Download Aerobic exercise training promotes physiological cardiac

Am J Physiol Heart Circ Physiol 309: H543–H552, 2015.
First published June 12, 2015; doi:10.1152/ajpheart.00899.2014.
Review
Aerobic exercise training promotes physiological cardiac remodeling
involving a set of microRNAs
Tiago Fernandes,1 Valério G. Baraúna,2 Carlos E. Negrão,1,3 M. Ian Phillips,4 and Edilamar M. Oliveira1
1
School of Physical Education and Sport, University of São Paulo, São Paulo, Brazil; 2Department of Physiological Sciences,
Federal University of Espírito Santo, Vitoria, Brazil; 3Heart Institute (InCor), Medical School, University of São Paulo, São
Paulo, Brazil; and 4Laboratory of Stem Cells, Keck Graduate Institute, Claremont, California
Submitted 17 December 2014; accepted in final form 7 June 2015
cardiac hypertrophy; angiogenesis; swimming training; running training; microRNA
THIS ARTICLE is part of a collection on Exercise Training in
Cardiovascular Disease: Cell, Molecular, and Integrative
Perspectives. Other articles appearing in this collection, as
well as a full archive of all collections, can be found online at
http://ajpheart.physiology.org/.
EXERCISE TRAINING IS the most effective nonpharmacological
intervention to reduce cardiovascular disease (CVD). Its prescription is recommended by the guidelines of the most important entities, such as the American College of Sport Medicine and the American Heart Association (39).
Exercise training is well known to promote beneficial adaptations in the cardiovascular system which can vary according
to type, intensity, and duration of exercise (32). Exercise
training induces marked beneficial systemic effects on metabolism control, skeletal muscle, cognitive function, and cardio-
Address for reprint requests and other correspondence: E. M. Oliveira, Lab.
of Biochemistry and Molecular Biology of the Exercise School of Physical
Education and Sport, Univ. of São Paulo, Av. Professor Mello Moraes, 65
Cidade Universitária, São Paulo SP, 05508-900, Brazil (e-mail: edilamar
@usp.br).
http://www.ajpheart.org
vascular function (30, 39). Among them, the set of adaptations
induced in the myocardium are collectively referred to as
“athlete’s heart” and includes increased cardiac mass, formations of new blood vessels, and decreased collagen content
(15a, 17, 20, 23, 77, 91). Individuals with high levels of
physical activity have a lower prevalence and lower death rates
from CVD (32, 86). Thus exercise training has been established not only as a way to maintain a healthy lifestyle but also
as an important and safe nonpharmacological prescription for
prevention and treatment of CVD.
Pathological cardiac hypertrophy is associated with poor
prognosis and is a hallmark of heart failure (72, 73, 103). In
contrast, exercise training-induced physiological cardiac hypertrophy presents cardioprotective effects and is not related to
heart failure (74). Exercise training has been described as being
able to counteract structural and functional cardiac changes in
CVD by contributing to the phenotypical changes of pathological into physiological cardiac hypertrophy (31, 65, 73, 74).
Despite strong evidence linking exercise training to reduction in CVD risk, much uncertainty remains with regard to the
underlying mechanisms. Currently much more attention has
0363-6135/15 Copyright © 2015 the American Physiological Society
H543
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Fernandes T, Baraúna VG, Negrão CE, Phillips MI, Oliveira EM. Aerobic
exercise training promotes physiological cardiac remodeling involving a set of
microRNAs. Am J Physiol Heart Circ Physiol 309: H543–H552, 2015. First
published June 12, 2015; doi:10.1152/ajpheart.00899.2014.—Left ventricular (LV)
hypertrophy is an important physiological compensatory mechanism in response to
chronic increase in hemodynamic overload. There are two different forms of LV
hypertrophy, one physiological and another pathological. Aerobic exercise induces
beneficial physiological LV remodeling. The molecular/cellular mechanisms for
this effect are not totally known, and here we review various mechanisms including
the role of microRNA (miRNA). Studies in the heart, have identified antihypertrophic miRNA-1, -133, -26, -9, -98, -29, -378, and -145 and prohypertrophic
miRNA-143, -103, -130a, -146a, -21, -210, -221, -222, -27a/b, -199a/b, -208, -195,
-499, -34a/b/c, -497, -23a, and -15a/b. Four miRNAs are recognized as cardiacspecific: miRNA-1, -133a/b, -208a/b, and -499 and called myomiRs. In our studies
we have shown that miRNAs respond to swimming aerobic exercise by 1)
decreasing cardiac fibrosis through miRNA-29 increasing and inhibiting collagen,
2) increasing angiogenesis through miRNA-126 by inhibiting negative regulators of
the VEGF pathway, and 3) modulating the renin-angiotensin system through the
miRNAs-27a/b and -143. Exercise training also increases cardiomyocyte growth
and survival by swimming-regulated miRNA-1, -21, -27a/b, -29a/c, -30e, -99b,
-100, -124, -126, -133a/b, -143, -144, -145, -208a, and -222 and running-regulated
miRNA-1, -26, -27a, -133, -143, -150, and -222, which influence genes associated
with the heart remodeling and angiogenesis. We conclude that there is a potential
role of these miRNAs in promoting cardioprotective effects on physiological
growth.
Review
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EXERCISE TRAINING, CARDIAC HYPERTROPHY, AND microRNAs
Cardiac Remodeling Induced by Exercise Training
People engaged in chronic exercise programs have improved
cardiovascular function. This is observed not only in healthy
subjects but mainly in those with any type of cardiovascular
risk factor or disease (6, 39, 40). Even in people over 70 yr old,
exercise training can lower systolic, diastolic, and median
blood pressure (13). The health benefits of an active lifestyle
are multifactorial and include not only biological adaptation
but also changes in other social habits, such as decreases in
smoking and drinking excessive amounts of alcohol (27).
Exercise training reduces the body mass index by decreasing
adipocyte mass, increases insulin sensitivity as well as glucose
uptake, increases muscle strength and endurance, increases
antioxidant levels, and increases HDL, while decreasing LDL
and total triglycerides (43, 48, 95). From the cardiovascular
point of view, exercise training reduces both diastolic and
systolic blood pressure, increases the left ventricular (LV)
ejection fraction, decreases end-diastolic pressure, improves
vascular function, and increases cardiac angiogenesis and cardiac muscle mass (33, 60, 75). Among these adaptations, our
focus in this review will primarily be on the increase in cardiac
muscle mass termed herein as exercise training-induced cardiac hypertrophy.
Cardiac hypertrophy. Cardiac hypertrophy is an adaptive
response of the heart to increased cardiac workload and involves a variety of mechanical, hemodynamic, and hormonal
factors (70). Although any increase in heart mass is broadly
defined as a hypertrophic response, there are two very different
forms of ventricular hypertrophy, one physiological and another pathological (5). At the cellular level both hypertrophic
processes implicate in adaptations such as increased cardiomyocyte size, enhanced protein synthesis rate, and reorganizations
of the sarcomere structure; however, there are many differences that distinguish them and will be discussed below. First,
they should be distinguished by the structural and functional
adaptations as being physiological versus pathological remodeling; second, by the stimuli that induce the hypertrophy,
which are pressure versus volume overload (19, 59, 96).
Physiological cardiac hypertrophy may be exemplified by
the LV remodeling induced by exercise training, or pregnancy
or during the postnatal growth of the heart from the birth to
adulthood. It is also observed in other species such as in snakes
that LV mass can increase even after large meals (2). The LV
remodeling induced by physiological stimuli leads to preserved
or even enhanced LV function, decreased collagen content,
lack of fibrosis, increased angiogenesis, improved myocardial
antioxidant capacity (78), and decreased mitochondrial dysfunction (7) and has been shown to prevent cardiomyocyte
apoptosis (44).
Oppositely, pathological hypertrophy is associated with severe CVD illness that leads to increased risk of heart failure
arrhythmia and ultimately death (41). LV remodeling induced
by pathological stress leads to progressive declines in cardiac
output, myocardial rarefaction, increased apoptosis, cardiomyocyte metabolism switch from fatty acid to glucose use, and
increased fibrosis (35, 49).
Altogether, there are basically two ways to distinguish
between physiological and pathological cardiac hypertrophy:
pathological LV remodeling is accompanied by LV dysfunction (either diastolic, systolic, or both) (29) and disproportional
increase between muscle mass to angiogenesis (88), whereas
physiological LV remodeling preserves, or even enhances,
ventricular function and there is coordinated growth of both
muscle mass and angiogenesis (23, 74).
Different cardiac hypertrophy phenotypes at the molecular
level. At the molecular level, reexpression of fetal genes is used
as a biomarker of pathological cardiac hypertrophy. Among
them, atrial and brain natriuretic peptide, ␣-skeletal myosin,
and ␣- to ␤-myosin heavy chain (MHC) expression ratio have
been the most frequently reported (45, 51, 102). Although the
best known effects of atrial and brain natriuretic peptide are
natriuresis and blood pressure regulation, these small peptides
also contribute to preventing cardiac hypertrophy and fibrosis
in the adult heart (66). The main release factor of the atrial
peptides factor is the wall strain induced by the increased
workload, but other mechanisms are still being uncovered (96).
The ␣ and ␤ are subunits of the cardiac MHC filaments.
␣-MHC has the highest ATPase activity and contractile velocity, whereas the ␤-MHC has the lowest ATPase activity and
contractile velocity (36). A decreased ␣- to ␤-MHC expression
ratio has been found in pathological cardiac hypertrophy,
whereas exercise training prevents this response or even increases ␣- to ␤-MHC expression ratio (10, 67).
Although cardiac hypertrophy involves a variety of mechanical, hemodynamic, and hormonal factors, the main factor to
determine the morphological phenotype of LV remodeling is
the hemodynamic cardiac workload. Both pathological and
physiological cardiac hypertrophy may be triggered by pressure or volume cardiac overload. These two different stimuli
induce distinct morphological adaptations to the heart; in
particular, to the LV. The LV remodeling by pressure overload
is characterized by concentric hypertrophy, whereas LV remodeling by volume overload induces eccentric hypertrophy
(70). At the cellular level, concentric hypertrophy is characterized by parallel addition of new sarcomeres and lateral growth
of individual cardiomyocytes. This hypertrophy generally
leads to increased LV wall thickness with either decreased LV
chamber diameter (pathological) or no change on LV chamber
diameter (physiological exercise training induced) (34). The
eccentric hypertrophy due to volume overload is characterized
by addition of sarcomeres in series and longitudinal cardiomyocyte growth. The phenotype of this remodeling is typically
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been given to cellular and molecular mechanisms in an attempt
to distinguish between pathological and physiological cardiac
hypertrophy. Distinct intracellular pathways have been recognized in both situations and will be reviewed here in view of
their modulation by microRNAs (miRNAs). miRNAs, small
noncoding regions of the genome, are a new class of gene
regulators, which have been shown to play a key role in a
myriad of cellular processes, including growth, fibrosis, apoptosis, angiogenesis, and cardiac function under physiological
and pathological conditions.
miRNAs are considered promising therapeutic targets for
CVD (4, 15, 71, 74, 85, 90). We have found numerous
miRNAs that play specific roles in regulating gene expression
by exercise training (15a, 20, 21, 24, 65, 91) and confirmed by
Ma et al. (58) and Martinelli et al. (61). The aim of this review
is provide an overview of exercise training effects on physiological cardiac remodeling and the involvement of miRNAs in
this process.
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EXERCISE TRAINING, CARDIAC HYPERTROPHY, AND microRNAs
next section, we will focus on specific intracellular pathways
involved in LV remodeling induced by aerobic exercise training.
miRNAs, Cardiac Hypertrophy, and Exercise Training
miRNA: biogenesis and gene regulation. miRNAs comprise
a novel class of endogenous, small (⬃22 nucleotides in length),
noncoding RNAs that play important regulatory roles in many
physiological and pathological processes (71, 74, 90). There
are over 2,000 miRNAs known to be encoded in the human
genome, and collectively these miRNAs regulate the expression of thousands of protein-coding gene targets at posttranscriptional levels. Thus it is estimated that miRNAs regulate
⬃30% of human genes (4, 47, 71, 74, 90). All miRNAs from
humans and other species are included in the database
miRBase (v21.0, June 2014, http://www.mirbase.org).
The biogenesis of miRNAs is accomplished through sequential enzymatic reactions. miRNAs are initially transcribed by
RNA polymerase II in the nucleus to form large primary
transcript (pri-miRNA) transcripts and are polyadenylated at its
3=-end and capped at its 5=-extremity (4, 47). The pri-miRNAs
harbor a local hairpin structure that is then cropped by a
nuclear enzyme Drosha and their cofactor Pasha (also known
as DGCR8) into pre-miRNAs (⬃70 nucleotides). Together,
RanGTP and exportin 5 transport the pre-miRNA into the
cytoplasm. Subsequently, the enzyme Dicer removes the terminal loop of the pre-miRNAs to generate the miRNA duplex
(⬃22 nucleotides). The duplex is loaded into the miRNAassociated multiprotein RNA-induced silencing complex,
which includes the Argonaute proteins. One strand of the
miRNA is preferentially retained in this complex and becomes
the mature miRNA; the opposite strand, known as the passenger strand, is eliminated from the complex (4, 47, 50, 90).
Mature miRNAs can bind most commonly, but not exclusively, to 3=-untranslated regions of messenger RNAs
(mRNAs) of protein-coding genes and negatively regulate their
expression (4, 47, 71, 74, 90). The posttranscriptional regula-
Fig. 1. The schematic physiological cardiac
remodeling induced by exercise training. Exercise training is characterized by a uniform
profile of myocardium growth without fibrosis and cardiac dysfunction. Aerobic training
promotes eccentric hypertrophy with the addition of sarcomeres in series to lengthen the
cardiomyocyte and to increase the width of
the cell in parallel. In contrast, resistance
training promotes concentric hypertrophy
with the addition of sarcomeres in parallel to
an increase in cross-sectional cardiac area.
Mitochondrial RNA (miRNA)-1, -21, -26b,
-27a/b, -30e, -99b, -100, -124, -133a/b, -143,
-144, -145, -150, -208a, and -222 are involved in cardiomyocyte growth and survival, miRNA-29a/c regulate antifibrosis
process, and miRNA-126 modulates angiogenesis in response to aerobic exercise training.
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associated with LV dilatation (pathological) or proportional
increase in both LV dilatation and LV wall thickness (physiological exercise training induced) (34). Figure 1 exemplifies
both pressure and volume-induced physiological cardiac hypertrophy.
At this time, it should be highlighted that different exercise
training protocols predominantly change cardiac workload either by pressure or by volume overload, which leads to different cardiac hypertrophy phenotypes (57, 94) (Fig. 1).
The first observation of cardiac enlargement in trained individuals was by the Swedish clinician Henschen (42) and dates
back to the 1890s, but the first description of different types of
cardiac hypertrophy among athletes, resulting from different
modalities, was found by Mongaroth et al. (69) and came only
in 1975. Later, with the development of noninvasive and more
powerful devices for cardiovascular studies, the understanding
of the athlete’s heart phenomenon has progressed meaningfully.
Aerobic exercises such as running or swimming that involve
rhythmic contraction of large skeletal muscle mass, performed
for extended periods (e.g., 30 – 60 min), and that are dependent
on the supply of oxygen to the active muscles facilitate venous
return and increase the end-diastolic volume (volume overload
or increased preload) (69).
On the other hand, resistance or strength exercises, such as
weightlifting, involve smaller muscle mass, but strength contraction is limited to a few repetitions (generally, ⬍20) until
exhaustion and increases systemic vascular resistance (pressure
overload or increased afterload) because of isometric contraction with heavier loads. For example, systolic blood pressure
higher than 250 mmHg has been found during this type of
exercise (59). Finally, it should also be reminded that the
magnitude of cardiac hypertrophy is much less in response to
the resistance/strength exercises than aerobic exercises (92).
Although we and others have used an animal model of resistance training to study cardiovascular adaptations of physiological concentric cardiac hypertrophy (1, 3, 26), data are still
scarce with regard to the molecular mechanism involved. In the
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EXERCISE TRAINING, CARDIAC HYPERTROPHY, AND microRNAs
enriched in brain. Similarly, Carè et al. (8) showed that
miRNA-133 is also downregulated in hypertrophic hearts induced by transverse aortic constriction, which represses family
members of the Rho kinase, Ras homolog gene family-A, and
cell division control protein 42, as well as negative elongation
factor complex member A, a negative regulator of RNA
polymerase II. Studies have shown that Rho kinase inhibition
improves LV geometry and reduces collagen deposition accompanied by improved diastolic function in transverse aortic
constriction-induced cardiac hypertrophy (76). On the other
hand, Van Rooij et al. (95c) showed that overexpression of
miRNA-208a is required for cardiomyocyte hypertrophy, fibrosis, and expression of ␤-MHC in response to stress and
hypothyroidism. miRNA-208 targets purine-rich element-binding protein B (Pur␤), heterochromatin protein 1 (HP-1␤), and
transcription factors Sox6 and Sp3 related to MHC gene
switching mainly by stimulating ␤-MHC expression (95a). In
addition, overexpression of miRNA-499 also elicits cardiac
hypertrophy resulting in cardiac systolic dysfunction (87).
Therefore, new target genes and signaling pathways have been
described to regulate cardiac hypertrophy via myomiRs (15,
71, 74). Although miRNA studies predominate in the field of
cardiovascular disorders, little is known about their expression
patterns or role in physiological conditions, especially exercise-regulated miRNAs.
In the same way as miRNAs, long noncoding RNAs (lncRNAs) are part of the noncoding RNAs interacting with the
major pathways of cell growth, proliferation, differentiation,
and survival. Recently discovered, lncRNAs have been described as regulating gene expression and may act as miRNA
sponges to reduce miRNA levels (38, 97, 100). The number of
noncoding RNAs encoded within the human genome is unknown; however, recent transcriptomic and bioinformatic studies suggest that there are thousands of them (37). Notably,
Wang et al. (97) demonstrated that lncRNA, AK048451, which
the authors called of CHRF, sequesters the miRNA-489, preventing the miRNA from acting on its target gene myeloid
differentiation primary response gene 88. The authors described this as resulting from induced pathological cardiac
hypertrophy in response to angiotensin II treatment. Thus, for
the first time, the authors showed the participation of the
lncRNA-miRNA-mRNA axis in the cardiac hypertrophy, revealing a promising area of cardiovascular research that may
contribute to the understanding of physiological cardiac hypertrophy induced by exercise training.
Exercise training-regulated cardiac miRNAs. The miRNAs
are essential in different cell processes involved in the regulation of cardiovascular phenotypes, such as cardiomyocyte
growth, remodeling, and vascularization (15, 25, 90). miRNAs
have also been described as participating in the beneficial
adaptations promoted by exercise training, mainly physiological cardiac hypertrophy (8, 15a, 20, 24, 58, 61, 91) (Fig. 1).
Interestingly, in Table 1, we identified miRNAs and target
genes involved in physiological cardiac remodeling induced by
aerobic exercise training, both swimming and running exercises. Despite their importance, few studies have been conducted based on this concept. Carè et al. (8) conducted the first
study showing the effects of high-intensity interval training
(treadmill) on miRNA expression in cardiac hypertrophy. The
authors showed that miRNA-1 and -133 expression were reduced in both physiological cardiac hypertrophy induced by
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tion realized by the miRNAs in 3=-untranslated regions is
dependent on the degree of complementarity between them and
the target mRNA. Because of the fact that they have small
sequences and act without the need for complete pairing, a
single miRNA can regulate up to 200 mRNAs, and more than
one miRNA can regulate a single mRNA (50). Thus miRNAs
that bind to target mRNAs with imperfect complementarity
repress target gene expression via translational silencing. In
contrast, miRNAs that bind to their target mRNAs with
perfect complementarily induce mRNA degradation (4, 47,
50, 71, 74, 90).
miRNAs in the heart. miRNAs are emerging as pivotal
modulators of cardiovascular development and disease (74,
90). Although several miRNAs have been described since their
discovery in 1993 by Lee et al. (53), the knowledge of the
molecular mechanisms involved in numerous biological functions still need to be investigated. The first evidence that
miRNA plays a significant role in the development of the
cardiovascular system came from a study showing that the
deletion of Dicer, an enzyme key for miRNA processing,
disrupted embryonic angiogenesis during mouse development
(101). Later studies with specific deletion of Dicer in the heart
showed misexpression of cardiac contractile proteins and profound sarcomere disarray accompanied by dilated cardiomyopathy, heart failure, and postnatal lethality (11). Thus da
Costa Martins et al. (14) showed that conditional Dicer deletion in the postnatal myocardium promoted pathological cardiac remodeling and dysfunction, suggesting the important role
of miRNAs in the control of cardiovascular homeostasis.
The first studies of miRNA in cardiac hypertrophy used
microarray platforms to analyze the cardiac miRNA expression
signature after pathological stimuli (thoracic aortic-banded
mouse model and calcineurin-overexpressing transgenic mice)
and indicated that miRNAs are aberrantly expressed in hypertrophic mouse hearts (12, 15, 85, 95b). Over the last decade,
miRNA expression profile under either experimental or clinical
conditions of cardiac hypertrophy has been revealed, showing
miRNA downstream genes with hypertrophic targets. Studies
have identified antihypertrophic miRNAs (miRNA-1, -133,
-26, -9, -98, -29, -378, and -145) and prohypertrophic miRNAs
(miRNA-143, -103, -130a, -146a, -21, -210, -221, -222, -27a/b,
-199a/b, -208, -195, -499, -34a/b/c, -497, -23a, and -15a/b) in
the heart (15, 18, 71, 74). Antagomir and miR-mimic approaches, knockout mice, adenoviral vector, pharmacologic
inhibitors (2=-O-methyl-modified antisense oligonucleotides
and locked nucleic acid), and transgenic mice regulating
miRNA expression under control of the cardiac MHC-6 promoter have been used to silence or stimulate miRNAs anti- or
prohypertrophic, in vitro and in vivo studies (14, 17, 68, 71).
Abnormal miRNA regulation has been shown to be involved in
CVD, suggesting that miRNAs might affect cardiac structure
and function (15, 71, 74, 90).
Among the miRNAs described, four are recognized as cardiac-specific: miRNA-1, -133a/b, -208a/b, and -499, called
myomiRs. Sayed et al. (85) showed that cardiac miRNA-1 is
downregulated in hypertrophic hearts by transverse aortic constriction, and it is involved in post-mitotic muscle growth and
function through a serum response factor-dependent mechanism. This downregulation is required for the release of its
growth-related targets, including RasGTPase-activating protein, cyclin-dependent kinase 9, fibronectin, and Ras homolog
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EXERCISE TRAINING, CARDIAC HYPERTROPHY, AND microRNAs
Table 1. Effects of aerobic exercise training on miRNA expression in physiological cardiac remodeling
Exercise Training
miRNA
Target Gene
Outcome
Reference
2miRNA-1
2miRNA-133a
IGF-1, IGF-1R
RhoA, Cdc42, NelfA
Hypertrophy
8, 18
Swimming
(continuous exercise)
2miRNA-1
2miRNA-133a/b
—
RhoA, Cdc42, NelfA
Hypertrophy
23, 91
Swimming
(continuous exercise)
1miRNA-29a/c
Collagen I/III
Fibrosis
65, 91
Swimmimg
(continuous exercise)
2miRNA-208a
Pur␤
Hypertrophy
24
Swimming
(continuous exercise)
1miRNA-126
Spred-1, PI3KR2
Angiogenesis
89
Swimming
(continuous exercise)
1miRNA-27a/b
2miRNA-143
ECA
ECA2
Hypertrophy
20
Wheel running
(voluntary exercise)
2miRNA-27a
2miRNA-143
2miRNA-26b
1miRNA-150
GATA4*
Hypertrophy
61
Swimming
(continuous exercise)
1miRNA-21, -144
1miRNA-145
2miRNA-124
PTEN
TSC2
PI3K (p110␣)
Hypertrophy
58
Swimming
(continuous exercise)
1miRNA-30e
1miRNA-133b
1miRNA-208a
2miRNA-99b
2miRNA-100
Bcl-2
Hypertrophy
80
Swimming and wheel running (continuous exercise)
1miRNA-222
p27
HIPK1
HMBOX1
Hypertrophy
56
—
IGF-1,* PI3K*
GS3K-␤,* C-MYB*
—
—
IGF-1R, Akt, mTOR
IGF-1R, Akt, mTOR
*Predicted target gene. IGF-1, insulin-like growth factor 1; IGF-1R, insulin-like growth factor-1 receptor; GATA4; GATA binding protein 4; C-MYB, cellular
homolog of MYB avian myeloblastosis oncogene homolog; GS3K-␤, glycogen synthase kinase-3␤; PTEN, phosphatase and tensin homolog; TSC2, tuberous
sclerosis complex 2; ECA and ECA2, angiotensin-converting enzymes 1 and 2; Spred-1, sprouty-related protein 1; PI3KR2, phosphoinositol-3 kinase (PI3K)
regulatory subunit 2; Pur␤, purine-rich element binding protein B; RhoA, Ras homologue gene family-A; Cdc42, cell division control protein 42; NelfA, negative
elongation factor complex member A; Bcl-2, B-cell lymphoma 2; Akt, protein kinase B; mTOR, mammalian target of rapamycin; p27, cell-cycle inhibitor;
HIPK1, protein kinase; HMBOX1, transcriptional repressor.
interval training and by cardiac-specific Akt transgenic mice.
We also observed that miRNA-1 and -133a/b are similarly
downregulated in the eccentric cardiac hypertrophy induced by
two different swimming training protocols when compared
with the sedentary group (91). Irrespective of the exercise
(running or swimming) and volume training (moderate and
high), the expression profiles of these myomiRs were similar
among the studies (8, 91). Intriguingly, as described above,
these miRNAs were also reduced in pathological cardiac hypertrophy (8).
We also evaluated the expression of the myomiR-208a in the
heart of the animals subjected to the same two swimming
exercise training protocols. Unlike that found in pathological
hypertrophy (95a), the data showed a reduction in cardiac
miRNA-208a in the group with higher volume of exercise,
parallel to an increase in the target gene Pur␤ compared with
the sedentary group. Increased levels of Pur␤ inhibited ␤-MHC
expression accompanied by increased ␣-MHC and improved
ventricular compliance (24). Interestingly, higher levels of
circulating miRNA-208a and -499 have been used as systemic
biomarkers of cardiac damage in patients with CVD. In contrast, miRNA-208b and -499 levels were not changed after 24
h of a marathon run, whereas the miRNA-1, -133a, and -206
were correlated to performance parameters (maximum oxygen
consumption and running speed) indicating their potential role
as biomarkers of aerobic capacity (68).
In an attempt to explain the differences between pathological
and physiological cardiac hypertrophy based on miRNA signatures, Lin et al. (55) identified miRNAs differentially expressed in physiological cardiac hypertrophy using transgenic
mice with elevated cardiac phosphotidyinositol 3-kinase
(PI3K) activity, compared with pathological hypertrophy with
decreased PI3K activity and myocardial infarction. Although it
was not the effect of exercise training, the authors were the first
to detail a signature of miRNAs in physiological cardiac
hypertrophy, demonstrating a potential role of these miRNAs
in promoting cardioprotective effects on physiological growth.
PI3Ks catalyze the phosphorylation of membrane lipids,
known as the phosphoinositides, and thus activate a series of
intracellular signaling molecules such as Akt1, which is a
major downstream effector of PI3K. Akt1 is phosphorylated in
physiological cardiac hypertrophy and exerts diverse beneficial
functions such as inhibition of cardiomyocyte apoptosis, improvement in calcium transients, and cardiac hypertrophy (46,
62). A series of studies led by the McMullen’s group (63, 64,
98) has shown the role of insulin-like growth factor 1 (IGF1)/IGF-1 receptor (IGF-1R)/PI3K (110␣) in the development
of physiological cardiac hypertrophy.
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Running
(interval exercise)
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EXERCISE TRAINING, CARDIAC HYPERTROPHY, AND microRNAs
VEGF pathway by inhibiting Raf-1/ERK 1/2 and PI3K/Akt/
endothelial nitric oxide synthase (eNOS) pathways, respectively (25). Interestingly, our study revealed some of the
molecular mechanisms involved in physiological cardiac remodeling in response to exercise training. VEGF is considered
the most potent angiogenic factor and interacts with two
specific receptors: fms-like tyrosine kinase (Flt-1 or VEGFR1)
and fetal liver kinase (Flk-1 or VEGFR2). Once activated,
these receptors result in a series of intracellular signaling
pathways that lead to both angiogenic and vasodilator responses. One of the first effects of intracellular activation by
VEGF discovered was an increase in eNOS activity and expression. VEGF mediates the activation of ezrin/calpain/PI3K/
Akt cascade, which leads to eNOS Ser1179 phosphorylation
and Ca2⫹-independent nitric oxide generation (16). VEGF can
also activate AMPK activity through the Ca2⫹/calmodulin
pathway, which, in turn, also activates eNOS to induce angiogenesis and vasodilation (93). There are no doubts about the
role of VEGF as an important mediator of the exercise traininginduced angiogenic response, as has been reviewed elsewhere
(22, 79).
Fernandes et al. (20) showed increase of miRNA-27a and
-27b in cardiac hypertrophy induced by swimming training
targeting angiotensin-converting enzyme (ACE) in normotensive rats. Inactivation of the classic renin-angiotensin system
(RAS) by exercise training contributed to a physiological
cardiac hypertrophy by reducing the levels of ACE-ANG II
axis. In contrast, we observed a decrease of miRNA-143
targeting ACE2 in the heart of rats. Activation of nonclassic
RAS by exercise training counteracted the classic cardiac RAS
by stimulating ACE2-ANG-(1–7) axis in physiological cardiac
hypertrophy. Recently, Martinelli et al. (61) determined the
profile of miRNAs in voluntary exercise (wheel running)induced LV hypertrophy. In agreement with Fernandes et al.
(20), the authors also observed a reduction in the expression of
miRNA-143 with only 7 days of exercise training, but no
change in expression after 35 days of training. On the other
hand, the authors detected a reduction in miRNA-27a levels at
7 days of exercise training and no change in expression after 35
days of training. The different results in the studies could
mainly be due to the type, intensity, and duration of exercise
training used. Thus exercise training of greater intensity and
long duration has been shown to promote alterations in the
expression of miRNA-27a/b and -143 after periods of chronic
exercise involved in the physiological cardiac remodeling.
Martinelli et al. (61) also observed a reduction in miRNA26a expression after 7 days and increase in miRNA-150 expression after 35 days of voluntary wheel running exercise.
The predicted target genes of miRNA-26b and -150 may be
involved in physiological cardiac hypertrophy induced by
exercise training, since they are related to survival pathways,
such as IGF-1/PI3K signaling and glycogen synthase kinase3␤, respectively. Interestingly, Ma et al. (58) identified
miRNAs that target the PI3K/Akt/mammalian target of rapamycin (mTOR) signaling pathway in swimming training-induced cardiac hypertrophy. The authors observed that exercise
training increased cardiac miRNA-21 and -144 expression
associated with a reduction in their target gene phosphatase and
tensin homolog (negative regulator of the PI3K/Akt/mTOR
pathway). In addition, an increase in miRNA-145 was accompanied by a decrease in tuberous sclerosis complex 2 after
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IGF-1/IGF-1R intracellular signaling has been the moststudied pathway responsible for physiological cardiac hypertrophy. High-circulating levels of this factor are encountered
both during postnatal development and in response to exercise
training. IGF-1 is mainly produced by the liver but also by
cardiomyocytes in response to exercise (28). IGF-1R is a
tyrosine kinase receptor that, upon IGF-1 binding, activates the
PI3K-Akt cascade. Mice with constitutively active PI3K
(110␣) or overexpression of IGF-1 show increased heart
weight and are protected from ischemic injury and heart failure
(54, 55).
Our group was the first to identify miRNAs based on
miRNAs signature in cardiac hypertrophy induced by aerobic
exercise training (15a, 20, 91). Soci et al. (91) showed that the
expression of miRNA-29c, which targets the collagen gene,
increased in parallel with cardiac hypertrophy induced by both
swimming exercise training protocols (moderate and high exercise volume) correlated with a decrease in collagen I and III
expression and hydroxyproline concentration relevant to the
improved LV compliance and function. Thus miRNA-29 reduces collagen fibrosis in the physiologically hypertrophic
heart. On the other hand, low levels of miRNA-29 were
previously associated with fibrosis in myocardial infarction
(95d). Recently, Melo et al. (65) showed that swimming
training restored cardiac miRNA-29a and -29c levels and
prevented collagen type I and III expression on the border and
in the remote regions of the myocardial infarction, suggesting
the cardiac effect of exercise training in myocardial-infarcted
rats as a way to prevent or minimize the harmful effects in
CVD.
Similarly, Liu et al. (56) identified miRNAs signature in
physiological cardiac hypertrophy induced by two different
types of aerobic training: voluntary wheel running and ramp
swimming model. Interestingly, the authors showed that 55
miRNAs were differentially expressed by swimming, whereas
124 were differentially expressed by voluntary wheel running
and 16 were similarly regulated by two types of aerobic
training. miRNA-222 was chosen by to be upregulated in both
models of physiological cardiac hypertrophic targeting p27
(cell-cycle inhibitor), homeodomain-interacting protein kinase
1 (protein kinase), and homeobox-containing protein 1 (transcriptional repressor) genes involved in proliferation and hypertrophy of cardiomyocytes. Curiously, the authors were the
first to perform a functional study showing that the inhibition
of miRNA-222 in vivo blocks cardiac hypertrophy induced by
swimming. Moreover, miRNA-222 can be suggested as a
potential therapeutic target against pathological cardiac remodeling since it overexpression largely protected the heart from
damage caused by ischemic injury.
Angiogenesis, the growth of new blood vessels from existing vessels, is an important aspect of LV remodeling. In
physiological LV remodeling, there is coordinated growth of
both muscle mass and angiogenesis that is an important adaptation to enhance capacity and reserve to deliver oxygen to the
myocardium (52). Da Silva et al. (15a) investigated the role of
the miRNA-126 on cardiac angiogenesis induced by swimming
training. Exercise training promoted an increase in the expression of miRNA-126 and repression of their target genes
Spred-1 and PI3K regulatory subunit 2 related to vessel
growth. Sprouty-related, EVH1 domain-containing protein 1
and PI3K regulatory subunit 2 are negative regulators of the
Review
EXERCISE TRAINING, CARDIAC HYPERTROPHY, AND microRNAs
Conclusion
Exercise training has been widely recommended as a safe
and well-accepted nonpharmacological strategy to prevent
CVD and even restore cardiac function. We believe that by
understanding the molecular pathways behind the physiological cardiac adaptation induced by exercise training, we may
find new therapeutical targets to treat CVD. Among these new
targets, modulation of miRNAs seems to be a powerful therapy to
reach this goal. A potential therapeutic advantage of miRNAs is
that they target multiple genes involved in the same pathway
process which is different compared with traditional therapies
that target a single protein or gene. Furthermore, miRNA have
defined target with high specificity of treatment, long-duration
effect, and bioavailability, indicating miRNA therapy as a
more effective strategy. On the other hand, delivery, tissue
selectivity, and safety are important challenges of miRNAbased therapy to be overcome in the next years (9).
Surprisingly, little is known about the regulatory interaction
networks among the multiple classes of RNAs or the mechanisms regulated by exercise-induced miRNAs on physiological
cardiac remodeling. The analysis of miRNAs has made it
possible to understand the development of various types of
diseases. The elucidation of these processes regulated by
miRNAs and identification of new target genes in the pathogenesis of CVD are very valuable strategies for prevention and
treatment of the CVD. As reviewed here, very little is known
about the mechanisms regulated by exercise-induced miRNAs,
both by swimming and running, on physiological cardiac
remodeling.
Based on our findings and reports by other investigators, the
data indicate that different phenotypical changes observed in
response to both swimming and running exercise training can
be regulated by miRNAs and their target genes (Table 1 and
Fig. 1). A set of specific miRNAs contributes to the physiological cardiac remodeling induced by aerobic exercise training
(swimming regulated: miRNA-1, -21, -27a/b, -29a/c, -30e,
-99b, -100, -124, -126, -133a/b, -143, -144, -145, -208a, and
-222; and running-regulated: miRNA-1, -26, -27a, -133, -143,
-150, and -222), suggesting a potential role of these miRNAs in
promoting cardioprotective effects on physiological growth
(Fig. 1). Therefore, exercise-induced miRNAs, which could be
measured circulating in blood, could serve as predictors of
aerobic capacity required by the hypertrophic heart. Other
types of exercise training (i.e., resistance, interval and concurrent)-induced physiological cardiac hypertrophy can also be
promoted under the regulation of specific miRNAs, which may
also be important for the development of new therapies for
CVD. Further studies are still required to evaluate cardiac
miRNA signatures under pathological and physiological conditions. In addition, the functional role of miRNAs in the
physiological cardiac remodeling induced by exercise training
could increase our understanding of cardiac remodeling mechanisms.
GRANTS
This study was supported by Fundação de Amparo à Pesquisa do Estado de
São Paulo Grant FAPESP-2010/50048-1, as well as Grant FAPESP/SPRINT
2014/50673-4 (to E. M. Oliveira and M. I. Phillips); Conselho Nacional de
Desenvolvimento Científico e Tecnológico Grants CNPq-308267/2013-3,
476515/2012-2, and 485873/2012-5 and USP/PRP-NAPmiR and Pro-Infra;
and National Heart, Lung, and Blood Institute Grant R01-HL077602 (to M. I.
Phillips).
DISCLOSURES
No conflicts of interest, financial or otherwise, are declared by the author(s).
AUTHOR CONTRIBUTIONS
T.F., V.G.B., and E.M.O. conception and design of research; T.F. prepared
figures; T.F., V.G.B., M.I.P., and E.M.O. drafted manuscript; T.F., V.G.B.,
C.E.N., M.I.P., and E.M.O. approved final version of manuscript; C.E.N.,
M.I.P., and E.M.O. edited and revised manuscript.
REFERENCES
1. Alves JP, Nunes RB, Stefani GP, Dal Lago P. Resistance training
improves hemodynamic function, collagen deposition and inflammatory
profiles: experimental model of heart failure. PLoS One 9: e110317,
2014.
2. Andersen JB, Rourke BC, Caiozzo VJ, Bennett AF, Hicks JW.
Physiology: postprandial cardiac hypertrophy in pythons. Nature 434:
37–38, 2005.
3. Barauna VG, Magalhaes FC, Krieger JE, Oliveira EM. AT1 receptor
participates in the cardiac hypertrophy induced by resistance training in
rats. Am J Physiol Regul Integr Comp Physiol 295: R381–R387, 2008.
4. Bartel DP. MicroRNAs: genomics, biogenesis, mechanism, and function. Cell 116: 281–297, 2004.
5. Bernardo BC, Weeks KL, Pretorius L, McMullen JR. Molecular
distinction between physiological and pathological cardiac hypertrophy:
experimental findings and therapeutic strategies. Pharmacol Ther 128:
191–227, 2010.
6. Booth FW, Gordon SE, Carlson CJ, Hamilton MT. Waging war on
modern chronic diseases: primary prevention through exercise biology. J
Appl Physiol 88: 774 –787, 2000.
7. Campos JC, Gomes KM, Ferreira JCB. Impact of exercise training on
redox signaling in cardiovascular diseases. Food Chem Toxicol 62:
107–19, 2013.
8. Carè A, Catalucci D, Felicetti F, Bonci D, Addario A, Gallo P, Bang
ML, Segnalini P, Gu Y, Dalton ND, Elia L, Latronico MVG, Høydal
M, Autore C, Russo MA, Dorn GW, Ellingsen O, Ruiz-Lozano P,
Peterson KL, Croce CM, Peschle C, Condorelli G. MicroRNA-133
controls cardiac hypertrophy. Nat Med 13: 613–618, 2007.
9. Caroli A, Cardillo MT, Galea R, Biasucci LM. Potential therapeutic
role of microRNAs in ischemic heart disease. J Cardiol 61: 315–320,
2013.
10. Chain H, Myocardium FV, Lowes BD, Minobe W, Abraham WT,
Rizeq MN, Bohlmeyer TJ, Quaife RA, Roden RL, Dutcher DL,
Robertson AD, Voelkel NF, Badesch DB, Groves BM, Gilbert EM,
Bristow MR. Changes in Gene Expression in the Intact Human Heart. J
Clin Invest 100: 2315–2324, 1997.
AJP-Heart Circ Physiol • doi:10.1152/ajpheart.00899.2014 • www.ajpheart.org
Downloaded from http://ajpheart.physiology.org/ by 10.220.33.4 on October 26, 2016
swimming training (another negative regulator of the PI3K/
Akt/mTOR pathway). In contrast, exercise training decreased
cardiac miRNA-124 expression associated with an increase in
their target gene PI3K (p110-␣) involved in physiological
hypertrophy. Recently, Ramasamy et al. (80) also performed
microarray miRNA in swimming training-induced cardiac
hypertrophy, indicating that miRNA-30e, -133b, and -208
were significantly upregulated and miRNA-99b and -100
were significantly downregulated after real-time PCR confirmation in healthy rats. Target genes that regulate proliferation
and cell death were showed, suggesting that PI3/Akt/mTOR,
MAPK, and p53 signaling are involved in physiological cardiac growth.
Altogether, these data suggest that exercise training, both
swimming and running, can promote physiological cardiac
remodeling through regulation of specific target genes by
miRNAs. These exercise training-induced adaptations might
provide the additional aerobic performance required by the
exercised heart.
H549
Review
H550
EXERCISE TRAINING, CARDIAC HYPERTROPHY, AND microRNAs
31. Garciarena CD, Pinilla OA, Nolly MB, Laguens RP, Escudero EM,
Cingolani HE, Ennis IL. Endurance training in the spontaneously
hypertensive rat conversion of pathological into physiological cardiac
hypertrophy. Hypertension 53: 708 –714, 2009.
32. Golbidi S, Laher I. Exercise and the cardiovascular system. Cardiol Res
Pract 2012: 210852, 2012.
33. Gomez-Cabrera MC, Domenech E, Viña J. Moderate exercise is an
antioxidant: upregulation of antioxidant genes by training. Free Radic
Biol Med 44: 126 –131, 2008.
34. Grossman W, Jones D, McLaurin LP. Wall stress and patterns of
hypertrophy in the human left ventricle. J Clin Invest 56: 56 –64, 1975.
35. Gullestad L, Ueland T, Vinge LE, Finsen A, Yndestad A, Aukrust P.
Inflammatory cytokines in heart failure: mediators and markers. Cardiology 122: 23–35, 2012.
36. Gustafson TA, Bahl JJ, Markham BE, Roeske WR, Morkin E.
Hormonal regulation of myosin heavy chain and alpha-actin gene expression in cultured fetal rat heart myocytes. J Biol Chem 262: 13316 –
13322, 1987.
37. Hangauer MJ, Vaughn IW, McManus MT. Pervasive transcription of
the human genome produces thousands of previously unidentified long
intergenic noncoding RNAs. PLoS Genet 9: e1003569, 2013.
38. Hansen TB, Jensen TI, Clausen BH, Bramsen JB, Finsen B,
Damgaard CK, Kjems J. Natural RNA circles function as efficient
microRNA sponges. Nature 495: 384 –388, 2013.
39. Haskell WL, Lee IM, Pate RR, Powell KE, Blair SN, Franklin BA,
Macera CA, Heath GW, Thompson PD, Bauman A. Physical activity
and public health: updated recommendation for adults from the American
College of Sports Medicine and the American Heart Association. Circulation 116: 1081–1093, 2007.
40. Haykowsky MJ, Liang Y, Pechter D, Jones LW, McAlister FA,
Clark AM. A meta-analysis of the effect of exercise training on left
ventricular remodeling in heart failure patients: the benefit depends on
the type of training performed. J Am Coll Cardiol 49: 2329 –2336, 2007.
41. Hein S, Arnon E, Kostin S, Schönburg M, Elsässer A, Polyakova V,
Bauer EP, Klövekorn WP, Schaper J. Progression from compensated
hypertrophy to failure in the pressure-overloaded human: heart structural
deterioration and compensatory mechanisms. Circulation 107: 984 –991,
2003.
42. Henschen S. Skidlauf und Skidwettlauf. Eine medizinische Sportstudie.
Mitt Med Klin Upsala 2: 15, 1899.
43. Huang CJ, Webb HE, Zourdos MC, Acevedo EO. Cardiovascular
reactivity, stress, and physical activity. Front Physiol 4: 314, 2013.
44. Huang CY, Yang AL, Lin YM, Wu FN, Lin JA, Chan YS, Tsai FJ,
Tsai CH, Kuo CH, Lee SD. Anti-apoptotic and pro-survival effects of
exercise training on hypertensive hearts. J Appl Physiol 112: 883–891,
2012.
45. Izumo S, Nadal-Ginard B, Mahdavi V. Protooncogene induction and
reprogramming of cardiac gene expression produced by pressure overload. Proc Natl Acad Sci USA 85: 339 –43, 1988.
46. Kim KS, Abraham D, Williams B, Violin JD, Mao L, Rockman HA.
␤-Arrestin-biased AT1R stimulation promotes cell survival during acute
cardiac injury. Am J Physiol Heart Circ Physiol 303: H1001–H1010,
2012.
47. Kim VN. MicroRNA biogenesis: coordinated cropping and dicing. Nat
Rev Mol Cell Biol 6: 376 –385, 2005.
48. Kolka C. Treating diabetes with exercise—focus on the microvasculature. J Diabetes Metab 4: 308, 2013.
49. Kolwicz SC, Purohit S, Tian R. Cardiac metabolism and its interactions
with contraction, growth, and survival of cardiomyocytes. Circ Res 113:
603–616, 2013.
50. Krek A, Grün D, Poy MN, Wolf R, Rosenberg L, Epstein EJ,
MacMenamin P, da Piedade I, Gunsalus KC, Stoffel M, Rajewsky N.
Combinatorial microRNA target predictions. Nat Genet 37: 495–500,
2005.
51. Kuster DW, Merkus D, Blonden LA, Kremer A, van IJcken WF,
Verhoeven AJ, Duncker DJ. Gene reprogramming in exercise-induced
cardiac hypertrophy in swine: a transcriptional genomics approach. J Mol
Cell Cardiol 77: 168 –174, 2014.
52. Laughlin MH, Bowles DK, Duncker DJ. The coronary circulation in
exercise training. Am J Physiol Heart Circ Physiol 302: H10 –H23, 2012.
53. Lee RC, Feinbaum RL, Ambros V. The C. elegans heterochronic gene
lin-4 encodes small RNAs with antisense complementarity to lin-14. Cell
75: 843–854, 1993.
AJP-Heart Circ Physiol • doi:10.1152/ajpheart.00899.2014 • www.ajpheart.org
Downloaded from http://ajpheart.physiology.org/ by 10.220.33.4 on October 26, 2016
11. Chen JF, Murchison EP, Tang R, Callis TE, Tatsuguchi M, Deng Z,
Rojas M, Hammond SM, Schneider MD, Selzman CH, Meissner G,
Patterson C, Hannon GJ, Wang DZ. Targeted deletion of Dicer in the
heart leads to dilated cardiomyopathy and heart failure. Proc Natl Acad
Sci USA 105: 2111–2116, 2008.
12. Cheng Y, Ji R, Yue J, Yang J, Liu X, Chen H, Dean DB, Zhang C.
MicroRNAs are aberrantly expressed in hypertrophic heart: do they play
a role in cardiac hypertrophy? Am J Pathol 170: 1831–1840, 2007.
13. Cononie CC, Graves JE, Pollock ML, Phillips MI, Sumners C,
Hagberg JM. Effect of exercise training on blood pressure in 70- to
79-yr-old men and women. Med Sci Sports Exerc 23: 505–511, 1991.
14. Da Costa Martins PA, Bourajjaj M, Gladka M, Kortland M, Van
Oort RJ, Pinto YM, Molkentin JD, De Windt LJ. Conditional Dicer
gene deletion in the postnatal myocardium provokes spontaneous cardiac
remodeling. Circulation 118: 1567–1576, 2008.
15. Da Costa Martins PA, De Windt LJ. MicroRNAs in control of cardiac
hypertrophy. Cardiovasc Res 93: 563–572, 2012.
15a.Da Silva ND, Fernandes T, Soci UP, Monteiro AW, Phillips MI, De
Oliveira EM. Swimming training in rats increases cardiac MicroRNA126 expression and angiogenesis. Med Sci Sports Exerc 44: 1453–1462,
2012.
16. Dimmeler S, Fleming I, Fisslthaler B, Hermann C, Busse R, Zeiher
AM. Activation of nitric oxide synthase in endothelial cells by Aktdependent phosphorylation. Nature 399: 601–605, 1999.
17. Dorn GW. The fuzzy logic of physiological cardiac hypertrophy. Hypertension 49: 962–970, 2007.
18. Elia L, Contu R, Quintavalle M, Varrone F, Chimenti C, Russo MA,
Cimino V, De Marinis L, Frustaci A, Catalucci D, Condorelli G.
Reciprocal regulation of microrna-1 and insulin-like growth factor-1
signal transduction cascade in cardiac and skeletal muscle in physiological and pathological conditions. Circulation 120: 2377–2385, 2009.
19. Ellison GM, Waring CD, Vicinanza C, Torella D. Physiological
cardiac remodelling in response to endurance exercise training: cellular
and molecular mechanisms. Heart 98: 5–10, 2012.
20. Fernandes T, Hashimoto NY, Magalhães FC, Fernandes FB, Casarini DE, Carmona AK, Krieger JE, Phillips MI, Oliveira EM.
Aerobic exercise training-induced left ventricular hypertrophy involves
regulatory MicroRNAs, decreased angiotensin-converting enzyme-angiotensin II, and synergistic regulation of angiotensin-converting enzyme
2-angiotensin (1–7). Hypertension 58: 182–189, 2011.
21. Fernandes T, Magalhães FC, Roque FR, Phillips MI, Oliveira EM.
Exercise training prevents the microvascular rarefaction in hypertension
balancing angiogenic and apoptotic factors: role of microRNAs-16, -21,
and -126. Hypertension 59: 513–520, 2012.
22. Fernandes T, Nakamuta JS, Magalhães FC, Roque FR, LaviniRamos C, Schettert IT, Coelho V, Krieger JE, Oliveira EM. Exercise
training restores the endothelial progenitor cells number and function in
hypertension. J Hypertens 30: 2133–2143, 2012.
23. Fernandes T, Soci UP, Oliveira EM. Eccentric and concentric cardiac
hypertrophy induced by exercise training: microRNAs and molecular
determinants. Braz J Med Biol Res 44: 836 –847, 2011.
24. Fernandes T, Soci UP, Oliveira EM. MiRNA-208a targeting Pur␤ gene
regulates the ␤-MHC content in cardiac hypertrophy induced by exercise
training. Circ Res 128: A21942, 2013.
25. Fish JE, Santoro MM, Morton SU, Yu S, Yeh RF, Wythe JD, Ivey
KN, Bruneau BG, Stainier DYR, Srivastava D. miR-126 regulates
angiogenic signaling and vascular integrity. Dev Cell 15: 272–284, 2008.
26. Fontes MT, Silva TL, Mota MM, Barreto AS, Rossoni LV, Santos
MR. Resistance exercise acutely enhances mesenteric artery insulininduced relaxation in healthy rats. Life Sci 94: 24 –29, 2014.
27. Franklin BA, Cushman M. Recent advances in preventive cardiology
and lifestyle medicine: a themed series. Circulation 123: 2274 –2283,
2011.
28. Frystyk J. Exercise and the growth hormone-insulin-like growth factor
axis. Med Sci Sports Exerc 42: 58 –66, 2010.
29. Gaasch WH, Zile MR. Left ventricular structural remodeling in health
and disease: with special emphasis on volume, mass, and geometry. J Am
Coll Cardiol 58: 1733–40, 2011.
30. Garber CE, Blissmer B, Deschenes MR, Franklin BA, Lamonte MJ,
Lee IM, Nieman DC, Swain DP. Quantity and quality of exercise for
developing and maintaining cardiorespiratory, musculoskeletal, and neuromotor fitness in apparently healthy adults: guidance for prescribing
exercise. Med Sci Sports Exerc 43: 1334 –1359, 2011.
Review
EXERCISE TRAINING, CARDIAC HYPERTROPHY, AND microRNAs
75. Pal S, Radavelli-Bagatini S, Ho S. Potential benefits of exercise on
blood pressure and vascular function. J Am Soc Hypertens 7: 494 –506,
2013.
76. Phrommintikul A, Tran L, Kompa A, Wang B, Adrahtas A,
Cantwell D, Kelly DJ, Krum H. Effects of a Rho kinase inhibitor on
pressure overload induced cardiac hypertrophy and associated diastolic dysfunction. Am J Physiol Heart Circ Physiol 294: H1804 –
H1814, 2008.
77. Pluim BM, Zwinderman AH, van der Laarse A, van der Wall EE.
The athlete’s heart. A meta-analysis of cardiac structure and function.
Circulation 101: 336 –344, 2000.
78. Powers SK, Sollanek KJ, Wiggs MP, Demirel HA, Smuder AJ.
Exercise-induced improvements in myocardial antioxidant capacity: the
antioxidant players and cardioprotection. Free Radic Res 48: 43–51,
2014.
79. Prior BM, Yang HT, Terjung RL. What makes vessels grow with
exercise training? J Appl Physiol 97: 1119 –1128, 2004.
80. Ramasamy S, Velmurugan G, Shanmugha Rajan K, Ramprasath T,
Kalpana K. MiRNAs with apoptosis regulating potential are differentially expressed in chronic exercise-induced physiologically hypertrophied hearts. PLoS One 10: e0121401, 2015.
85. Sayed D, Hong C, Chen IY, Lypowy J, Abdellatif M. MicroRNAs play
an essential role in the development of cardiac hypertrophy. Circ Res
100: 416 –424, 2007.
86. Shephard RJ, Balady GJ. Exercise as cardiovascular therapy. Circulation 99: 963–972, 1999.
87. Shieh JT, Huang Y, Gilmore J, Srivastava D. Elevated miR-499 levels
blunt the cardiac stress response. PLoS One 6: e19481, 2011.
88. Shiojima I, Sato K, Izumiya Y, Schiekofer S, Ito M, Liao R, Colucci
WS, Walsh K. Disruption of coordinated cardiac hypertrophy and
angiogenesis contributes to the transition to heart failure. J Clin Invest
115: 2108 –2118, 2005.
90. Small EM, Olson EN. Pervasive roles of microRNAs in cardiovascular
biology. Nature 469: 336 –342, 2011.
91. Soci UP, Fernandes T, Hashimoto NY, Mota GF, Amadeu MA,
Rosa KT, Irigoyen MC, Phillips MI, Oliveira EM. MicroRNAs 29
are involved in the improvement of ventricular compliance promoted
by aerobic exercise training in rats. Physiol Genomics 43: 665–673,
2011.
92. Spence AL, Naylor LH, Carter HH, Buck CL, Dembo L, Murray CP,
Watson P, Oxborough D, George KP, Green DJ. A prospective
randomised longitudinal MRI study of left ventricular adaptation to
endurance and resistance exercise training in humans. J Physiol 589:
5443–5452, 2011.
93. Stahmann N, Woods A, Spengler K, Heslegrave A, Bauer R, Krause
S, Viollet B, Carling D, Heller R. Activation of AMP-activated protein
kinase by vascular endothelial growth factor mediates endothelial angiogenesis independently of nitric-oxide synthase. J Biol Chem 285: 10638 –
10652, 2010.
94. Starnes JW, Taylor RP. Exercise-induced cardioprotection: endogenous mechanisms. Med Sci Sports Exerc 39: 1537–1543, 2007.
95. Swift DL, Johannsen NM, Lavie CJ, Earnest CP, Church TS. The
role of exercise and physical activity in weight loss and maintenance.
Prog Cardiovasc Dis 56: 441–447, 2014.
95a.Van Rooij E, Quiat D, Johnson BA, Sutherland LB, Qi X, Richardson JA, Kelm RJ, Olson EN. A family of microRNAs encoded by
myosin genes governs myosin expression and muscle performance. Dev
Cell 17: 662–673, 2009.
95b.Van Rooij E, Sutherland LB, Liu N, Williams AH, McAnally J,
Gerard RD, Richardson JA, Olson EN. A signature pattern of stressresponsive microRNAs that can evoke cardiac hypertrophy and heart
failure. Proc Natl Acad Sci USA 103: 18255–18260, 2006.
95c.Van Rooij E, Sutherland LB, Qi X, Richardson JA, Hill J, Olson EN.
Control of stress-dependent cardiac growth and gene expression by a
microRNA. Science 316: 575–579, 2007.
95d.Van Rooij E, Sutherland LB, Thatcher JE, DiMaio JM, Naseem RH,
Marshall WS, Hill JA, Olson EN. Dysregulation of microRNAs after
myocardial infarction reveals a role of miR-29 in cardiac fibrosis. Proc
Natl Acad Sci USA 105: 13027–13032, 2008.
96. Volpe M. Natriuretic peptides and cardio-renal disease. Int J Cardiol
176: 630 –639, 2014.
AJP-Heart Circ Physiol • doi:10.1152/ajpheart.00899.2014 • www.ajpheart.org
Downloaded from http://ajpheart.physiology.org/ by 10.220.33.4 on October 26, 2016
54. Li B, Setoguchi M, Wang X, Andreoli AM, Leri A, Malhotra A,
Kajstura J, Anversa P. Insulin-like growth factor-1 attenuates the
detrimental impact of nonocclusive coronary artery constriction on the
heart. Circ Res 84: 1007–1019, 1999.
55. Lin RC, Weeks KL, Gao XM, Williams RB, Bernardo BC, Kiriazis
H, Matthews VB, Woodcock EA, Bouwman RD, Mollica JP, Speirs
HJ, Dawes IW, Daly RJ, Shioi T, Izumo S, Febbraio MA, Du XJ,
McMullen JR. PI3K (p110␣) protects against myocardial infarctioninduced heart failure: Identification of PI3K-regulated miRNA and
mRNA. Arterioscler Thromb Vasc Biol 30: 724 –732, 2010.
56. Liu X, Xiao J, Zhu H, Wei X, Platt C, Damilano F, Xiao C,
Bezzerides V, Boström P, Che L, Zhang C, Spiegelman BM, Rosenzweig A. miR-222 is necessary for exercise-induced cardiac growth and
protects against pathological cardiac remodeling. Cell Metab 21: 584 –
595, 2015.
57. Longhurst JC, Stebbins CL. The power athlete. Cardiol Clin 15:
413–29, 1997.
58. Ma Z, Qi J, Meng S, Wen B, Zhang J. Swimming exercise traininginduced left ventricular hypertrophy involves microRNAs and synergistic regulation of the PI3K/AKT/mTOR signaling pathway. Eur J Appl
Physiol 113: 2473–2486, 2013.
59. MacDougall JD, Tuxen D, Sale DG, Moroz JR, Sutton JR. Arterial
blood pressure response to heavy resistance exercise. J Appl Physiol 58:
785–790, 1985.
60. Mann N, Rosenzweig A. Can exercise teach us how to treat heart
disease? Circulation 126: 2625–2635, 2012.
61. Martinelli NC, Cohen CR, Santos KG, Castro MA, Biolo A, Frick L,
Silvello D, Lopes A, Schneider S, Andrades ME, Clausell N, Matte U,
Rohde LE. An analysis of the global expression of microRNAs in an
experimental model of physiological left ventricular hypertrophy. PLoS
One 9: e93271, 2014.
62. Matsui T, Nagoshi T, Rosenzweig A. Akt and PI 3-kinase signaling in
cardiomyocyte hypertrophy and survival. Cell Cycle 2: 220 –223, 2003.
63. McMullen JR, Shioi T, Huang WY, Zhang L, Tarnavski O, Bisping
E, Schinke M, Kong S, Sherwood MC, Brown J, Riggi L, Kang PM,
Izumo S. The insulin-like growth factor 1 receptor induces physiological
heart growth via the phosphoinositide 3-kinase (p110alpha) pathway. J
Biol Chem 279: 4782–4793, 2004.
64. McMullen JR, Shioi T, Zhang L, Tarnavski O, Sherwood MC, Kang
PM, Izumo S. Phosphoinositide 3-kinase (p110alpha) plays a critical
role for the induction of physiological, but not pathological, cardiac
hypertrophy. Proc Natl Acad Sci USA 100: 12355–12360, 2003.
65. Melo SF, Fernandes T, Baraúna VG, Matos KC, Santos AA, Tucci
PJ, Oliveira EM. Expression of microRNA-29 and collagen in cardiac
muscle after swimming training in myocardial-infarcted rats. Cell
Physiol Biochem 33: 657–669, 2014.
66. Mitsui T. Notes on the peroxidase activity of human basophil leukocytes.
Tokai J Exp Clin Med 13: 1–8, 1988.
67. Miyata S, Minobe W, Bristow MR, Leinwand LA. Myosin heavy
chain isoform expression in the failing and nonfailing human heart. Circ
Res 86: 386 –390, 2000.
68. Mooren FC, Viereck J, Kruger K, Thum T. Circulating microRNAs as
potential biomarkers of aerobic exercise capacity. Am J Physiol Heart
Circ Physiol 306: H557–H563, 2014.
69. Morganroth J, Maron BJ, Henry WL, Epstein SE. Comparative left
ventricular dimensions in trained athletes. Ann Intern Med 82: 521–524,
1975.
70. Nadruz W. Myocardial remodeling in hypertension. J Hum Hypertens
29: 1–6, 2015.
71. Neves Das VJ, Fernandes T, Roque FR, Soci UP, Melo SF, de
Oliveira EM. Exercise training in hypertension: role of microRNAs.
World J Cardiol 6: 713–727, 2014.
72. Oliveira EM, Krieger JE. Chronic ␤-adrenoceptor stimulation and
cardiac hypertrophy with no induction of circulating renin. Eur J Pharmacol 520: 135–141, 2005.
73. Oliveira RS, Ferreira JC, Gomes ER, Paixão NA, Rolim NP, Medeiros A, Guatimosim S, Brum PC. Cardiac anti-remodelling effect of
aerobic training is associated with a reduction in the calcineurin/NFAT
signalling pathway in heart failure mice. J Physiol 587: 3899 –3910,
2009.
74. Ooi JY, Bernardo BC, McMullen JR. The therapeutic potential of
miRNAs regulated in settings of physiological cardiac hypertrophy.
Future Med Chem 6: 205–222, 2014.
H551
Review
H552
EXERCISE TRAINING, CARDIAC HYPERTROPHY, AND microRNAs
97. Wang K, Liu F, Zhou LY, Long B, Yuan SM, Wang Y, Liu CY, Sun
T, Zhang XJ, Li PF. The long noncoding RNA CHRF regulates cardiac
hypertrophy by targeting miR-489. Circ Res 114: 1377–1388, 2014.
98. Weeks KL, McMullen JR. The athlete’s heart vs. the failing heart: can
signaling explain the two distinct outcomes? Physiology (Bethesda) 26:
97–105, 2011.
100. Wu C, Arora P. Long noncoding RNA-MicroRNA-mRNA: a novel
tripartite axis in the regulation of cardiac hypertrophy. Circ Cardiovasc
Genet 7: 729 –731, 2014.
101. Yang WJ, Yang DD, Na S, Sandusky GE, Zhang Q, Zhao G. Dicer is
required for embryonic angiogenesis during mouse development. J Biol
Chem 280: 9330 –9335, 2005.
102. Yap Bin L, Mukerjee D, Timms PM, Ashrafian H, Coghlan JG.
Natriuretic peptides, respiratory disease, and the right heart. Chest 126:
1330 –1336, 2004.
103. Zile MR, Gaasch WH, Patel K, Aban IB Ahmed A. Adverse left
ventricular remodeling in community-dwelling older adults predicts
incident heart failure and mortality. JACC Heart Fail 2: 512–522, 2014.
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