Download Aerobic Exercise Training Promotes Physiological Cardiac

Articles in PresS. Am J Physiol Heart Circ Physiol (June 12, 2015). doi:10.1152/ajpheart.00899.2014
1
Aerobic Exercise Training Promotes Physiological Cardiac Remodeling Involving a Set of
2
MicroRNAs
3
4
Tiago Fernandes1; Valério G. Baraúna2; Carlos E. Negrão1, 3; M. Ian. Phillips4; and Edilamar M.
5
Oliveira1
6
7
1
8
2
9
3
10
4
University of Sao Paulo, School of Physical Education and Sport, Sao Paulo, Brazil
Federal University of Espírito Santo, Department of Physiological Sciences, Vitoria, Brazil
University of Sao Paulo, Heart Institute (InCor), Medical School, Sao Paulo, Brazil
Keck Graduate Institute, Laboratory of Stem Cells, Claremont, CA, USA
11
12
13
Exercise Training, Cardiac Hypertrophy and microRNAs
14
15
16
Author for correspondence:
17
Edilamar Menezes de Oliveira, PhD
18
Laboratory of Biochemistry and Molecular Biology of the Exercise
19
School of Physical Education and Sport - University of Sao Paulo
20
Av. Professor Mello Moraes, 65 Cidade Universitária, São Paulo SP, 05508-900 Brazil.
21
Phone: (55-11) 3091-2118, FAX: (55-11) 3813-5921
22
E-mail: [email protected]
1
Copyright © 2015 by the American Physiological Society.
23
Author contributions:
24
Fernandes T, Barauna VG and Oliveira EM: drafted manuscript;
25
Fernandes T, Barauna VG and Oliveira EM: organizer;
26
Phillips MI, Negrão CE and Oliveira EM: edited and revised manuscript.
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
2
51
Abstract
52
Left ventricular (LV) hypertrophy is an important physiological compensatory
53
mechanism in response to chronic increase in hemodynamic overload. There are two
54
different forms of LV hypertrophy, one physiological and another pathological. Aerobic
55
exercise induces beneficial physiological LV remodeling. The molecular/cellular mechanisms
56
for this effect are not totally known and here we review various mechanisms including the
57
role of microRNA (miRNA). Studies in the heart, have identified anti-hypertrophic miRNA-1, -
58
133, -26, -9, -98, -29, -378 and -145 and pro-hypertrophic miRNAs-143, -103, -130a, -146a, -
59
21, -210, -221, -222,- 27a/b, -199a/b, -208, -195, -499, -34a/b/c, -497, -23a, -15a/b). Four
60
miRNAs are recognized as cardiac-specific, miRNA-1, -133a/b, -208a/b and -499 and called
61
myomiRs. In our studies we have shown that miRNAs respond to swimming aerobic exercise
62
by 1) decreasing cardiac fibrosis through miRNA-29 increasing and inhibiting collagen, 2)
63
increasing angiogenesis through miRNA-126 by inhibiting negative regulators of the VEGF
64
pathway, and 3) modulating the renin angiotensin system (RAS) through the miRNAs-27a/b
65
and -143. Exercise training also increases cardiomyocyte growth and survival by swimming-
66
regulated miRNA-1, -21, -27a/b, -29a/c, -30e, -99b, -100, -124, -126, -133a/b, -143, -144, -
67
145, -208a, -222 and running-regulated miRNA-1, -26, -27a, -133, -143, -150 and -222, which
68
influence genes associated with the heart remodeling and angiogenesis. We conclude that
69
there is a potential role of these miRNAs in promoting cardioprotective effects on
70
physiological growth.
71
Key Words: cardiac hypertrophy, angiogenesis, swimming training, running training,
72
microRNA.
73
3
74
75
Introduction
76
Exercise training is the most effective non-pharmacological intervention to reduce
77
cardiovascular diseases (CVD). Its prescription is recommended by the guidelines of the most
78
important entities, such as the American College of Sport Medicine and the American Heart
79
Association (39).
80
Exercise training is well known to promote beneficial adaptations in the
81
cardiovascular system which can vary according to type, intensity and duration of exercise
82
(32). Exercise training induces marked beneficial systemic effects on metabolism control,
83
skeletal muscle, cognitive function and cardiovascular function (30, 39). Among them, the
84
set of adaptations induced in the myocardium are collectively referred to as “athlete’s
85
heart”, and includes increased cardiac mass, formations of new blood vessels and decreased
86
collagen content (17, 20, 23, 77, 89, 91). Individuals with high levels of physical activity have
87
a lower prevalence and lower death rates from CVD (32, 86). Thus, exercise training has
88
been established not only as a way to maintain a healthy lifestyle but also as an important
89
and safe non-pharmacological prescription for prevention and treatment of CVD.
90
Pathological cardiac hypertrophy is associated with poor prognosis and is a hallmark
91
of heart failure (72, 73, 103). In contrast, exercise training-induced physiological cardiac
92
hypertrophy presents cardioprotective effects and is not related to heart failure (74).
93
Exercise training has been described as being able to counteract structural and functional
94
cardiac changes in CVD by contributing to the phenotypical changes of pathological into
95
physiological cardiac hypertrophy (31, 65, 73, 74).
96
Despite strong evidence linking exercise training to reduction in CVD risk, much
97
uncertainty remains with regard to the underlying mechanisms. Currently much more
4
98
attention has been given to cellular and molecular mechanisms in an attempt to distinguish
99
between pathological and physiological cardiac hypertrophy. Distinct intracellular pathways
100
have been recognized in both situations and will be reviewed here in view of their
101
modulation by microRNAs (miRNAs). MiRNAs, small non-coding regions of the genome, are a
102
new class of gene regulators, which have been shown to play a key role in a myriad of
103
cellular processes, including growth, fibrosis, apoptosis, angiogenesis, and cardiac function
104
under physiological and pathological conditions.
105
MiRNAs are considered promising therapeutic targets for CVD (4, 15, 71, 74, 85, 90).
106
We have found numerous miRNAs that play specific roles in regulating gene expression by
107
exercise training (20, 21, 24, 65, 89, 91) and confirmed by Ma et al. (58) and Martinelli et al.
108
(61). The aim of this review is provide an overview of exercise training effects on
109
physiological cardiac remodeling and the involvement of miRNAs in this process.
110
111
Cardiac Remodeling Induced by Exercise Training
112
People engaged in chronic exercise programs have improved cardiovascular function.
113
This is not only observed in healthy subjects but mainly in those with any type of
114
cardiovascular risk factor or disease (6, 39, 40). Even in people over 70 years old, exercise
115
training can lower systolic, diastolic and median blood pressure (13). The health benefits of
116
an active lifestyle are multifactorial and include not only biological adaptation but also
117
changes in other social habits, such as decrease in smoking and drinking excessive amounts
118
of alcohol (27).
119
Exercise training reduces the body mass index by decreasing adipocyte mass;
120
increases insulin sensitivity as well as glucose uptake; increases muscle strength and
121
endurance; increases antioxidant levels and increases HDL while decreasing LDL and total
5
122
triglycerides (43, 48, 95). From the cardiovascular point of view, exercise training reduces
123
both diastolic and systolic blood pressure, increases the LV ejection fraction; decreases end-
124
diastolic pressure; improves vascular function, and increases cardiac angiogenesis and
125
cardiac muscle mass (33, 60, 75). Among these adaptations, our focus in this review will
126
primarily be on the increase in cardiac muscle mass termed herein as exercise training-
127
induced cardiac hypertrophy.
128
129
Cardiac hypertrophy
130
Cardiac hypertrophy is an adaptive response of the heart to increased cardiac
131
workload and involves a variety of mechanical, hemodynamic and hormonal factors (70).
132
Although any increase in heart mass is broadly defined as a hypertrophic response, there are
133
two very different forms of ventricular hypertrophy, one physiological and another
134
pathological (5). At the cellular level the hypertrophic process implicates in adaptations such
135
as increased cardiomyocyte size, enhanced protein synthesis rate and re-organizations of the
136
sarcomere structure, there are many differences that distinguish them and will be discussed
137
below. Firstly, they should be distinguished by the structural and functional adaptations as
138
being Physiological vs. Pathological remodeling. Secondly, by the stimuli that induce the
139
hypertrophy, which are Pressure vs. Volume overload (19, 59, 96).
140
Physiological cardiac hypertrophy may be exemplified by the LV remodeling induced
141
by exercise training, pregnancy or during the postnatal growth of the heart from the birth to
142
adulthood. It’s also observed in other species such as in snakes, in which the LV mass can
143
increase even after large meals (2). The LV remodeling induced by physiological stimuli leads
144
to preserved or even enhanced LV function; decreased collagen content; lack of fibrosis,
145
increased angiogenesis; improved myocardial antioxidant capacity (78); decreased
6
146
mitochondrial dysfunction (7), and has been shown to prevent cardiomyocyte apoptosis
147
(44).
148
Oppositely, pathological hypertrophy is associated with severe CVD illness that lead
149
to increased risk of heart failure arrhythmia and ultimately death (41). LV remodeling
150
induced by pathological stress leads to progressive declines in cardiac output, myocardial
151
rarefaction, increased apoptosis, cardiomyocyte metabolism switch from fatty acid to
152
glucose use and increased fibrosis (35, 49).
153
Altogether, there are basically two ways to distinguish between physiological and
154
pathological cardiac hypertrophy: pathological LV remodeling is accompanied by LV
155
dysfunction (either diastolic, systolic or both) (29) and disproportional increase between
156
muscle mass to angiogenesis (88); while physiological LV remodeling preserves, or even
157
enhances, ventricular function and there is coordinated growth of both muscle mass and
158
angiogenesis (23, 74).
159
160
Different cardiac hypertrophy phenotypes at the molecular level
161
At the molecular level, reexpression of fetal genes is used as a biomarker of
162
pathological cardiac hypertrophy. Among them, atrial and brain natriuretic peptide (ANP and
163
BNP), α-skeletal myosin and α- to β-myosin heavy chain (MHC) expression ratio have been
164
the most frequently reported (45, 51, 102). Although the best known effects of ANP and BNP
165
are natriuresis and blood pressure regulation, these small peptides also contribute to
166
preventing cardiac hypertrophy and fibrosis in the adult heart (66). The main release factor
167
of the atrial peptides factor is the wall strain induced by the increased workload but other
168
mechanisms are still being uncovered (96).
169
The α- and β- are subunits of the cardiac MHC filaments. α-MHC has the highest
7
170
ATPase activity and contractile velocity while the β-MHC has the lowest ATPase activity and
171
contractile velocity (36). A decreased α- to β-MHC expression ratio has been found in
172
pathological cardiac hypertrophy while exercise training prevents this response or even
173
increases α- to β-MHC expression ratio (10, 67).
174
Although cardiac hypertrophy involves a variety of mechanical, hemodynamic and
175
hormonal factors, the main factor to determine the morphological phenotype of LV
176
remodeling is the hemodynamic cardiac workload. Both pathological and physiological
177
cardiac hypertrophy may be triggered by pressure or volume cardiac overload. These two
178
different stimuli induce distinct morphological adaptations to the heart, in particular to the
179
LV. The LV remodeling by pressure overload is characterized by concentric hypertrophy,
180
whereas LV remodeling by volume overload induces eccentric hypertrophy (70). At the
181
cellular level, concentric hypertrophy is characterized by parallel addition of new sarcomeres
182
and lateral growth of individual cardiomyocytes. This hypertrophy generally leads to
183
increased LV wall thickness with either decreased LV chamber diameter (pathological) or no
184
change on LV chamber diameter (physiological exercise training-induced) (34). The eccentric
185
hypertrophy due to volume overload is characterized by addition of sarcomeres in series and
186
longitudinal cardiomyocyte growth. The phenotype of this remodeling is typically associated
187
with LV dilatation (pathological) or proportional increase in both LV dilatation and LV wall
188
thickness (physiological exercise training-induced) (34). Figure 1 exemplifies both pressure
189
and volume-induced physiological cardiac hypertrophy.
190
At this time, it should be highlighted that different exercise training protocols change
191
cardiac workload predominantly either by pressure or by volume overload, which lead to
192
different cardiac hypertrophy phenotypes (57, 94) (Figure 1).
193
The first observation of cardiac enlargement in trained individuals was by the
8
194
Swedish clinician Henschen (42) and dates back to the 1890s, but the first description of
195
different types of cardiac hypertrophy among athletes, resulting from different modalities
196
were found by Mongaroth et al. (69) and came only in 1975. Later, with the development of
197
non-invasive and more powerful devices for cardiovascular studies, the understanding of the
198
athlete’s heart phenomenon has progressed evaluated.
199
Aerobic exercises such as running or swimming, involving rhythmic contraction of
200
large skeletal muscle mass, performed for extended periods (e.g., 30-60 minutes), and are
201
dependent on the supply of oxygen to the active muscles, facilitate venous return, and
202
increase the end-diastolic volume (volume overload or increased preload) (69).
203
On the other hand, resistance or strength exercises such as weightlifting, involve
204
smaller muscle mass, but strength contraction are limited to a few repetitions (generally less
205
than 20) until exhaustion, increase systemic vascular resistance (pressure overload or
206
increase after load) due to isometric contraction with heavier loads. For example, systolic
207
blood pressure higher than 250mmHg has been found during this type of exercise (59).
208
Finally it should also be strengthened that the magnitude of cardiac hypertrophy is much
209
less in response to the resistance/strength exercises than aerobic exercises (92). Although
210
we and other authors have used an animal model of resistance training to study
211
cardiovascular adaptations of physiological concentric cardiac hypertrophy (1, 3, 26), data
212
are still scarce with regard to the molecular mechanism involved. In the next section, we will
213
focus on specific intracellular pathways involved in LV remodeling induced by aerobic
214
exercise training.
215
216
MiRNAs, Cardiac Hypertrophy and Exercise Training
217
MiRNA- biogenesis and gene regulation
9
218
MiRNAs comprise a novel class of endogenous, small (∼22 nucleotides in length),
219
non-coding RNAs that play important regulatory roles in many physiological and pathological
220
processes (71, 74, 90). There are over 2000 miRNAs known to be encoded in the human
221
genome, and collectively these miRNAs regulate the expression of thousands of protein-
222
coding gene targets at post-transcriptional levels. Thus, it is estimated that miRNAs regulate
223
approximately 30% of human genes (4, 47, 71, 74, 90). All miRNAs from humans and other
224
species are included in the database miRBase (v21.0, June 2014, http://www.mirbase.org).
225
The biogenesis of miRNAs is accomplished through sequential enzymatic reactions.
226
MiRNAs are initially transcribed by RNA polymerase II in the nucleus to form large pri-miRNA
227
transcripts, and are polyadenylated at its 3’end and capped at its 5’extremity (Bartel 2004,
228
Kim, 2005). The pri-miRNAs harbor a local hairpin structure that is then cropped by a nuclear
229
enzyme Drosha and their cofactor Pasha (also known as DGCR8), into pre-miRNAs (∼70
230
nucleotides). Together, RanGTP and exportin 5 transport the pre-miRNA into the cytoplasm.
231
Subsequently, the enzyme Dicer removes the terminal loop of the pre-miRNAs to generate
232
the miRNA duplex (∼22 nucleotides). The duplex is loaded into the miRNA associated miRISC
233
(multiprotein RNA-induced silencing complex), which includes the Argonaute proteins. One
234
strand of the miRNA is preferentially retained in this complex and becomes the mature
235
miRNA; the opposite strand, known as the passenger strand is eliminated from the complex
236
(4, 47, 50, 90).
237
Mature miRNAs can bind most commonly, but not exclusively, to 3’-untranslated
238
regions (3’-UTR) of messenger RNAs (mRNAs) of protein-coding genes and negatively
239
regulate their expression (4, 47, 71, 74, 90). The post-transcriptional regulation realized by
240
the miRNAs in 3’-UTR is dependent on the degree of complementarity between them and
241
the target mRNA. Due to the fact that they have small sequences and act without the need
10
242
for complete pairing, a single miRNA can regulate up to 200 mRNAs, and more than one
243
miRNA can regulate a single mRNA (50). Thus, miRNAs that bind to target mRNAs with
244
imperfect complementarity repress target gene expression via translational silencing. In
245
contrast, miRNAs that bind to their target mRNAs with perfect complementarily induce
246
mRNAs degradation (4, 47, 50, 71, 74, 90).
247
248
MiRNAs in the heart
249
MicroRNAs are emerging as pivotal modulators of cardiovascular development and
250
disease (74, 90). Although several miRNAs have been described since their discovery in 1993
251
by Lee et al. (53), the knowledge of the molecular mechanisms involved in numerous
252
biological functions still need to be investigated. The first evidence that miRNA play a
253
significant role in the development of the cardiovascular system came from a study showing
254
that the deletion of Dicer, an enzyme key for miRNA processing, disrupted embryonic
255
angiogenesis during mouse development (101). Later studies with specific deletion of Dicer
256
in the heart showed miss expression of cardiac contractile proteins and profound sarcomere
257
disarray accompanied by dilated cardiomyopathy, heart failure, and postnatal lethality (11).
258
Thus, da Costa Martins et al. (14) showed that conditional Dicer deletion in the postnatal
259
myocardium promoted pathological cardiac remodeling and dysfunction, suggesting the
260
important role of miRNAs in the control of cardiovascular homeostasis.
261
The first studies of miRNA implication in cardiac hypertrophy using microarray
262
platforms to analyzed the cardiac miRNA expression signature after pathological stimuli
263
(thoracic aortic-banded mouse model and calcineurin-overexpressing transgenic mice),
264
indicated that miRNAs are aberrantly expressed in hypertrophic mouse hearts (12, 15, 82,
265
85). Over the last decade, miRNAs expression profile under either experimental or clinical
11
266
conditions of cardiac hypertrophy has been revealed, showing miRNA downstream genes
267
with hypertrophic targets. Studies have identified anti-hypertrophic miRNAs (miRNA-1, -133,
268
-26, -9, -98, -29, -378 and -145) and pro-hypertrophic miRNAs (miRNAs-143, -103, -130a, -
269
146a, -21, -210, -221, -222,- 27a/b, -199a/b, -208, -195, -499, -34a/b/c, -497, -23a, -15a/b) in
270
the heart (15, 18, 71, 74). Antagomir and miR-mimic approaches, knockout mice, adenoviral
271
vector, pharmacologic inhibitors (2’-O-methyl-modified antisense oligonucleotides, AMO;
272
locked nucleic acid, LNA) and transgenic mice regulating miRNA expression under control of
273
the cardiac Myh6 promoter have been used to silence or stimulate miRNAs anti- or pro-
274
hypertrophic in vitro and in vivo studies (14, 17, 68, 71). Abnormal miRNA regulation has
275
been shown to be involved in CVD; suggesting that miRNAs might affect cardiac structure
276
and function (15, 71, 74, 90).
277
Among the miRNAs described, four are recognized as cardiac-specific, miRNA-1, -
278
133a/b, -208a/b and -499 called of myomiRs. Sayed et al. (85) showed that cardiac miRNA-1
279
is down-regulated in hypertrophic hearts by transverse aortic constriction and it is involved
280
in post mitotic muscle growth and function through a serum response factor (SRF)-
281
dependent mechanism. This down regulation is required for the release of its growth-related
282
targets, including RasGTPase–activating protein (RasGAP), cyclin-dependent kinase 9 (Cdk9),
283
fibronectin, and Ras homolog enriched in brain (Rheb). Similar, Carè et al. (8) showed that
284
miRNA-133 is also down-regulated in hypertrophic hearts induced by transverse aortic
285
constriction, which represses family members of the Rho kinase, Ras homologue gene
286
family-A (RhoA) and cell division control protein 42 (Cdc42), as well as negative elongation
287
factor complex member A (NelfA), a negative regulator of RNA polymerase II. Studies have
288
shown that Rho kinase inhibition improves LV geometry and reduces collagen deposition
289
accompanied by improved diastolic function in transverse aortic constriction-induced cardiac
12
290
hypertrophy (76). On the other hand, Van Rooij et al. (83) showed that over expression of
291
miRNA-208a is required for cardiomyocyte hypertrophy, fibrosis, and expression of β-MHC in
292
response to stress and hypothyroidism. MiRNA-208 targets purine-rich element binding
293
protein B (Purβ), heterochromatin protein 1 (HP-1β) and transcription factors Sox6 and Sp3
294
related to MHC gene switching mainly by stimulating β-MHC expression (81). In addition,
295
overexpression of miRNA-499 also elicits cardiac hypertrophy resulting in cardiac systolic
296
dysfunction (87). Therefore, new target genes and signaling pathways have been described
297
to regulate cardiac hypertrophy via myomiRs (15, 71, 74). Although miRNA studies
298
predominate in the field of cardiovascular disorders, little is known about their expression
299
patterns or role in physiological conditions, especially exercise-regulated miRNAs.
300
In the same way as miRNAs, long non-coding RNAs (lncRNAs) are part of the non-coding
301
RNAs interacting with the major pathways of cell growth, proliferation, differentiation, and
302
survival. Recently discovered, lncRNAs have been described as regulating gene expression,
303
and may act as miRNA sponges to reduce miRNA levels (38, 97, 100). The number of non-
304
coding RNAs encoded within the human genome is unknown, however recent transcriptomic
305
and bioinformatic studies suggest that there are thousands of them (37). Notably, Wang et
306
al. (97) demonstrated that lncRNA, AK048451, which the authors called of CHRF, sequesters
307
the miRNA-489, preventing the miRNA from acting on its target gene Myd88. The authors
308
described this as resulting from induced pathological cardiac hypertrophy in response to
309
angiotensin II treatment. Thus, for the first time, the authors showed the participation of the
310
lncRNA-miRNA-mRNA axis in the cardiac hypertrophy, revealing a promising area of
311
cardiovascular research that may contribute to the understanding of physiological cardiac
312
hypertrophy induced by exercise training.
313
13
314
315
Exercise training-regulated cardiac miRNAs
316
The miRNAs are essential in different cell processes involved in the regulation of
317
cardiovascular phenotypes, such as cardiomyocyte growth, remodeling, and vascularization
318
(15, 25, 90). MiRNAs have also been described as participating in the beneficial adaptations
319
promoted by exercise training, mainly physiological cardiac hypertrophy (8, 20, 24, 58, 61,
320
89, 91) (Figure 1). Interestingly, in table 1, we identified miRNAs and targets genes involved
321
in physiological cardiac remodeling induced by aerobic exercise training, both swimming and
322
running exercises. Despite their importance; few studies have been conducted based on this
323
concept. Carè et al. (8) conducted the first study showing the effects of high intensity
324
interval training (treadmill), on miRNA expression in cardiac hypertrophy. The authors
325
showed that miRNA-1 and -133 expression were reduced in both physiological cardiac
326
hypertrophy induced by interval training and by cardiac-specific Akt transgenic mice. We also
327
observed that miRNA-1 and -133a/b are similarly down-regulated in the eccentric cardiac
328
hypertrophy induced by two different swimming training protocols when compared with the
329
sedentary group (91). Irrespective of the exercise (running or swimming) and volume
330
training (moderate and high), the expression profiles of these myomiRs were similar among
331
the studies (8, 91). Intriguingly, as described above, these miRNAs were also reduced in
332
pathological cardiac hypertrophy (8).
333
We also evaluated the expression of the myomiR-208a in the heart of the animals
334
subjected to the same two swimming exercise training protocols. Unlike that found in
335
pathological hypertrophy (81), the data showed a reduction in cardiac miRNA-208a in the
336
group with higher volume of exercise, parallel to an increase in the target gene Purβ in
337
comparison with the sedentary group. Increased levels of Purβ inhibited β-MHC expression
14
338
accompanied by increased α-MHC and improved ventricular compliance (24). Interestingly,
339
higher levels of circulating miRNA-208a and -499 have been used as systemic biomarkers of
340
cardiac damage in patients with CVD. In contrast, miRNA-208b and -499 levels were not
341
changed after 24 hours of a marathon run, while the miRNA-1, -133a, and -206 were
342
correlated to performance parameters (VO2max and running speed) indicating their potential
343
role as biomarkers of aerobic capacity (68).
344
In an attempt to explain the differences between pathological and physiological
345
cardiac hypertrophy based on miRNA signatures, Lin et al. (55) identified miRNAs
346
differentially expressed in physiological cardiac hypertrophy using transgenic mice with
347
elevated cardiac PI3K activity (caPI3K), in comparison with pathological hypertrophy with
348
decreased PI3K activity (dnPI3K) and myocardial infarction. Although it was not the effect of
349
exercise training, the authors were the first to detail a signature of miRNAs in physiological
350
cardiac hypertrophy, demonstrating a potential role of these miRNAs in promoting
351
cardioprotective effects on physiological growth. PI3Ks catalyze the phosphorylation of
352
membrane lipids, known as the phosphoinositides, and thus activate a series of intracellular
353
signaling molecules such as Akt1, which is a major downstream effector of PI3K. Akt1 is
354
phosphorylated in physiological cardiac hypertrophy and exerts diverse beneficial functions
355
such as inhibition of cardiomyocyte apoptosis, improvement in calcium transients and
356
cardiac hypertrophy (46, 62). A series of studies led by the McMullen JR group has shown
357
the role of IGF-1/ IGF-1R/ PI3K(110α) in the development of physiological cardiac
358
hypertrophy (63, 64, 98).
359
IGF-1/ IGF-1R intracellular signaling has been the most studied pathway responsible
360
for physiological cardiac hypertrophy. High circulating levels of this factor are encountered
361
both during postnatal development and in response to exercise training. IGF-1 is mainly
15
362
produced by the liver but also by cardiomyocytes in response to exercise (28). IGF-1R is a
363
tyrosine kinase receptor which, upon IGF-1 binding, activates the PI3K-Akt cascade. Mice
364
with constitutively active PI3K(110α) or overexpression of Insulin-like growth factor 1 (IGF-1)
365
show increased heart weight and are protected from ischemic injury and heart failure (54,
366
55).
367
Our group was the first to identify miRNAs based on miRNAs signature in cardiac
368
hypertrophy induced by aerobic exercise training (20, 89, 91). Soci et al. (91) showed that
369
the expression of miRNA-29c, which targets the collagen gene, increased in parallel with
370
cardiac hypertrophy induced by both swimming exercise training protocols (moderate and
371
high exercise volume) correlated with a decrease in collagen I and III expression and OH-
372
proline concentration relevant to the improved LV compliance and function. Thus miRNA-29
373
reduces collagen fibrosis in the physiologically hypertrophic heart. On the other hand, low
374
levels of miRNA-29 were previously associated with fibrosis in myocardial infarction (84).
375
Recently, Melo et al. (65) showed that swimming training restored cardiac miRNA-29a and
376
-29c levels and prevented collagen type I and III expression on the border and in the remote
377
regions of the myocardial infarction suggesting the cardiac effect of exercise training in
378
myocardial-infarcted rats as a way to prevent or minimize the harmful effects in CVD.
379
Similarity, Liu et al. (56) identified miRNAs signature in physiological cardiac
380
hypertrophy induced by two different types of aerobic training: voluntary wheel running and
381
ramp swimming model. Interestingly, the authors showed that 55 miRNAs were differentially
382
expressed by swimming while 124 were differentially expressed by voluntary wheel running
383
and 16 were similarly regulated by two types of aerobic training. MiRNA-222 was chosen by
384
to be upregulared in both models of physiological cardiac hypertrophic targeting p27 (cell-
385
cycle inhibitor), HIPK1 (protein kinase) and HMBOX1 (transcriptional repressor) genes
16
386
involved in proliferation and hypertrophy of cardiomyocytes. Curiously, the authors were the
387
first to perform a functional study showing that the inhibition of miRNA-222 in vivo blocks
388
cardiac hypertrophy induced by swimming. Moreover, miRNA-222 can be suggested as a
389
potential therapeutic target against pathological cardiac remodeling since it overexpression
390
largely protected the heart from damage caused by ischemic injury.
391
Angiogenesis, the growth of new blood vessels from existing vessels, is an important
392
aspect of LV remodeling. In physiological LV remodeling there is coordinated growth of both
393
muscle mass and angiogenesis which is an important adaptation to enhance capacity and
394
reserve to deliver oxygen to the myocardium (52). Da Silva et al. (89) investigated the role of
395
the miRNA-126 on cardiac angiogenesis induced by swimming training. Exercise training
396
promoted an increase in the expression of miRNA-126 and repression of their target genes
397
Spred-1 and PI3KR2 related to vessel growth. Spred-1 and PI3KR2 are negative regulators of
398
the VEGF pathway by inhibiting Raf-1/ ERK 1/2 and PI3K/ Akt/ eNOS pathways, respectively
399
(25). Interestingly, our study revealed some of the molecular mechanisms involved in
400
physiological cardiac remodeling in response to exercise training. VEGF is considered the
401
most potent angiogenic factor and interacts with two specific receptors: fms-like tyrosine
402
kinase (Flt-1 or VEGFR1) and fetal liver kinase (Flk-1 or VEGFR2). Once activated, these
403
receptors result in a series of intracellular signaling pathways that lead to both angiogenic
404
and vasodilator responses. One of the first effects of intracellular activation by VEGF
405
discovered was an increase in eNOS activity and expression. VEGF mediates the activation of
406
ezrin/ calpain/ PI3K/ Akt cascade which leads to eNOS Ser1179 phosphorylation and Ca2+-
407
independent NO generation (16). VEGF can also activate AMPK activity through the Ca2+/
408
Calmodulin pathway, which in turn, also activates eNOS to induce angiogenesis and
409
vasodilation (93). There are no doubts about the role of VEGF as an important mediator of
17
410
the exercise training–induced angiogenic response, as has been reviewed elsewhere (22, 79).
411
Fernandes et al. (20) showed increased of miRNA-27a and -27b in cardiac
412
hypertrophy induced by swimming training targeting angiotensin converting enzyme (ACE),
413
in normotensive rats. Inactivation of the classic renin angiotensin system (RAS) by exercise
414
training contributed to a physiological cardiac hypertrophy by reducing the levels of ACE-
415
ANG II axis. In contrast, we observed a decrease of miRNA-143 targeting ACE2 in the heart of
416
rats. Activation of non-classic RAS by exercise training counteracted the classic cardiac RAS
417
by stimulating ACE2- Ang- (1-7) axis in physiological cardiac hypertrophy. Recently, Martinelli
418
et al. (61) determined the profile of miRNAs in voluntary exercise (wheel running)-induced
419
LV hypertrophy. In agreement with Fernandes et al. (20), the authors also observed a
420
reduction in the expression of miRNA-143 with only 7 days of exercise training, but no
421
change in expression after 35 days of training. On the other hand, the authors detected a
422
reduction in miRNA-27a levels at 7 days of exercise training and no change in expression
423
after 35 days of training. The different results in the studies could mainly be due to the type,
424
intensity and duration of exercise training used. Thus, exercise training of greater intensity
425
and long duration has been shown to promote alterations in the expression of miRNA-27a/b
426
and -143 after periods of chronic exercise involved in the physiological cardiac remodeling.
427
Martinelli et al. (61) also observed a reduction in miRNA-26a expression after 7 days
428
and increase in miRNA-150 expression after 35 days of voluntary wheel running exercise.
429
The predicted target genes of miRNA-26b and -150 may be involved in physiological cardiac
430
hypertrophy induced by exercise training, since they are related to survival pathways, such
431
as IGF-1/PI3K signaling and GS3K-β, respectively. Interestingly, Ma et al. (58) identified
432
miRNAs that target the PI3K/ AKT/ mTOR signaling pathway in swimming training-induced
433
cardiac hypertrophy. The authors observed that exercise training increased cardiac miRNA18
434
21 and -144 expression associated with a reduction in their target gene PTEN (negative
435
regulator of the PI3K/ AKT/ mTOR pathway). In addition, an increase in miRNA-145 was
436
accompanied by a decrease in TSC2 (tuberous sclerosis complex 2) after swimming training
437
(another negative regulator of the PI3K/ AKT/ mTOR pathway). In contrast, exercise training
438
decreased cardiac miRNA-124 expression associated with an increase in their target gene
439
PI3K (p110-α) involved in physiological hypertrophy. Recently, Ramasamy et al. (80) also
440
performed microarray miRNA in swimming training-induced cardiac hypertrophy indicating
441
that miRNA-30e, -133b and -208 were significantly upregulated and miRNA-99b and -100,
442
were significantly downregulated after real-time PCR confirmation in healthy rats. Target
443
genes that regulate proliferation and cell death were showed, suggesting that
444
PI3/Akt/mTOR, MAPK and p53 signaling are involved in physiological cardiac growth.
445
Altogether, these data suggest that exercise training, both swimming and running,
446
can promote physiological cardiac remodeling through regulation of specific target genes by
447
miRNAs. These exercise training-induced adaptations might provide the additional aerobic
448
performance required by the exercised heart.
449
450
Conclusion
451
Exercise training has been widely recommended as a safe and well accepted non-
452
pharmacological strategy to prevent CVD and even restore cardiac function. We believe that
453
understanding the molecular pathways behind the physiological cardiac adaptation induced
454
by exercise training we may find new therapeutical targets to treat CVD. Among these new
455
targets, modulation of miRNAs seems to be a powerful therapy to reach this goal. A
456
potential therapeutic advantage of miRNAs is that they target multiple genes involved in the
457
same pathway process which is different compared to traditional therapies that target a
19
458
single protein or gene. Furthermore, miRNA have defined target with high specificity of
459
treatment, long duration effect and bioavailability, indicating miRNA therapy as a more
460
effective strategy. On the other hand, delivery, tissue selectivity and safety are important
461
challenge of miRNA-based therapy to be overcome in the next years (9).
462
Surprisingly, little is known about the regulatory interaction networks among the
463
multiple classes of RNAs or the mechanisms regulated by exercise-induced miRNAs on
464
physiological cardiac remodeling. The analysis of miRNAs has made it possible to understand
465
the development of various types of diseases. The elucidation of these processes regulated
466
by miRNAs and identification of new target genes in the pathogenesis of CVD are very
467
valuable strategies for prevention and treatment of the CVD. As reviewed here, very little is
468
known about the mechanisms regulated by exercise-induced miRNAs, both by swimming
469
and running, on physiological cardiac remodeling.
470
Based on our findings and reports by other investigators, the data indicate that
471
different phenotypical changes observed in response to both swimming and running exercise
472
training can be regulated by miRNAs and their target genes (Table 1 and Figure 1). A set of
473
specific miRNAs contributes to the physiological cardiac remodeling induced by aerobic
474
exercise training (swimming-regulated miRNA-1, -21, -27a/b, -29a/c, -30e, -99b, -100, -124,
475
-126, -133a/b, -143, -144, -145, -208a, -222 and running-regulated miRNA-1, -26, -27a, -133,
476
-143, -150 and -222), suggesting a potential role of these miRNAs in promoting
477
cardioprotective effects on physiological growth (Figure 1). Therefore, exercise-induced
478
miRNAs, which could be measured circulating in blood, could serve as predictors of aerobic
479
capacity required by the hypertrophic heart. Other types of exercise training (i.e., resistance,
480
interval and concurrent)-induced physiological cardiac hypertrophy can also be promoted
481
under the regulation of specific miRNAs which may also be important for the development
20
482
of new therapies for CVD. Further studies are still required to evaluate cardiac miRNA
483
signatures under pathological and physiological conditions. In addition, the functional role of
484
miRNAs in the physiological cardiac remodeling induced by exercise training could increase
485
our understanding of cardiac remodeling mechanisms.
486
487
Grants
This study was supported by Fundação de Amparo à Pesquisa do Estado de São Paulo
488
489
(FAPESP-2009/18370-3 and 2010/50048-1), Conselho Nacional de Desenvolvimento
490
Científico e Tecnológico (CNPq-308267/2013-3, 476515/2012-2 and 485873/2012-5) and
491
USP/PRP-NAPmiR and Pro-Infra. M Ian Phillips was supported by National Institutes of
492
Health (NIH- R01-HL077602). Oliveira EM and M Ian Phillips (FAPESP/SPRINT 2014/50673-4).
493
Disclosures
None.
494
495
496
References
497
498
499
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.
500
501
2.
Andersen JB, Rourke BC, Caiozzo VJ, Bennett AF, Hicks JW. Physiology: postprandial
cardiac hypertrophy in pythons. Nature 434: 37–38, 2005.
502
503
504
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: R381–7, 2008.
505
506
4.
Bartel DP. MicroRNAs: Genomics, Biogenesis, Mechanism, and Function. Cell 116:
281–297, 2004.
507
508
509
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.
21
510
511
512
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.
513
514
7.
Campos JC, Gomes KMS, Ferreira JCB. Impact of exercise training on redox signaling
in cardiovascular diseases. Food Chem Toxicol 62: 107–19, 2013.
515
516
517
518
8.
Carè A, Catalucci D, Felicetti F, Bonci D, Addario A, Gallo P, Bang M-L, 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.
519
520
9.
Caroli A, Cardillo MT, Galea R, Biasucci LM. Potential therapeutic role of microRNAs
in ischemic heart disease. J. Cardiol. 61: 315–320, 2013.
521
522
523
524
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.
525
526
527
528
11.
Chen J-F, 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 D-Z.
Targeted deletion of Dicer in the heart leads to dilated cardiomyopathy and heart
failure. Proc Natl Acad Sci U S A 105: 2111–2116, 2008.
529
530
531
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.
532
533
534
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.
535
536
537
538
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.
539
540
15.
Da Costa Martins PA, De Windt LJ. MicroRNAs in control of cardiac hypertrophy.
Cardiovasc. Res. 93: 563–572, 2012.
541
542
543
16.
Dimmeler S, Fleming I, Fisslthaler B, Hermann C, Busse R, Zeiher AM. Activation of
nitric oxide synthase in endothelial cells by Akt-dependent phosphorylation. Nature
399: 601–605, 1999.
544
545
17.
Dorn GW. The fuzzy logic of physiological cardiac hypertrophy. Hypertension 49: 962–
970, 2007.
22
546
547
548
549
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.
550
551
552
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.
553
554
555
556
557
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 2angiotensin (1-7). Hypertension 58: 182–189, 2011.
558
559
560
561
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. In: Hypertension. 2012, p.
513–520.
562
563
564
565
22.
Fernandes T, Nakamuta JS, Magalhães FC, Roque FR, Lavini-Ramos 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.
566
567
568
23.
Fernandes T, Soci UPR, Oliveira EM. Eccentric and concentric cardiac hypertrophy
induced by exercise training: MicroRNAs and molecular determinants. Brazilian J.
Med. Biol. Res. 44: 836–847, 2011.
569
570
571
24.
Fernandes T, Soci UP OE. MiRNA-208a targeting Purβ gene regulates the β-MHC
content in cardiac hypertrophy induced by exercise training. Circ Res 128: A21942,
2013.
572
573
574
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.
575
576
577
26.
Fontes MT, Silva TLBT, Mota MM, Barreto AS, Rossoni L V, Santos MR V. Resistance
exercise acutely enhances mesenteric artery insulin-induced relaxation in healthy rats.
Life Sci 94: 24–9, 2014.
578
579
27.
Franklin BA, Cushman M. Recent advances in preventive cardiology and lifestyle
medicine: A Themed series. Circulation 123: 2274–2283, 2011.
580
581
28.
Frystyk J. Exercise and the growth hormone-insulin-like growth factor axis. Med. Sci.
Sports Exerc. 42: 58–66, 2010.
23
582
583
584
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.
585
586
587
588
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.
589
590
591
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.
592
32.
Golbidi S, Laher I. Exercise and the cardiovascular system. Cardiol. Res. Pract. 1 2012.
593
594
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.
595
596
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.
597
598
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.
599
600
601
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.
602
603
604
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, 2013.
605
606
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: 384–8, 2013.
607
608
609
610
39.
Haskell WL, Lee I-M, 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.
611
612
613
614
40.
Haykowsky MJ, Liang Y, Pechter D, Jones LW, McAlister FA, Clark AM. A MetaAnalysis 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.
615
616
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
24
the pressure-overloaded human: Heart structural deterioration and compensatory
mechanisms. Circulation 107: 984–991, 2003.
617
618
619
620
42.
Henschen S. Skidlauf und Skidwettlauf. Eine medizinische Sportstudie. Mitt Med Klin
Upsala 2: 15, 1899.
621
622
43.
Huang C-J, Webb HE, Zourdos MC, Acevedo EO. Cardiovascular reactivity, stress, and
physical activity. Front Physiol 4: 314, 2013.
623
624
625
44.
Huang C-Y, Yang A-L, Lin Y-M, Wu F-N, Lin JA, Chan Y-S, Tsai F-J, Tsai C-H, Kuo C-H,
Lee S-D. Anti-apoptotic and pro-survival effects of exercise training on hypertensive
hearts. J Appl Physiol 112: 883–91, 2012.
626
627
628
45.
Izumo S, Nadal-Ginard B, Mahdavi V. Protooncogene induction and reprogramming
of cardiac gene expression produced by pressure overload. [Online]. Proc Natl Acad
Sci U S A 85: 339–43, 1988..
629
630
631
46.
Kim K-S, Abraham D, Williams B, Violin JD, Mao L, Rockman H a. β-Arrestin-biased
AT1R stimulation promotes cell survival during acute cardiac injury. Am J Physiol Heart
Circ Physiol 303: H1001–10, 2012.
632
633
47.
Kim VN. MicroRNA biogenesis: coordinated cropping and dicing. Nat Rev Mol Cell Biol
6: 376–385, 2005.
634
635
48.
Kolka C. Treating Diabetes with Exercise - Focus on the Microvasculature. [Online]. J
Diabetes Metab 4: 308, 2013.
636
637
49.
Kolwicz SC, Purohit S, Tian R. Cardiac metabolism and its interactions with
contraction, growth, and survival of cardiomyocytes. Circ Res 113: 603–16, 2013.
638
639
640
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.
641
642
643
51.
Kuster DWD, Merkus D, Blonden LA, Kremer A, van IJcken WFJ, Verhoeven AJM,
Duncker DJ. Gene reprogramming in exercise-induced cardiac hypertrophy in swine: A
transcriptional genomics approach. J Mol Cell Cardiol 77C: 168–174, 2014.
644
645
52.
Laughlin MH, Bowles DK, Duncker DJ. The coronary circulation in exercise training.
Am J Physiol Heart Circ Physiol 302: H10–23, 2012.
646
647
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.
648
649
650
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.
25
651
652
653
654
655
55.
Lin RCY, Weeks KL, Gao XM, Williams RBH, 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(p110α) protects against myocardial
infarction-induced heart failure: Identification of PI3K-regulated miRNA and mRNA.
Arterioscler Thromb Vasc Biol 30: 724–732, 2010.
656
657
658
659
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.
660
57.
Longhurst JC, Stebbins CL. The power athlete. [Online]. Cardiol Clin 15: 413–29, 1997.
661
662
663
58.
Ma Z, Qi J, Meng S, Wen B, Zhang J. Swimming exercise training-induced left
ventricular hypertrophy involves microRNAs and synergistic regulation of the
PI3K/AKT/mTOR signaling pathway. Eur J Appl Physiol 113: 2473–2486, 2013.
664
665
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.
666
667
60.
Mann N, Rosenzweig A. Can exercise teach us how to treat heart disease? Circulation
126: 2625–35, 2012.
668
669
670
671
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, 2014.
672
673
62.
Matsui T, Nagoshi T, Rosenzweig A. Akt and PI 3-kinase signaling in cardiomyocyte
hypertrophy and survival. Cell Cycle 2: 220–223, 2003.
674
675
676
677
63.
McMullen JR, Shioi T, Huang W-Y, 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 3kinase(p110alpha) pathway. J Biol Chem 279: 4782–4793, 2004.
678
679
680
681
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 U S A 100:
12355–12360, 2003.
682
683
684
65.
Melo SFS, Fernandes T, Baraúna VG, Matos KC, Santos A a S, Tucci PJF, Oliveira EM.
Expression of MicroRNA-29 and Collagen in Cardiac Muscle after Swimming Training in
Myocardial-Infarcted Rats. Cell Physiol Biochem 33: 657–69, 2014.
685
686
66.
Mitsui T. Notes on the peroxidase activity of human basophil leukocytes. [Online].
Tokai J Exp Clin Med 13: 1–8, 1988.
26
687
688
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.
689
690
68.
Mooren FC, Viereck J, Kruger K, Thum T. Circulating microRNAs as potential
biomarkers of aerobic exercise capacity. Am J Physiol Circ Physiol 306: H557–63, 2014.
691
692
69.
Morganroth J, Maron BJ, Henry WL, Epstein SE. Comparative left ventricular
dimensions in trained athletes. Ann Intern Med 82: 521–524, 1975.
693
70.
Nadruz W. Myocardial remodeling in hypertension. J Hum Hypertens 29: 1–6, 2015.
694
695
71.
Neves VJ Das, Fernandes T, Roque FR, Soci UPR, Melo SFS, de Oliveira EM. Exercise
training in hypertension: Role of microRNAs. World J Cardiol 6: 713–27, 2014.
696
697
72.
Oliveira EM, Krieger JE. Chronic β-adrenoceptor stimulation and cardiac hypertrophy
with no induction of circulating renin. Eur J Pharmacol 520: 135–141, 2005.
698
699
700
701
73.
Oliveira RSF, Ferreira JCB, Gomes ERM, Paixão NA, Rolim NPL, 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.
702
703
74.
Ooi JYY, Bernardo BC, McMullen JR. The therapeutic potential of miRNAs regulated in
settings of physiological cardiac hypertrophy. Future Med Chem 6: 205–222, 2014.
704
705
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.
706
707
708
709
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.
710
711
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.
712
713
714
78.
Powers SK, Sollanek KJ, Wiggs MP, Demirel H a, Smuder a J. Exercise-induced
improvements in myocardial antioxidant capacity: the antioxidant players and
cardioprotection. Free Radic. Res. (2013). doi: 10.3109/10715762.2013.825371.
715
716
79.
Prior BM, Yang HT, Terjung RL. What makes vessels grow with exercise training? J
Appl Physiol 97: 1119–1128, 2004.
717
718
719
80.
Ramasamy S, Velmurugan G, Shanmugha Rajan K, Ramprasath T, Kalpana K. MiRNAs
with Apoptosis Regulating Potential Are Differentially Expressed in Chronic ExerciseInduced Physiologically Hypertrophied Hearts. PLoS One 10: e0121401, 2015.
27
720
721
722
81.
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.
723
724
725
726
82.
Van Rooij E, Sutherland LB, Liu N, Williams AH, McAnally J, Gerard RD, Richardson
JA, Olson EN. A signature pattern of stress-responsive microRNAs that can evoke
cardiac hypertrophy and heart failure. Proc Natl Acad Sci U S A 103: 18255–18260,
2006.
727
728
729
83.
Van Rooij E, Sutherland LB, Qi X, Richardson JA, Hill J, Olson EN. Control of stressdependent cardiac growth and gene expression by a microRNA. Science 316: 575–579,
2007.
730
731
732
84.
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 U S A 105: 13027–13032, 2008.
733
734
85.
Sayed D, Hong C, Chen I-Y, Lypowy J, Abdellatif M. MicroRNAs play an essential role
in the development of cardiac hypertrophy. Circ Res 100: 416–424, 2007.
735
86.
Shephard RJ BG. Exercise as cardiovascular therapy. Circulation 99: 963–72, 1999.
736
737
87.
Shieh JTC, Huang Y, Gilmore J, Srivastava D. Elevated miR-499 levels blunt the cardiac
stress response. PLoS One 6, 2011.
738
739
740
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.
741
742
743
89.
Da Silva ND, Fernandes T, Soci UPR, Monteiro AWA, Phillips MI, De Oliveira EM.
Swimming training in rats increases cardiac MicroRNA-126 expression and
angiogenesis. Med Sci Sports Exerc 44: 1453–1462, 2012.
744
745
90.
Small EM, Olson EN. Pervasive roles of microRNAs in cardiovascular biology. Nature
469: 336–342, 2011.
746
747
748
749
91.
Soci UPR, 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.
750
751
752
753
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: 5443–52, 2011.
754
755
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
28
growth factor mediates endothelial angiogenesis independently of nitric-oxide
synthase. J Biol Chem 285: 10638–10652, 2010.
756
757
758
759
94.
Starnes JW, Taylor RP. Exercise-induced cardioprotection: endogenous mechanisms.
Med Sci Sports Exerc 39: 1537–43, 2007.
760
761
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: 441–7, 2014.
762
96.
Volpe M. Natriuretic peptides and cardio-renal disease. Int J Cardiol 176: 630–9, 2014.
763
764
765
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.
766
767
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.
768
769
99.
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.
770
771
100. Wu C AP. Long Noncoding RNA-MicroRNA-mRNA: A Novel Tripartite Axis in the
Regulation of Cardiac Hypertrophy. Circ Cardiovasc Genet 7: 729–731, 2014.
772
773
774
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.
775
776
102. Yap L Bin, Mukerjee D, Timms PM, Ashrafian H, Coghlan JG. Natriuretic peptides,
respiratory disease, and the right heart. Chest 126: 1330–6, 2004.
777
778
779
103. Zile MR, Gaasch WH, Patel K, Aban IB AA. Adverse Left Ventricular Remodeling in
Community-Dwelling Older Adults Predicts Incident Heart Failure and Mortality. J Am
Coll Cardiol - Hear Fail 2: 512–522, 2014.
780
29
Figure 1.
Figure 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 the cross-sectional cardiac area. MiRNAs -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 anti-fibrosis process and miRNA-126 modulates angiogenesis in response to aerobic
exercise training.
Table 1. Effects of aerobic exercise training on miRNAs expression in physiological cardiac remodeling.
Exercise Training
miRNA
Target Gene
Outcome
Reference
Running
↓miRNA-1,
IGF-1, IGF-1R
(interval exercise)
↓miRNA-133a
RhoA, Cdc42, NelfA
Hypertrophy
8, 18
Swimming
↓miRNA-1,
-
(continuous exercise)
↓miRNA-133a/b
RhoA, Cdc42, NelfA
Hypertrophy
23, 91
↑miRNA-29a/c
Collagen I/III
Fibrosis
65, 91
↓miRNA-208a
Purβ
Hypertrophy
24
↑miRNA-126
Spred-1, PI3KR2
Angiogenesis
89
Swimming
↑miRNA-27a/b
ECA
↓miRNA-143
ECA2
Hypertrophy
20
(continuous exercise)
↓miRNA-27a
GATA4*
Wheel Running
↓miRNA-143
-
↓miRNA-26b
IGF-1*, PI3K*
Hypertrophy
61
(voluntary exercise)
↑miRNA-150
GS3K-β*, C-MYB*
Swimming
↑miRNA-21, -144
PTEN
↑miRNA-145
TSC2
Hypertrophy
58
(continuous exercise)
Swimming
(continuous exercise)
Swimmimg
(continuous exercise)
Swimming
(continuous exercise)
Swimming
(continuous exercise)
↓miRNA-124
PI3K (p110α)
↑miRNA-30e
Bcl-2
↑miRNA-133b
-
↑miRNA-208a
-
↓miRNA-99b
IGF-1R, Akt, mTOR
↓miRNA-100
IGF-1R, Akt, mTOR
(continuous exercise)
80
Hypertrophy
56
p27
Swimming and Wheel
Running
Hypertrophy
↑miRNA-222
HIPK1
HMBOX1
*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-β: glycogen synthase kinase 3 beta, PI3K: phosphoinositide 3-kinase,
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 regulatory subunit 2, Purβ: purine-rich element binding protein B, RhoA: Ras
homologue gene family-A, Cdc42: cell division control protein42, 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.