IL-6/sIL-6R trans-signalling, but not TNF-alpha in-
duced angiogenesis in a HUVEC and synovial cell
co-culture system. Rheumatol Int 29: 1449 –1454,
173. Haskell WL, Alderman EL, Fair JM, Maron DJ,
Mackey SF, Superko HR, Williams PT, Johnstone
IM, Champagne MA, Krauss RM. Effects of inten-
sive multiple risk factor reduction on coronary
atherosclerosis and clinical cardiac events in men
and women with coronary artery disease. The
Stanford Coronary Risk Intervention Project
(SCRIP). Circulation 89: 975–990, 1994.
174. Haugen F, Norheim F, Lian H, Wensaas AJ, Du-
eland S, Berg O, Funderud A, Skalhegg BS,
Raastad T, Drevon CA. IL-7 is expressed and
secreted by human skeletal muscle cells. Am J
Physiol Cell Physiol 298: C807–C816, 2010.
175. He C, Bassik MC, Moresi V, Sun K, Wei Y, Zou Z,
An Z, Loh J, Fisher J, Sun Q, Korsmeyer S, Packer
M, May HI, Hill JA, Virgin HW, Gilpin C, Xiao G,
Bassel-Duby R, Scherer PE, Levine B. Exercise-
induced BCL2-regulated autophagy is required
for muscle glucose homeostasis. Nature 481:
511–515, 2012.
176. He C, Sumpter R Jr, Levine B. Exercise induces
autophagy in peripheral tissues and in the brain.
Autophagy 8: 1548–1551, 2012.
177. Hellsten Y, Apple FS, Sjodin B. Effect of sprint
cycle training on activities of antioxidant en-
zymes in human skeletal muscle. J Appl Physiol
81: 1484–1487, 1996.
178. Henningsen J, Rigbolt KT, Blagoev B, Pedersen
BK, Kratchmarova I. Dynamics of the skeletal
muscle secretome during myoblast differentia-
tion. Mol Cell Proteomic 9: 2482–2496, 2010.
179. Henson DA, Nieman DC, Nehlsen-Cannarella SL,
Fagoaga OR, Shannon M, Bolton MR, Davis JM,
Gaffney CT, Kelln WJ, Austin MD, Hjertman JM,
Schilling BK. Influence of carbohydrate on cyto-
kine and phagocytic responses to2hofrowing.
Med Sci Sports Exerc 32: 1384–1389, 2000.
180. Higuchi M, Cartier LJ, Chen M, Holloszy JO. Su-
peroxide dismutase and catalase in skeletal mus-
cle: adaptive response to exercise. J Gerontol
40: 281–286, 1985.
181. Hirschi KK, Ingram DA, Yoder MC. Assessing
identity, phenotype, and fate of endothelial pro-
genitor cells. Arterioscler Thromb Vasc Biol 28:
1584–1595, 2008.
182. Hirst JA, Farmer AJ, Ali R, Roberts NW, Stevens
RJ. Quantifying the effect of metformin treat-
ment and dose on glycemic control. Diabetes
Care 35: 446454, 2012.
183. Hiscock N, Chan MH, Bisucci T, Darby IA, Feb-
braio MA. Skeletal myocytes are a source of in-
terleukin-6 mRNA expression and protein release
during contraction: evidence of fiber type speci-
ficity. FASEB J 18: 992–994, 2004.
184. Hittel DS, Axelson M, Sarna N, Shearer J, Huff-
man KM, Kraus WE. Myostatin decreases with
aerobic exercise and associates with insulin resis-
tance. Med Sci Sports Exerc 42: 2023–2029,
185. Hittel DS, Berggren JR, Shearer J, Boyle K, Hou-
mard JA. Increased secretion and expression of
myostatin in skeletal muscle from extremely
obese women. Diabetes 58: 30–38, 2009.
186. Hoffman-Goetz L, Pervaiz N, Guan J. Voluntary
exercise training in mice increases the expression
of antioxidant enzymes and decreases the ex-
pression of TNF-alpha in intestinal lymphocytes.
Brain Behav Immun 23: 498–506, 2009.
187. Hohnloser SH, Klingenheben T, Zabel M, Li YG.
Heart rate variability used as an arrhythmia risk
stratifier after myocardial infarction. Pacing Clin
Electrophysiol 20: 2594–2601, 1997.
188. Hojman P, Pedersen M, Nielsen AR, Krogh-Mad-
sen R, Yfanti C, Akerstrom T, Nielsen S, Pedersen
BK. Fibroblast growth factor-21 is induced in hu-
man skeletal muscles by hyperinsulinemia. Diabe-
tes 58: 2797–2801, 2009.
189. Hollander J, Fiebig R, Gore M, Bejma J,
Ookawara T, Ohno H, Ji LL. Superoxide dismu-
tase gene expression in skeletal muscle: fiber-
specific adaptation to endurance training. Am J
Physiol Regul Integr Comp Physiol 277: R856
R862, 1999.
190. Holloway KV, O’Gorman M, Woods P, Morton
JP, Evans L, Cable NT, Goldspink DF, Burniston
JG. Proteomic investigation of changes in human
vastus lateralis muscle in response to interval-
exercise training. Proteomics 9: 5155–5174,
191. Hopper I, Billah B, Skiba M, Krum H. Prevention
of diabetes and reduction in major cardiovascular
events in studies of subjects with prediabetes:
meta-analysis of randomised controlled clinical
trials. Eur J Cardiovasc Prev Rehabil 18: 813– 823,
192. Horsley V, Jansen KM, Mills ST, Pavlath GK. IL-4
acts as a myoblast recruitment factor during
mammalian muscle growth. Cell 113: 483– 494,
193. Huang AM, Jen CJ, Chen HF, Yu L, Kuo YM, Chen
HI. Compulsive exercise acutely upregulates rat
hippocampal brain-derived neurotrophic factor.
J Neural Transm 113: 803–811, 2006.
194. Huang CC, Lin WT, Hsu FL, Tsai PW, Hou CC.
Metabolomics investigation of exercise-modu-
lated changes in metabolism in rat liver after
exhaustive and endurance exercises. Eur J Appl
Physiol 108: 557–566, 2010.
195. Huh JY, Panagiotou G, Mougios V, Brinkoetter
M, Vamvini MT, Schneider BE, Mantzoros CS.
FNDC5 and irisin in humans: I. Predictors of cir-
culating concentrations in serum and plasma and
II. mRNA expression and circulating concentra-
tions in response to weight loss and exercise.
Metabolism 61: 1725–1738, 2012.
196. Huntsman HD, Zachwieja N, Zou K, Ripchik P, Valero
MC, De Lisio M, Boppart MD. Mesenchymal stem
cells contribute to vascular growth in skeletal muscle
in response to eccentric exercise. Am J Physiol Heart
Circ Physiol 304: H72–H81, 2013.
197. Iellamo F, Legramante JM, Massaro M, Raimondi
G, Galante A. Effects of a residential exercise
training on baroreflex sensitivity and heart rate
variability in patients with coronary artery dis-
ease: A randomized, controlled study. Circula-
tion 102: 2588–2592, 2000.
198. Inoue M, Senju S, Hirata S, Ikuta Y, Hayashida Y,
Irie A, Harao M, Imai K, Tomita Y, Tsunoda T,
Furukawa Y, Ito T, Nakamura Y, Baba H,
Nishimura Y. Identification of SPARC as a candi-
date target antigen for immunotherapy of vari-
ous cancers. Int J Cancer 127: 1393–1403, 2010.
199. Irrcher I, Ljubicic V, Hood DA. Interactions be-
tween ROS and AMP kinase activity in the regu-
lation of PGC-1alpha transcription in skeletal
muscle cells. Am J Physiol Cell Physiol 296:
C116–C123, 2009.
200. Isaksen B, Fagerhol MK. Calprotectin inhibits ma-
trix metalloproteinases by sequestration of zinc.
Mol Pathol 54: 289–292, 2001.
201. Izumiya Y, Bina HA, Ouchi N, Akasaki Y, Khari-
tonenkov A, Walsh K. FGF21 is an Akt-regulated
myokine. FEBS Lett 582: 3805–3810, 2008.
202. Jackson MJ. Free radicals generated by contract-
ing muscle: by-products of metabolism or key
regulators of muscle function? Free Radic Biol
Med 44: 132–141, 2008.
203. Jackson MJ, Papa S, Bolanos J, Bruckdorfer R,
Carlsen H, Elliott RM, Flier J, Griffiths HR, Heales
S, Holst B, Lorusso M, Lund E, Oivind Moskaug J,
Moser U, Di Paola M, Polidori MC, Signorile A,
Stahl W, Vina-Ribes J, Astley SB. Antioxidants,
reactive oxygen and nitrogen species, gene in-
duction and mitochondrial function. Mol Aspects
Med 23: 209–285, 2002.
204. Jacquemin V, Butler-Browne GS, Furling D, Mouly V.
IL-13 mediates the recruitment of reserve cells for
fusion during IGF-1-induced hypertrophy of human
myotubes. J Cell Sci 120: 670681, 2007.
205. Jamart C, Francaux M, Millet GY, Deldicque L,
Frere D, Feasson L. Modulation of autophagy