Download Working out the heart: Functional remodeling by endurance exercise

Journal of Molecular and Cellular Cardiology 60 (2013) 47–49
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Journal of Molecular and Cellular Cardiology
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Editorial
Working out the heart: Functional remodeling by endurance exercise training
Physical training, particularly in the case of aerobic exercise, has
been shown to produce several physiological changes, among which
are increase in the maximal oxygen uptake and general physical fitness, improvement in the sensitivity of some visceral reflexes, and decrease in the sympathetic drive to the heart, accompanied by increase
in the vagal tone (e.g., [1,2]).
The reported effects of exercise on the heart in the absence of
cardiovascular affections include enhancement of contractility, acceleration of Ca 2+ transient and/or contraction kinetics, reduction of
the oxygen requirements at increasing workloads, ischemic protection, and induction of anti-oxidant enzymes and chaperones [2–7].
Depending on the exercise modality, intensity and duration, myocardial hypertrophy may ensue. However, this so-called physiological
hypertrophy differs from the hypertrophic growth that usually develops in response to chronic arterial hypertension and myocardial
infarction. The latter is usually accompanied by increased expression
of cell stress biomarkers (e.g., atrial natriuretic peptide), fibrosis, relative capillary rarefaction and greater propensity to arrhythmias,
which are not observed in the physiological type of hypertrophy
[8–11]. Thus, although hypertrophic growth is an adaptive response
of the heart to increased hemodynamic load, physiological hypertrophy and pathological hypertrophy are quite distinct regarding the signaling pathway, morphological pattern, molecular and functional
alterations, and evolution, as compensated pathological hypertrophy
may progress to heart failure [2,8,9]. Nevertheless, it should be noticed that cardiac dysfunction and some phenotypic changes commonly observed in pathological hypertrophy can be induced by very
intense and/or prolonged physical activity [12].
Would these 2 types of cardiac remodeling be superimposable? In
the current issue of Journal of Molecular and Cellular Cardiology,
Carneiro-Júnior et al., in their article The benefits of endurance training
in cardiomyocyte function in hypertensive rats are reversed within
four weeks of detraining [13], contribute to shed light on this issue
reporting the molecular and functional effects of low-intensity endurance training (running) on the heart of spontaneously hypertensive
rats, in which development of hypertension is associated with heightened sympathetic activity [14]. In their study, the authors observed
that training, although not effective at normalizing the blood pressure, was able to reverse the myocardial overexpression of stress
markers, one of the hallmarks of the pathologically hypertrophied
heart. Their results are in agreement with previous data that indicate
that different modalities of endurance training can lead to morphological, molecular and functional conversion of the pathological to
the physiological hypertrophy phenotype in this hypertension
model [15,16]. It should be pointed out, however, that this has not
always been the case: failure of chronic exercise at improving
cardiac function and producing beneficial effects was reported for
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compensated and decompensated hypertrophy induced by aortic
constriction [17].
Carneiro-Júnior et al. [13] also described increased amplitude and
acceleration of the timecourse of electrically-evoked Ca 2+ transients
and contractions in myocytes from trained normotensive and hypertensive animals. These changes, which were correlated with heightened exercise capacity, are reported both in the absence or in the
presence of cardiovascular affections [2,4].
While the increase in contraction amplitude could be partially
explained by enhanced myofilament sensitivity to Ca 2+ after training
[2], changes in cell Ca 2+ handling might significantly contribute to
the improvement of the contractile activity. Most authors have observed that long-term exercise training increases the ventricular expression of the sarcoplasmic reticulum (SR) Ca 2+-ATPase (SERCA)
and/or the ratio of SERCA and phospholamban, its endogenous negative regulator [2,4,13,15]. Such alterations should result in increased
SERCA activity, which could explain the concurrently observed faster
decline of Ca 2+ transients, as SERCA is the main pathway for removal
of cytosolic Ca 2+ in mammalian myocardium [18].
From the physiological point of view, upregulation of SERCA expression and activity should permit adequate ventricular filling at higher
heart rates, which are reached during exercise, thus allowing that cardiac output be compatible with the greater metabolic requirement of the
tissues. This is possibly the reason why the rate of decline of the Ca2+
transients and SERCA protein levels have shown correlation with exercise capacity [13,19]. Additionally, augmented SERCA activity may result in increase in the SR Ca2+ content. This change might greatly
impact the amount of Ca2+ released from the organelle and made available for the myofilaments, mostly because the fraction of the SR Ca2+
content that is released at systole (fractional SR Ca2+ release) is determined, in a positive and non-linear fashion, by the amount of Ca2+
stored in the SR [20,21]. Although the excitation–contraction coupling
efficiency has not been examined by Carneiro-Júnior et. al. [13], such a
mechanism might explain the greater Ca2+ transients observed by
them and other authors, considering that the SR is the source of most
of the Ca2+ that activates contraction. It still remains to be established
whether exercise training and its associated increase in myocardial
SERCA expression lead to greater SR Ca2+ loading and fractional release.
In the case of hypertension models, the amount of released Ca 2+ or the
fractional release was found to be enhanced during the early phases of
compensated hypertrophy [22], whereas it tends to decrease in the
chronic state and progression to heart failure [23,24].
In this respect, it is noteworthy that, under unphysiological conditions (e.g., arterial hypertension, myocardial infarction), SERCA activity and expression are usually decreased [25], in contrast to its
consistent enhancement reported after exercise training. This divergence in the two kinds of hypertrophic remodeling might be at least
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Editorial
partially dependent on the hemodynamic and neurohumoral conditions in each situation. Increase in the mechanical load was shown
to result in acute myocardial SERCA upregulation. However, increased
afterload and/or prolonged β-adrenergic stimulation (which is
expected to occur in chronic hypertension, for instance) also increases the cardiac expression of brain natriuretic peptide (BNP). Evidence indicates that BNP upregulation, which occurs after aortic
constriction and in the failing myocardium, seems to be implicated
in the suppression of load-induced SERCA upregulation [25,26].
Thus, it is possible that the reversal of the overexpression of natriuretic peptides by chronic exercise, as reported by Carneiro-Júnior
et al. [13] and others, may play a role in the SERCA upregulation observed in the hearts of trained animals. Because training did not diminish the blood pressure in hypertensive rats, it is possible that
the decrease in basal sympathetic tone or the increase in venous return during the exercise sessions might be related to the augmented
SERCA expression. The increase in end-diastolic ventricular volume
during exercise might also be linked to redox RyR regulation in response to stretch [27].
Ca 2 + influx also is a key factor in excitation–contraction coupling.
Even for unchanged SR Ca 2+ load, the fractional SR Ca 2+ release can
be enhanced by increase in the trigger of the release process, namely,
the L-type Ca 2+ current [20]. How exercise affects this trigger is a
controversial issue and requires better clarification, as either increase,
decrease or no change in the peak density of this current has been
reported after aerobic exercise training [11,28,29].
Another potential mechanism affecting excitation–contraction
coupling is the direct regulation of the SR Ca 2+ release channel (or
ryanodine receptor, RyR). Little information is available on the effects
of physical activity on RyR function and regulation. Sánchez et al. [5]
described exercise-induced increase in myocardial NADPH oxidase
activity, RyR S-glutathionylation and in the rate of Ca 2+-induced
Ca 2+ release after exercise, which suggests involvement of RyR regulation by reactive oxygen species. This mechanism might mediate
stretch-dependent regulation of SR Ca 2+ release [27].
While available evidence points out that exercise training can lead
to myocardial remodeling associated with stimulation of Ca 2+ cycling, and enhanced contractility and exercise capacity, it also
indicates that this remodeling depends on the persistence of its inductor, namely, the regular physical activity. Two weeks detraining
are sufficient for attenuation of the ventricular hypertrophy, the enhanced aerobic capacity, and the changes in Ca 2+ transients and contraction brought about by long-term (8–13 weeks) endurance
training. After 4 weeks of exercise cessation, such changes are no longer apparent [2,13]. These observations indicate the remarkable plasticity of myocardial regulation and the reversible nature of this type
of remodeling of the myocardium, which requires continuous recruitment of regulatory mechanisms for its maintenance.
The growing knowledge on the cardiac effects of exercise has revealed important aspects of the dynamic and complex nature of the regulation of the myocardium, at molecular and functional levels. At the
same time, it has pointed out the clinical relevance and potential of regular, moderate physical activity as a valuable non-pharmacological alternative for prevention of cardiovascular dysfunctions, as well as for
improvement of cardiac performance of the diseased myocardium.
Disclosures
None.
Funding
This work was funded by grant of the Conselho Nacional de
Desenvolvimento Científico e Tecnológico (CNPq—302996/2011-7 to
JWMB).
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Editorial
José W.M. Bassani⁎
Rosana A. Bassani
Centro de Engenharia Biomédica and
Dept. of Engenharia Biomédica/FEEC,
Universidade Estadual de Campinas, Campinas SP, Brazil
⁎Corresponding author at: Centro de Engenharia
Biomédica/UNICAMP, R. Alexander Fleming 163, 13083-881 Campinas,
SP, Brazil. Tel.: +55 19 3521 9274; fax: +55 19 32893346.
E-mail address: [email protected] (J.W.M. Bassani).
31 January 2013
Available online 9 April 2013
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