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Cell Metab. Author manuscript; available in PMC 2018 May 02.
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Published in final edited form as:

Cell Metab. 2017 May 02; 25(5): 1012–1026. doi:10.1016/j.cmet.2017.04.025.

Molecular Mechanisms Underlying Cardiac Adaptation to

Exercise
Rick B. Vega1, John P. Konhilas2, Daniel P. Kelly1, and Leslie A. Leinwand3
1Centerfor Metabolic Origins of Disease, Sanford Burnham Prebys Medical Discovery Institute at
Lake Nona, Orlando, Florida, 32827, USA
2Department of Physiology, Sarver Molecular Cardiovascular Research Program, University of
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Arizona, Tucson, Arizona, 85724, USA

3Molecular,Cellular and Developmental Biology, BioFrontiers Institute, Univ. of Colorado, Boulder,
Colorado, 80309, USA

Abstract
Exercise elicits coordinated multi-organ responses including skeletal muscle, vasculature, heart
and lung. In the short term, the output of the heart increases to meet the demand of strenuous
exercise. Long term exercise instigates remodeling of the heart including growth and adaptive
molecular and cellular re-programming. Signaling pathways such as the insulin-like growth factor
1/PI3K/Akt pathway mediate many of these responses. Exercise-induced, or physiologic, cardiac
growth contrasts with growth elicited by pathological stimuli such as hypertension. Comparing the
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molecular and cellular underpinnings of physiologic and pathologic cardiac growth has unveiled
phenotype-specific signaling pathways and transcriptional regulatory programs. Studies suggest
that exercise pathways likely antagonize pathological pathways, and exercise training is often
recommended for patients with chronic stable heart failure or following myocardial infarction.
Herein, we summarize the current understanding of the structural and functional cardiac responses
to exercise as well as signaling pathways and downstream effector molecules responsible for these
adaptations.

Introduction
The mammalian heart is a pump, supplying blood and a constant supply of oxygen and
nutrients to itself and peripheral organs (Olver et al., 2015). This workload can account for
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20% of total oxygen consumption and is supported by a complex cellular metabolic and
contractile system of the heart to sustain maximal pump efficiency. This is especially true
during intense bouts of exercise where oxygen consumption by the heart may increase up to
10-fold (Olver et al., 2015). In a remarkable display of metabolic flexibility, cardiac
myocytes can match this increased demand illustrating an extraordinary energy potential and
reserve capacity (Poole et al., 2012). Often referred to as the “athlete's heart,” the heart

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remodels in response to chronic exercise to match the increased workload by increasing in

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size in the absence of cardiac myocyte proliferation. This physiologic growth is

accompanied by increases in energy production capacity, primarily mitochondrial. This
hypertrophic growth of the heart is characterized by normal contractile function at rest. This
is in contrast to pathologic growth that results from prolonged hypertension or ischemic
heart disease, where cardiac contractile function as well as energy metabolic production
declines (Doenst et al., 2013; Ingwall, 2008, 2009; Maillet et al., 2013; Scheuer and
Buttrick, 1987). Historically, investigators have quantified the extent of cardiac growth by
measuring how much the heart wall thickens (Fulton and Rajiah, 2017). However, wall
thickening can occur with either an increase, decrease or no change in ventricular volume.
To account for the proportionality between wall thickness and ventricular volume, cardiac
growth is also characterized as either concentric or eccentric, reflecting the precise
morphological and geometrical features of the enlarged heart (Figure 1) (Blomqvist and
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Saltin, 1983; Scheuer and Tipton, 1977). Both physiologic and pathologic growth show
changes in heart wall thickness and volume, yet pathologic growth often progresses to severe
cardiac remodeling and heart failure, whereas physiologic growth does not.

In addition to direct effects on the heart, it is well-established that regular exercise results in
improved quality of life and increased lifespan (Arem et al., 2015; Moore et al., 2012).
Furthermore, exercise and particularly aerobic exercise, is a central component of cardiac
rehabilitation and reduces cardiovascular morbidity and mortality in patients with heart
disease (Gasiorowski and Dutkiewicz, 2013; Gayda et al., 2016; Guyatt and Devereaux,
2004; Ribeiro et al., 2016; Sharma et al., 2001). While the benefits of regular physical
activity are clearly multifactorial reflecting the integrated responses of many organ systems,
the specific cellular and molecular mechanisms of how exercise attenuates and often
reverses much of the metabolic and contractile derangements in the diseased heart remain
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ill-defined (Hirai et al., 2015; Poole et al., 2012).

At the cellular and molecular level, it is clear that activation of upstream signaling pathways
and resultant transcriptional responses are distinct between physiologic and pathologic
cardiac growth (O'Neill and Abel, 2005). In this review, we focus on the morphologic,
cellular, metabolic, and molecular adaptations of the heart to chronic exercise. For the first
part of this discussion, we take a “systems” approach to define adaptions of the heart to
exercise with consideration of an intact cardiovascular (CV) system (cardiac, neural, and
vascular systems). We will demonstrate that the heart has an innate ability to identify and
distinguish between the types of hemodynamic stress/exercise (dynamic vs static) but also
whether and how the heart senses physiologic versus pathologic signals. We describe the
morphological characteristics of cardiac growth and the implications for cardiac disease
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progression. Finally, we will incorporate a description of how the response to exercise

compares among human subjects and laboratory animals and males and females.

In the second part of this review, we outline the molecular and cellular events that result in
physiologic cardiac adaptation. Many of the molecular mechanisms that mediate the heart's
response to exercise have been identified. For instance, the insulin-like growth factor 1
(IGF-1) and downstream signaling pathway represents one of the critical mediators of
physiologic growth. In addition, considerable evidence from mouse genetic models

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demonstrates that activation of physiologic growth directly antagonizes pathologic growth.

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Finally, we examine how delineation of the mechanisms and molecular events involved in
the response of the heart to exercise may unveil new therapeutic approaches for heart failure.

Cardiovascular system response to exercise

The CV system displays remarkable adaptability during acute and long-term bouts of
physical exertion. Central to this adaptability is the coordinated integration of systemic,
cellular and molecular signaling pathways within the CV system to meet the body's needs.
For example, during acute bouts of exercise, the heart can increase its pumping capacity by
4-8 times as measured by the amount of blood pumped per unit time (cardiac output). This
increase in cardiac function is driven mainly by a 3-4 fold increase in heart rate (60 bpm to
200 bpm) with a small contribution (2-fold) from the strength of contraction or contractility
(Evans, 1985; Hellsten and Nyberg, 2015; Xiang and Hester, 2011). Changes in cellular
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signaling as a result of sympathetic but not parasympathetic activation underlie this increase
in heart rate and contractility to acutely impact cardiac output. Because the CV system is a
closed network, the immense increase in blood flow raises blood pressure, which serves to
maintain adequate flow and nutrient delivery to both exercising and non-exercising tissues.
Despite an early increase in vascular resistance, exercising skeletal muscles can increase its
blood flow through the release of local factors causing blood vessels to dilate, shunting
oxygen-rich blood to metabolically active tissues (primarily working skeletal muscle). In the
short term, these local cues initiate cellular signaling pathways in the vascular system that
can redistribute blood flow to working muscle up to 10 fold, illustrating the power of these
local regulatory control mechanisms. Accordingly, sustained exercise ultimately leads to a
global reduction in vascular resistance (Fagard, 2003; Lauschke and Maisch, 2009).
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The response of the heart to acute exercise demonstrates the extraordinary reserve capacity
of the CV system. Because the end-goal of these hemodynamic adaptations is to meet the
prevailing needs of increased oxygen and metabolic demand, sustained or long-term exercise
training (endurance or strength) induces physiologic and morphological adaptive changes in
the CV system and heart. Typically, athletic conditioning can be categorized as either
endurance/dynamic training or power/strength training (Fagard, 2003; Fagard, 1996; Pluim
et al., 2000). This categorization is largely based on the type of load imposed on the heart;
dynamic sports such as running require a sustained elevation in cardiac function (volume
overload) whereas static sports such as power lifting produce brief instances of elevated
pressure loads (pressure overload). On the other hand, activities such as cycling and rowing
continuously invoke both dynamic and static conditioning throughout the exercise period. In
general, many training programs will often incorporate elements of both dynamic and static
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activities, and, as a result, instigate a mixed-type load on the CV system.

Depending on the type of exercise, the CV system will accommodate the physiologic need
and adapt based on the dominant type of hemodynamic load. Therefore, categorizing
exercise “type” can also be based on the resultant physiologic and morphological changes in
the heart and CV system. In general, long term changes that occur with endurance exercise
training are enhanced aerobic capacity in skeletal muscle and reduced resting cardiac output,
which is paralleled by slower heart rate and increased strength of contraction. Strength

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training, on the other hand, may not induce a change in basal cardiac function even though
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blood pressure and heart rate can increase dramatically during training maneuvers
(MacDougall et al., 1985; Pluim et al., 2000). In addition, because strength training results
in skeletal muscle growth, the overall perfusion to the skeletal muscles is higher due to the
augmentation of skeletal cross-sectional area. The suggestion is that the heart and CV
system have the innate ability to distinguish between exercise types presumably due to
differences in hemodynamic load.

Both types of exercise result in cardiac growth. The cardiac myocyte is terminally
differentiated and increases in size following exercise. Therefore, it is generally accepted
that the growth of the heart due to exercise is from the collective increase in cardiac myocyte
cell size and not from an increase in cardiac cell number. Along with an increase in cardiac
mass, the heart undergoes changes in cardiac morphology that are dependent on the type of
exercise training (Blomqvist and Saltin, 1983; Dickhuth et al., 1994; Fagard, 2003; Scheuer
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and Tipton, 1977; Teske et al., 2010). Physiologic cardiac growth, or more appropriately,
adaptive remodeling (to signify the non-pathologic nature of this type of cardiac growth) can
also be categorized as either concentric or eccentric (Figure 1) (Fagard, 1996; Lauschke and
Maisch, 2009; Pluim et al., 2000). Designation of cardiac growth in this way depends on the
geometric relationship between ventricular chamber size and ventricular wall thickness, or
relative wall thickness (RWT). Typically, eccentric remodeling describes an increase in
cardiac mass where RWT is maintained implicating a coordinated increase in chamber size
and wall thickness. Alternatively, concentric remodeling is characterized by an increase in
cardiac mass accompanied by a disproportionate increase in wall thickness relative to
chamber size. Although both types of cardiac growth normalize (eccentric) or reduce
(concentric) ventricular wall stress, concentric cardiac growth is correlated with worse
clinical outcomes when coupled to cardiac disease (see below).
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As mentioned above, athletic conditioning may be dynamic (running) or static (strength

training), which in turn dictates the type of hemodynamic load imposed unto the heart.
Although heart rate is the predominant determinant of cardiac function, dynamic
conditioning increases venous return to the heart leading to increase contractility via the so-
called Starling effect, enhancing the amount of blood ejected by the heart. This type of
chronic “volume overload” induces eccentric remodeling. On the other hand, strength
training imposes a sudden elevation in pressure inducing a brief, but dramatic increase in
blood pressure, which in turn increases the impedance against which the heart must pump.
For example, peak pressures of 480/350 and 320/250 mmHg have been recorded in subjects
performing strength training (MacDougall et al., 1985). This profound increase in blood
pressure, though intermittent and brief, provokes concentric remodeling of the heart
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(Blomqvist and Saltin, 1983; Devereux and Reichek, 1977; Fagard, 2003; Lauschke and
Maisch, 2009). Again, these designations cannot be universally applied because athletic
training is rarely purely dynamic or static. For example, exercise training programs which
evoke elements of both dynamic and static stimuli lead to a mixed-type of hypertrophic
remodeling (Fagard, 2003).

Dynamic (intermittent) changes in cardiac structure and geometry in response to exercise

training is distinct from that due to chronic hemodynamic stress such as hypertension.

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Regardless of the type of hypertrophic response, exercise-induced remodeling is generally

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considered adaptive in that progression to heart failure does not occur. For example,
physiologic (exercise) cardiac growth is fundamentally distinct from pathologic
(hypertension) cardiac growth in that the former results in preserved or enhanced cardiac
function and adaptive geometry. Hypertrophic hearts resulting from cardiac disease steadily
decline in function over time progressing from concentric growth (elevated RWT) to a
dilated state (decreased RWT) (Fagard, 1996; Frey et al., 2004). Moreover, physiologic
growth may be limited in magnitude compared to pathologic growth. Perhaps the most
critical feature of physiologic growth is its reversibility; growth due to exercise is fully
reversible without apparent adverse consequences (Maillet et al., 2013; Shiojima et al.,
2005). Although anti-hypertensive therapy may reverse cardiac growth, it is unclear whether
this regression is without lasting effect, given that underlying cellular responses such as
fibrosis may not resolve (Fagard et al., 2009). It should also be noted that other types of
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physiologic growth include cardiac growth due to pregnancy or normal postnatal growth and
development.

Animal models of physiologic growth

While it is clear that physiologic cardiac growth is fundamentally distinct from pathologic
cardiac growth, a major line of research has focused on the question of whether cardiac
remodeling following exercise training can evolve into a pathologic form (Lauschke and
Maisch, 2009; Maron, 2009; Pelliccia et al., 2012). This issue is especially relevant in the
case of hypertrophic cardiomyopathy (HCM), an inherited disorder with a 0.2-0.5%
prevalence in the general population. In many instances, the hypertrophic phenotype due to
exercise overlaps with HCM, or differences may be subtle that cannot be distinguished by
measures of cardiac geometry. Specifically, in most instances, HCM does not evolve into a
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dilated dysfunctional heart. However, HCM patients are at significant risk for sudden death.
Indeed, published reports indicate that 35-50% of sudden cardiac deaths in young athletes is
attributable to HCM. Recognizing the critical need to demarcate clear differences between
training-induced and diseased-induced cardiac growth, animal models of exercise have been
employed to study cardiac remodeling and adaption to exercise. As discussed below, the
results of these studies have identified distinct molecular and metabolic signatures that
distinguish physiologic from pathologic forms of cardiac growth.

Animal models, especially rodents, hold many practical advantages including short gestation
periods, large litters, compressed lifespans, identical genetic backgrounds if studying a
single wild type strain, and inexpensive housing. However, other animal species have been
used such as horses, rabbits, dogs and swine (DiCarlo and Bishop, 1988; Evans and Rose,
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1988; Laughlin et al., 1991; Stepien et al., 1998; White et al., 1987). Currently, however, the
genetically modified mouse model is the cornerstone for interrogating cellular and molecular
pathways underlying cardiac biology. Apart from important strain differences, rodents
undergo physiologic adaptations to exercise with the type and extent of adaptation
dependent on the exercise type. Three types of rodent exercise training protocols dominate
the literature: (1) treadmill running, (2) voluntary wheel running and (3) swim training. The
majority of investigations have used a motorized treadmill, subjecting rodents to treadmill
protocols that vary in intensity, incline and duration (Kasper, 2013; Perrino et al., 2011;

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Wang et al., 2010). These early, foundational studies in treadmill-induced adaptation

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employed endurance running protocols, where treadmill speed, duration or incline was
progressively increased or remained fixed. The detail of such protocols has been
comprehensively outlined in other reviews (Perrino et al., 2011; Wang et al., 2010). In most
instances, rats and mice demonstrate a predictable physiologic adaptation to an endurance
exercise regimen that recapitulates human physiology, regardless of the training protocol.
Similar to human counterparts, rats and mice also undergo exercise-induced cardiac growth
ranging from a 5-24% increase in cardiac mass (Diffee and Nagle, 2003; Fenning et al.,
2003; Kemi et al., 2002; Moore et al., 1993). Existing data suggest that a training period of
at least 3-4 weeks is necessary to elicit a significant increase in cardiac mass, again
mimicking the requirement for minimum conditioning period in humans to induce
physiologic cardiac growth.

An alternative treadmill training protocol uses intervals of high-intensity with low-intensity

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treadmill at varying inclines (Haram et al., 2009). Studies using this type of high-intensity
interval training report a more robust cardiac hypertrophic response than continuous
protocols with increases in cardiac mass up to 30% (Haram et al., 2009; Kemi et al., 2005;
Kemi et al., 2002). This approach may also prove relevant to humans given that in the
clinical literature, there is an emerging interest in high-intensity interval training over that of
standard exercise protocols, which incorporates a longer training period (20-60 minutes) at
lower exercise intensities for patients with cardiovascular disease (Gayda et al., 2016; Pattyn
et al., 2014; Ribeiro et al., 2016). Again, a more detailed description of specific interval
training protocols is documented elsewhere (Cardozo et al., 2015; Perrino et al., 2011; Wang
et al., 2010). Although this is an ongoing area of research, patients undergoing high-intensity
interval training show greater or equivalent benefits as compared with established cardiac
rehabilitation programs for most of the parameters, with overall lower exercise times
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(Ribeiro et al., 2016). Many factors contribute to these improved benefits such as the starting
fitness level of the patient. A major confounder, however, is that patients may simply prefer
this type of interval training and exhibit improved adherence to the exercise prescription
confounding interpretation of comparative studies. Accordingly, pre-clinical studies may
provide valuable insight into the distinct cellular and molecular responses to these different
protocols.

Swim training is another well-established aerobic exercise modality to study the physiologic
response of the heart to exercise (Scheinowitz et al., 2003; Tatsuguchi et al., 2004) and for
the assessment of the potential protective impact on cardiac disease (McMullen et al., 2007;
McMullen et al., 2003). For these studies, mice or rats are placed in a swim tank for a given
duration. The fundamental difference between swim and treadmill exercise is how exercise
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intensity is modified; swim training protocols vary intensity by progressively adding weight
“carried” by the animal (Almeida et al., 2009). When comparing cardiac growth from swim
or treadmill exercise training, swim training induces an impressive 30-50% increase in
cardiac mass (Almeida et al., 2009; McMullen et al., 2007; McMullen et al., 2003), which is,
on average, more than that from treadmill exercise.

Considering the forced nature of swim and treadmill exercise protocols, there is concern that
the type of cardiac growth may not be purely physiologic given the stress involved.

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Although mice are typically acclimated to the exercise environment, it can be argued that
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swim or treadmill conditioning deviate from naturally-occurring rodent activities and

initiate, at least in part, a stress-induced cardiac growth. Interestingly, the mouse heart is able
to recognize an intermittent, pathological overload meant to mimic the intermittent nature of
an exercise load as distinctly pathological (Perrino et al., 2006). For this reason, we and
others have employed a voluntary exercise paradigm, where rodents have free, unobstructed
access to a cage wheel (Allen et al., 2001; Eldomiaty et al., 2016; Konhilas et al., 2015;
Konhilas et al., 2004; McMullan et al., 2016). There is ample evidence that voluntary wheel
running is a complex behavior resulting from natural rodent tendencies and laboratory
environment (Konhilas et al., 2015; Meijer and Robbers, 2014; Richter et al., 2014). Activity
from cage wheel exercise generally improves depressive-like behaviors (Eldomiaty et al.,
2016), although this is challenged by studies suggesting an anxiolytic or addictive-like
component to wheel running (Duman et al., 2008; Fuss et al., 2010; Richter et al., 2014).
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Apart from the impact on neural or behavioral function, cage wheel running provides
sufficient aerobic training to induce physiologic cardiac growth in both rats and mice (Allen
et al., 2001; Konhilas et al., 2004; Natali et al., 2001). Similar to humans and forced training,
a minimum of 3-4 weeks of training is required to instigate a 5-20% increase in cardiac mass
depending on strain, sex, diet, age or any combination of these variables (Allen et al., 2001;
Konhilas et al., 2015; Konhilas et al., 2004; Lerman et al., 2002; McMullan et al., 2016).
Interestingly, long-term or loaded cage wheel exercise does not increase the amount of
cardiac growth (Konhilas et al., 2006; Konhilas et al., 2005; Natali et al., 2001).

Regardless of exercise type, the pre-clinical exercise training models have been invaluable
for determining putative cellular and molecular mechanism underlying cardiac adaptation as
will be described below. Still, there are important limitations when attempting to translate
rodent models of exercise to humans. Apart from the obvious size differences, the complex
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hemodynamic response with regards to heart rate, vascular and sympathetic/parasympathetic

systems to increased workload is unique to each species. Consequently, the type of cardiac
remodeling cannot be identical in rodents when compared to humans. In addition, just as
human genotype influences exercise performance, the exercise response in rodents has a
significant genetic component, varying across inbred mouse strains. Therefore, choice of
model or strain may confound or bias results towards the particular model. Despite the
limitations, including some specific for transgenic mice(Davis et al., 2012), this work has
clearly facilitated our understanding of the cardiac exercise response.

Sex dimorphisms in cardiac adaptation to exercise

A major limitation of many published human exercise studies is that males and females are
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typically grouped, or only one sex is studied, when comparing trained and untrained
subjects. Whether examining humans or rodents, the anatomical arrangement of the heart
and peripheral cardiovascular system is identical between males and females. However, the
size of the female heart is smaller than age- and race-matched men (Vasan et al., 1997).
Moreover, the exercise response is likely influenced by sex-specific hormonal and metabolic
factors. Looking at a human study population comparing men and women (average age of 57
years) free of clinically overt cardiovascular disease, all volumetric parameters measured by
magnetic resonance imaging (MRI) were higher in males, even when adjusted for subject

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height, weight or body surface area (Cain et al., 2009; Salton et al., 2002). In these same
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studies, no differences in LV functional parameters were evident although these data are not
always consistent (Cain et al., 2009; Huxley, 2007; Salton et al., 2002). In a large-scale
prospective study of female athletes, investigators reported that LV thickness and cavity
dimensions rarely exceed the upper, clinical limit (Pelliccia et al., 1996). Subsequently,
many reports have emerged showing that females do indeed undergo exercise-induced
growth, especially when adjusted for body mass (George et al., 1999; George et al., 1995;
Maron, 2009). A recent echocardiographic analysis of over 1,000 elite athletes stratified
male and female athletes by type of exercise (Finocchiaro et al., 2016). In this
comprehensive assessment of cardiac adaptation, the study demonstrated increased chamber
dimensions in female athletes compared to male counterparts, only when adjusted for body
surface area. The suggestion is that a greater percentage of female athletes undergoing
dynamic training exhibit eccentric cardiac growth compared to male athletes. Further,
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female athletes rarely demonstrate concentric cardiac growth (Finocchiaro et al., 2016).

Animal models of exercise training also exhibit sex-dependent patterns in cardiac

adaptation/growth. In both rats and mice, the proportionate increase in cardiac mass
following treadmill exercise is greater in females than males (Kemi et al., 2002; Wisloff et
al., 2001b). Compared to males, swim-trained female rats exhibit a greater increase in
absolute heart mass (Mole, 1978). Our group found that female mice exposed to a voluntary
cage wheel exhibit approximately 3-fold greater percent increase in heart mass than their
male counterparts. Because females spent more time running on the cage wheel, we
normalized the extent of growth to distance run; females still demonstrate a great
hypertrophic response even when the extent of growth is adjusted for activity (Konhilas et
al., 2004). A similar sex difference was observed with treadmill exercise in mice, where
females demonstrated more robust cardiac growth than male counterparts (Foryst-Ludwig et
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al., 2011). Our subsequent work provided evidence that the sex dimorphism in cardiac
adaptation to exercise is dependent on many factors. For example, simply switching from a
traditional soy-based diet to a calorically similar casein-based diet eliminated the sex
difference such that males responded to cage wheel running similarly to females eating
either diet (Konhilas et al., 2015). Taken together, the results of numerous studies indicate
that exercise training in rodents (and humans) is a complex behavior and that cardiac
adaptation is impacted by many factors including sex and diet.

Cellular adaptions to exercise

As noted above, the presence of hypertrophic remodeling in athletes presents a unique
problem considering the significant rate of sudden cardiac death, particularly in young
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athletes (Maron, 2009). The diagnosis is made even more problematic because, whether
induced by exercise or by an inherited mutation, cardiac growth may be modest or not
evident (Tardiff, 2011). Adding to the complexity, cardiac growth/remodeling from disease
is a progressive process making prognostic predictions difficult without prior knowledge of
pre-disease cardiac architecture. Therefore, delineation of the cellular manifestations of
exercise-induced cardiac remodeling will not only help delineate mechanisms involved in
the adaptive responses, but could provide predictive tools relevant to the more precise
diagnosis of a clinical hypertrophic phenotype. However, to date, only a few cellular features

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distinguishing physiologic from pathologic cardiac growth have been defined, the most
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robust of which is interstitial fibrosis.

During early postnatal development, cardiac myocytes lose their ability to proliferate and
become terminally differentiated. As a consequence, enlargement of the heart during
development and in response to exercise or pathologic conditions is caused by an increase in
cardiac myocyte size. It has been suggested that changes in myocyte width, length or both
depends on the specific type of cardiac growth (concentric vs eccentric), and whether
cardiac growth is induced by physiologic (exercise) or pathologic (cardiac disease) stimuli
(Maillet et al., 2013; Wisloff et al., 2001a). However, a direct correlation is not always
consistent (Gerdes et al., 1992; Gerdes et al., 1996; Wisloff et al., 2002). Independent of the
specific changes in myocyte morphology, cardiac growth fundamentally normalizes wall
stress regardless of the physiologic or pathologic origin of the hemodynamic load. As a
result, cardiac function is dependent on the 3-dimensional geometry and solely dictated by
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myocyte function. Incidentally, male and female hearts begin with an equivalent number of
cardiac myocytes and, therefore, the difference in cardiac size, although proportional to body
mass, is due to larger myocyte size in males compared to females (de Simone, 1995; Luczak
and Leinwand, 2009; Olivetti et al., 1995). As discussed previously, cardiac growth can be
designated as either concentric or eccentric based on RWT, a measure of ventricular
geometry. The pathological nature of this assignment depends on the extent and origin of
cardiac growth. However, pathologic growth is accompanied by several histological features
that are distinct from physiologic growth. Pathologic growth may be accompanied by an
accumulation of interstitial and perivascular fibrosis. In addition, pathologic cardiac growth
may manifest non-uniform myocyte alignment, termed myocyte disarray (Maron et al.,
1986; Varnava et al., 2001). Myocyte disarray is particularly prominent in HCM and other
inherited forms of cardiomyopathy. In contrast, fibrosis and myocyte disarray has not been
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observed following chronic exercise in rats or mice of either sex (Burgess et al., 1996;
Konhilas et al., 2006; Perez et al., 2013; Thomas et al., 2000) and, presumably, human
athletes. Although collagen accumulation is absent in exercising rodents, previous studies
have shown that treadmill exercise training increases collagen turnover and alters collagen
cross-linking and sub-type in the aging rat (Takala et al., 1991; Thomas et al., 1992; Thomas
et al., 2000). It has also been shown that specific patterns in collagen cross-linking can
markedly influence ventricular diastolic (relaxation) properties (Todaka et al., 1997).

Molecular and metabolic responses in exercise-induced adaptive cardiac

growth: Gene regulatory mechanisms
Numerous studies have documented cardiac transcriptomic changes following exercise
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training (Budiono et al., 2012; Chung et al., 2012; Iemitsu et al., 2005; Solskov et al., 2012;
Strom et al., 2005). The results of these studies indicate that re-progamming of cardiac
structure and function during cardiac growth, whether due to exercise or pathologic stimuli,
involves a cascade of gene regulatory mechanisms. Comparison of the transcriptome of
pathologic forms of cardiac growth with that of physiologic growth has proven informative.
By and large, the transcriptional signatures of physiologic cardiac growth are distinct from
pathologic hypertrophic response (Strom et al., 2005). Pathologic growth is characterized by

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activation of the so-called “fetal gene” program including induction of natriuretic peptides
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and fetal sarcomeric isoform genes (Figure 2). This pattern is largely not observed in
exercise transcriptomes (Strom et al., 2005). Early studies in mice demonstrated that
swimming exercise and aortic banding (a pathologic hypertrophic stimulus) displayed
distinct gene expression pattern changes (McMullen et al., 2003). In contrast to robust
changes in atrial or brain natriuretic peptide (ANP, BNP) seen with banding, no change was
observed with swimming. Similarly, the fetal β-myosin heavy chain was markedly
upregulated by aortic constriction but not by swimming (McMullen et al., 2003). Metabolic
gene expression patterns are also distinct in pathologic versus physiologic cardiac growth
(Figure 2). Expression of genes involved in fuel metabolism and bioenergetics undergo a
well-characterized re-programming during pathologic cardiac hypertrophic growth, and in
the failing heart. This metabolic gene regulatory re-programming is also reminiscent of a
“fetal” shift in that the capacity for burning the main fuel, fatty acids, is reduced and the
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expression of nuclear and mitochondrial genes involved in many mitochondrial energy

transduction and respiratory pathways are downregulated (Aubert et al., 2013). Conversely,
genes involved in some glucose utilization pathways are upregulated. Significant genetic and
experimental evidence suggests that this energy metabolic re-programming may contribute
to the development of heart failure. The alterations in fuel metabolic genes are of particular
interest. Whereas the expression of genes involved in mitochondrial fatty acid oxidation
(FAO), the chief source of ATP in the normal adult heart, are downregulated in disease
(Aubert et al., 2013), this program remains unaltered in response to exercise (Beisvag et al.,
2009). In addition, expression of cardiac genes encoding several fatty acid transporters, fatty
acid binding proteins, and related lipid metabolic pathways are increased in response to
exercise training but not in pathologic cardiac growth or heart failure (Riehle et al., 2014;
Strom et al., 2005). These gene regulatory re-programming events are also reflected in fuel
oxidation rates. Specifically, palmitate oxidation rates, as a measure of FAO, are increased in
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isolated working heart preparations from exercise-trained rats (Burelle et al., 2004).
Conversely, FAO rates are reduced in pathologic cardiac growth and heart failure (Vega et
al., 2015). A mitochondrial biogenic response is also observed in the heart following
exercise training in contrast to the reduction of oxidative capacity in the diseased heart.
Components of the electron transport chain, mtDNA, and citrate synthase activity are all
increased in mouse hearts with swimming (Riehle et al., 2014). Consistent with the changes
in expression of fatty acid utilization genes, mitochondrial respiration in isolated cardiac
strips from trained mice is also increased when palmitoylcarnitine is used as a substrate
(O'Neill et al., 2007).

Quantitative assessment of metabolites representative of major energy metabolic pathways

(targeted metabolomics) provides additional correlates to the cardiac metabolic gene
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expression changes that occur in response to exercise versus pathologic stimuli. Just as
transcriptomics can provide a signature representative of alterations in gene expression,
metabolomics provides a signature reflective of the changes in energy metabolism by
measuring metabolite intermediate pools. Several studies have reported cardiac metabolomic
measurements in experimental and clinical heart failure samples (Bedi et al., 2016; Lai et al.,
2014; Sansbury et al., 2014). These studies have consistently shown changes in acylcarnitine
levels reflective of alterations in mitochondrial FAO rates. Interestingly, direct comparison of

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 Vega et al. Page 11

pre-clinical models of heart failure and exercise reveals striking differences. Levels of
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acylcarnitines were increased in the early stages of a pressure-overload cardiac growth/

myocardial infarct model in mice while voluntary wheel running mice displayed lower
acylcarnitine abundance (Lai et al., 2014). A similar pattern was also observed with TCA
cycle intermediates. Collectively, combined with gene expression changes discussed above,
these results have unveiled robust differences in metabolic re-programming in pathologic
versus exercise-trained physiologic cardiac growth. The maintenance of high capacity for
FAO and, thus, ATP production, is consistent with an adaptive response to the increased
workload. In contrast, pathologic cardiac growth results in a marked shift towards the lower
capacity fetal program, likely a maladaptive energetic response.

What factors mediate the cardiac gene regulatory responses to exercise? Some lessons have
been learned from the delineation of the transcriptional regulatory circuitry involved in
mitochondrial biogenesis in heart and the effects of exercise on skeletal muscle gene
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expression. The peroxisome proliferator activated receptor γ coactivator-1a (PGC-1a) is a

transcriptional coactivator originally identified as a cold-inducible factor involved in
mitochondrial biogenesis in the brown adipocyte (Puigserver et al., 1998). In skeletal
muscle, expression of PGC-1a is dramatically induced by an acute bout of exercise
(Pilegaard et al., 2003). PGC-1a has been shown to mediate the mitochondrial adaptations in
muscle in response to exercise. Targeted disruption of PGC-1a and the related PGC-1b in
skeletal muscle markedly alters mitochondrial function and diminishes exercise performance
(Wende et al., 2007; Zechner et al., 2010). PGC-1a is also activated by exercise in the heart
(O'Neill et al., 2007; Riehle et al., 2014). Some evidence suggests that PGC-1a mediates the
mitochondrial biogenic response and changes in fuel and energy metabolism in heart
following exercise. Specifically, mouse models with altered exercise-induced activation of
PGC-1a expression exhibit a defect in the induction of mtDNA content and palmitate
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oxidation in heart (Riehle et al., 2014). However, additional studies are needed in heart-
specific PGC-1 deficient mice to confirm the role of PGC-1 as being necessary for the
mitochondrial and energy metabolic adaptations observed with exercise.

The pleiotropic actions of cardiac PGC-1α are mediated through direct interaction and
activation of a downstream cascade of transcription factors including nuclear receptors
(Figure 3) (Vega et al., 2015). For instance, PGC-1α binds and co-activates the peroxisome
proliferator activated receptor a (PPARα) to regulate fatty acid import, storage and oxidation
in the heart (Djouadi et al., 1999; Finck et al., 2002; Gilde et al., 2003). Importantly, PPARα
and PGC-1a signaling is inhibited in pathologic growth and heart failure (Aubert et al.,
2013), consistent with the downstream fuel and energy metabolic changes described above.
PGC-1a also promotes a broader mitochondrial biogenic response through its interaction
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with the estrogen-related receptor (ERR) and nuclear receptor factor 1 (NRF-1) (Scarpulla et
al., 2012). In the cardiac myocyte, ERR directly activates expression of genes involved in
virtually all aspects of mitochondrial energy metabolism including the TCA cycle, electron
transport and oxidative phosphorylation, in addition to FAO enzymes (Dufour et al., 2007).
ERRα, the major isoform in the heart, is also required for maximal ATP synthesis and
adaptation to pressure overload (Huss et al., 2007). Notably however, despite being a logical
candidate, the precise role for ERR in cardiac adaptation to exercise has not been
determined.

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 Vega et al. Page 12

Unbiased profiling studies have identified several other transcriptional regulators, in addition
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to PGC-1a, to be involved in the response of the heart to exercise. One of these is CCAAT-
enhancer binding protein β (C/EBPβ). C/EBPβ was found to be downregulated in the heart
following a chronic swimming protocol (Bostrom et al., 2010). Interestingly, knockdown of
C/EBPβ resulted in cardiac myocyte growth and activation of genes similar to what is
observed with exercise, including PGC-1a (Bostrom et al., 2010). These effects are due, at
least in part, to increased levels of the CBP/p300–interacting transactivator with ED-rich
carboxy-terminal domain-4 (CITED4). CITED4 promoted a cellular proliferation response
to exercise in the heart (Bostrom et al., 2010). Overexpression of CITED4 in the heart
resulted in growth with preserved function in the absence of activation of the fetal gene
program (Bezzerides et al., 2016). CITED4 also protected the heart against ischemia/
reperfusion injury (Bezzerides et al., 2016). At this point, the precise targets of CITED4 in
mediating this response are not known. Acute exercise also induces expression of the nuclear
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factor-erythroid 2 p45-related factor 2 (NFE2L2 or Nrf2) (Muthusamy et al., 2012). Nrf2

activates antioxidant gene expression and provides protection against oxidative stress.
Moderate exercise in older mice also activates the Nrf2-antioxidant pathway(Gounder et al.,
2012).

Non-coding RNAs have also been implicated in the molecular regulatory circuitry that
contributes to the response of the heart to exercise. A large number of miRNAs have now
been shown to be critical regulators of cardiac health and disease (van Rooij and Olson,
2012). Not surprisingly, numerous miRNAs are regulated in the heart with exercise
(Fernandes et al., 2015; Liu et al., 2015). To date, these miRNAs have been shown to
regulate genes involved in cardiac structure and function on multiple levels. For instance, a
miRNA expressed in cardiac fibroblasts, miR-29, was shown to repress expression of genes
involved in the fibrotic response and is activated by exercise in the heart (Soci et al., 2011;
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van Rooij et al., 2008). Profiling of exercise models also identified miR-222 as a critical
mediator of physiologic growth (Liu et al., 2015). miR-222 promoted a physiologic growth
phenotype in cardiac myocytes in vitro with increased α-MHC/β-MHC ratio and inhibited
fetal gene markers such as ANF and BNP. And consistent with a recurrent theme, miR-222
was necessary for physiologic growth growth in vivo and was cardioprotective following
ischemic injury (Liu et al., 2015).

Cellular signaling pathways involved in the cardiac exercise response

A key question in understanding the molecular adaptions to exercise in the heart is the
identification of the cellular signaling pathways responsible for transmitting the physiologic
stimuli to downstream transcriptional and other regulatory mechanisms. The use of genetic
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mouse models has identified key cellular receptor and downstream signaling pathway
mediators of the cardiac response to exercise and physiologic growth (summarized in Table
1). Arguably, the key central signaling pathway in this regard is the phosphoinositide 3-
kinase (PI3K)/Akt pathway (Table 1 and Figure 3). A significant finding was the
identification of PI3K(p110a) as a critical mediator of physiologic but not pathologic
hypertrophic growth (McMullen et al., 2003). Notably, signaling through PI3K(p110a) was
shown to be necessary for hypertrophic growth by exercise training but not pressure
overload resultant from aortic banding in mice (McMullen et al., 2003). Activation of

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 Vega et al. Page 13

PI3K(p110a), either by exercise or genetically, was also cardioprotective and directly

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antagonized pathologic cardiac growth (McMullen et al., 2007; Weeks et al., 2012). Akt
serves as an effector kinase downstream of PI3K signaling and is critical for the physiologic
growth program. Akt1-deficient mice displayed impaired cardiac growth in response to
swimming exercise (DeBosch et al., 2006). Interestingly, Akt1-/- mice also exhibited an
exaggerated hypertrophic response to aortic banding further demonstrating the antagonism
between physiologic and pathologic growth programs (DeBosch et al., 2006). The PI3K/Akt
pathway is primarily responsible for transmitting signals from growth factors, namely
insulin and insulin-like growth factor 1 (IGF-1). Interestingly, cardiac IGF-1 expression and
levels are associated with physiologic growth in athletes (Serneri et al., 1999). The IGF-1
receptor (IGF-1R) has also been shown to be both necessary and sufficient to induce
physiologic growth in mice (Kim et al., 2008; McMullen et al., 2004).

Additional evidence supports the idea that signaling through IGF-1R, as well as the insulin
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receptor (IR), transduces key components of the cardiac metabolic adaptation to exercise.
Interestingly, cardiac-specific IR knockout mice displayed impaired mitochondrial
respiration and ATP synthesis rates (Boudina et al., 2009). Surprisingly, these changes occur
in the absence of altered PGC-1a levels although PPARα expression is reduced (Boudina et
al., 2009). However, deletion of the insulin receptor substrate (IRS), required for both
IGF-1R and IR signaling, prevented PGC-1a activation and increased mitochondrial capacity
following exercise (Riehle et al., 2014). These results provide evidence that coordination of
growth programs and metabolic re-programming may occur by IGF-1- and insulin-triggered
signaling pathways.

Other cellular signaling events are capable of activating the PI3K/Akt pathway. For instance,
activation of the ErbB2/ErbB4 tyrosine kinase receptors by the growth factor neuregulin-1
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can stimulate PI3K signaling (D'Uva et al., 2015; Fukazawa et al., 2003). Notably, the
neuregulin-1/ErbB2/ErbB4 pathway regulates cardiomyocyte proliferation and
differentiation during development, and may affect a cardiac regenerative response in the
adult heart (Bersell et al., 2009; D'Uva et al., 2015). Neuregulin-1 expression is upregulated
in the heart with exercise training (Cai et al., 2016; Waring et al., 2014). Interestingly,
exercise has been shown, at least in some contexts, to induce markers of cardiomyocyte
proliferation (Bostrom et al., 2010; Cai et al., 2016). However, the precise role for
neuregulin-1 signaling in the adaptation to exercise, including cardiomyocyte proliferation,
is unknown.

Nitric oxide (NO) has also been shown to be a mediator of the beneficial effects of exercise
in the heart. NO generated by endothelial nitric oxide synthase (eNOS) activates soluble
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guanylate cyclase (sGC) leading to increases in cGMP and activation of protein kinase G
(PKG). The sGC/PKG pathway has been shown to be cardioprotective (Rainer and Kass,
2016). There is substantial evidence for a link between these pathways and the cardiac
benefits of exercise. Exercise was shown to protect against ischemia/reperfusion injury
through activation of endothelial nitric oxide synthase (eNOS) and subsequent increase in
cardiac and circulating levels of NO (Calvert et al., 2011). The benefits of exercise following
myocardial infarction are lost in eNOS knockout animals (de Waard et al., 2010).
Interestingly, these effects may also be dependent on b3-adrenergic receptors. eNOS

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 Vega et al. Page 14

activation by exercise also prevents cardiac remodeling in response to chronic adrenergic

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activation (Yang et al., 2014). Finally, there is evidence that eNOS contributes to the cardiac
metabolic remodeling with exercise. Specifically, increases in mitochondrial biogenesis as
well as PGC-1a levels were absent in eNOS deficient mice following swim training (Vettor
et al., 2014).

Translational and Therapeutic Implications

There is evidence, largely from pre-clinical models, to suggest that exercise and the
physiologic cardiac hypertrophic program antagonizes pathologic growth and improves
cardiac function in the context of pathologic conditions that typically lead to heart failure.
Indeed, most of the murine genetic models that have been identified to control physiologic
growth also impact pathologic growth, demonstrating the inherent dichotomy of these
growth programs (Table 1). Apart from these genetic manipulations of signaling pathways
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and other factors, exercise training has a direct effect on cardiac pathologic remodeling. Low
intensity exercise training has been shown to delay the onset of heart failure in the
spontaneously hypertensive heart failure rat without effects on hypertension (Emter et al.,
2005). Training also improved cardiac function in surgical and genetic models of heart
failure or hypertrophic cardiomyopathy in mice (Konhilas et al., 2006; McMullen et al.,
2007; Vanzelli et al., 2013). In humans, the largest study to examine the effects of exercise in
heart failure patients was the HF-ACTION trial that examined the safety and efficacy of
exercise in over 2300 patients with heart failure with reduced ejection fraction (HFrEF)
(O'Connor et al., 2009). The study examined the effects of a combination of walking,
treadmill and stationary bike exercise at prescribed percentages of maximal heart rate five
times per week. The results of HF-ACTION demonstrated non-significant reductions in
cardiovascular mortality or heart failure hospitalization in those patients prescribed exercise
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as compared to the usual care group (O'Connor et al., 2009). However, these findings were
significant when adjusted for baseline characteristics. Importantly, there were significant
improvements in physical fitness and 6-minute walk test that indicate improvements in
quality of life (Flynn et al., 2009). It is important to note that the HF-ACTION trial only
enrolled patients with reduced ejection fraction. It is now well recognized that a significant
proportion of HF patients have heart failure with preserved ejection fraction (HFpEF). While
a large randomized trial assessing the impact of exercise in HFpEF patients has not been
performed, a number of smaller studies have been reported. A retrospective analysis of these
latter studies has shown improvements in cardiorespiratory fitness and quality of life that
were not associated with changes in either diastolic or systolic function in HFpEF patients
(Pandey et al., 2015). This suggests that exercise-mediated improvements in these patients
may not be due to primary effects on cardiac function but rather peripheral effects on
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skeletal muscle, endothelial function or arterial stiffness (affecting peripheral vascular

resistance). Given the low number of patients enrolled in the HFpEF trials to date, larger
controlled and randomized studies are needed to confirm these findings. In addition,
assessment of the type of exercise most beneficial in both HFpEF and HFrEF cohorts is
warranted.

As noted above, virtually every signaling pathway or factor that promotes physiologic
growth also provides cardioprotection or antagonizes pathologic growth in pre-clinical

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 Vega et al. Page 15

studies (Table 1) (Bezzerides et al., 2016; Bostrom et al., 2010; Liu et al., 2015; Weeks et al.,
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2012). This rationale, together with the HF-ACTION trial results, cardiac rehabilitation may
now be prescribed for HFrEF patients. However, significant barriers exist for exercise
therapy in these patients. Historically, adherence to a strict exercise regimen has been
difficult. Even in HF-ACTION, overall adherence and the amount of time spent exercising
fell over the trial period (O'Connor et al., 2009). These patients are typically older and have
additional co-morbidities that prevent participation or adherence to an exercise regimen.
Therefore, targeted therapies that promote exercise-signaling pathways in the heart hold
promise to complement exercise regimens. However, finding safe and efficacious targets to
promote physiologic hypertrophic pathways is a challenge. The IGF-1/PI3K pathway is a
well-validated target in pre-clinical models. In addition, growth hormone (GH) replacement
therapy represents one strategy to increase circulating IGF-1 levels. Indeed, early pre-
clinical studies demonstrated a benefit of GH in experimental heart failure (Isgaard et al.,
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1997; Yang et al., 1995). Unfortunately, however, clinical trials with GH have been mixed
and have not provided strong rationale for this approach (reviewed in (Arcopinto et al.,
2013)). Targeting energy metabolism and mitochondrial dysfunction would seem to be
another attractive option, possibly in combination with agents that enhance upstream
signaling events. Targeting factors within the downstream PGC-1 cascade may prove
effective. For example, PPARδ shares many targets with PPARα in the heart but also
activates glucose oxidation driving a more balanced fuel utilization profile (Burkart et al.,
2007). PPARδ also mediates the response to exercise in cooperation with AMPK signaling
in skeletal muscle (Narkar et al., 2008). Therefore, selective PPARδ ligands seem an
attractive target for promoting exercise-like effects in the setting of heart failure. This study
also demonstrated that AMPK synergized with PPARδ in skeletal muscle suggesting that
direct AMPK activators could function as exercise mimetics. AMPK activation has a variety
of metabolic effects that could be of benefit in heart failure (Kim and Dyck, 2015). PGC-1a
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is also a direct target of AMPK providing a direct link to mitochondrial biogenesis and
energy production (Jäger, PMID: 17609368). However, concerns over AMPK activation and
excessive glycogen storage in cardiac myocytes have dampened enthusiasm for this
approach (Arad et al., 2007). ERR may also prove to be an effective target, although to date
potent activators have not been identified. In addition, the mitochondrial targeted antioxidant
molecule SS-31 interacts with the mitochondrial-specific phospholipid cardiolipin (Birk et
al., 2013). SS-31, also known as elamipretide, promotes mitochondrial respiration and
improves cardiac function in a canine microembolization heart failure model (Birk et al.,
2014; Sabbah et al., 2016). This molecule is now being tested in the clinic.

Summary and future perspectives

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A greater appreciation and understanding of the specific and quantifiable benefits of exercise
on cardiac structure and function has emerged over the last decade or so. Physical activity
and reversal of sedentary behavior has a clear benefit on mortality risk, attributable in large
part to a reduction of death from cardiovascular disease. Much of the work in this area has
focused on the adaptations of the heart to exercise training. Endurance training produces
growth of cardiac myocyte size with preserved contractile function. This occurs in the
absence of interstitial or perivascular fibrosis or myocyte disarray commonly associated with

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 Vega et al. Page 16

pathologic forms of growth. In this regard, we now recognize that specific growth factors
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and signaling pathways orchestrate a “physiologic” or adaptive hypertrophic program that is

characterized by increased cardiac myocyte size in the absence of activation of the fetal gene
program. In addition, exercise training results in metabolic adaptive cardiac remodeling
enhanced capacity for fuel utilization and a mitochondrial biogenic response coordinated, at
least in part, by PGC-1a. The same signaling pathways responsible for cardiac myocyte
growth also regulate mitochondrial adaptations demonstrating a coordinated evolved
response to ensure adequate energy production to meet the increased demands of exercise.
Importantly, these adaptations also antagonize pathologic signaling in the setting of heart
failure or provide cardioprotection from ischemic insult. Despite mounting evidence that
activation of pathways associated with physiologic growth would provide therapeutic
benefit, issues related to druggability, non-cardiac side effects and efficacy remain major
challenges. However, we believe that the potential benefit of the elusive “exercise mimetic”
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remains high enough for continued research in this area.

Acknowledgments
The authors would like to acknowledge the following funding sources. To J.K., National Institutes of Health
Independent Scientist Award (K02 HL105799); American Heart Association (16GRNT31390006); Sarver Heart
Center at the University of Arizona and the Steven M. Gootter Foundation. To L.A.L., NIH HL117138. To D.P.K.,
NIH grants R01 DK045416 (D.P.K.), R01 HL058493 (D.P.K.), and R01 HL128349 (D.P.K.).

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Figure 1. Concentric compared to eccentric cardiac growth due to physiologic or pathologic

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stress
The normal heart will adapt to an increase in hemodynamic demand whether it is due to
physiologic (e.g. exercise) or to pathologic (e.g. hypertension) stimuli. This hypertrophic
growth, follows 2 typical patterns of growth determined by geometric relationship between
ventricular internal diameter (LVD) and ventricular wall thickness, or relative wall thickness
(RWT): (1) a concomitant increase in ventricular wall thickness and LVD (eccentric),
usually driven by volume overload; (2) a disproportionate increase in wall thickness
compared to LVD (concentric), driven by pressure overload. Typically, eccentric or
concentric growth due exercise (Physiologic) is limited to a 12-15% increase in overall heart
weight and does not progress to heart failure. In contrast, cardiac growth due to disease such
as hypertension, myocardial infarction, or hypertrophic cardiomyopathy (Pathologic)
usually exhibits a more robust hypertrophic response (concentric or eccentric) and often
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progress to a heart failure state. Pathologic eccentric growth may represent early transition to
a dilated state; pathologic concentric growth results in profound thickening of the ventricular
wall with a reduction in LVD.
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 Vega et al. Page 27
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Figure 2. Molecular and metabolic signatures distinguish pathologic and physiologic cardiac
remodeling
Different external stimuli trigger distinct growth programs in the cardiomyocyte. In response
to hypertension or pressure overload (Pathologic), the cardiomyocyte activates a growth
program characterized by the induction of a fetal gene program including increased
natriuretic peptide expression and changes in sarcomere isoform gene expression. This
program eventually leads to a more global pathologic remodeling including left ventricular
dilation and diminished cardiac function en route to the syndrome of heart failure. In
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contrast, exercise (Physiologic) elicits a growth program without induction of the fetal-gene
program and an increase in energy metabolic capacity that matches the increase energy
demands imposed by chronic exercise. This latter program maintains normal cardiac
function. MHC, myosin heavy chain; ANF, atrial natriuretic factor; BNP, brain natriuretic
peptide; FAO, fatty acid oxidation; PPARα, peroxisome proliferator activated receptor α;
PGC-1, PPARγ coactivator-1α.
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Figure 3.
Cellular signaling pathways and transcriptional regulatory circuits mediating physiologic
cardiac hypertrophic growth. Multiple growth factor pathways feed into the PI3K(p110α)-
Akt signaling pathway including insulin growth factor 1 (IGF-1) and insulin to promote the
physiologic hypertrophic response to exercise. These pathways directly antagonize
pathologic growth growth. Exercise also enhances capacity for fuel oxidation and ATP
production through peroxisome proliferator activated γ coactivator-1α (PGC-1α) regulated
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pathways that increase mitochondrial biogenesis and expression of genes involved in fatty
acid β-oxidation. There is also evidence that cross-talk from growth factor signaling or
eNOS to PGC-1α coordinates growth and metabolic pathways through unknown
mechanisms (dotted line). Growth factors and signaling molecules that promote physiologic
growth are shown in green; shown in red are those factors that antagonize physiologic
growth. Transcription factors and coregulators are shown in blue. IRS-1, insulin receptor
substrate 1; CREB, cAMP response element binding protein; eNOS, endothelial nitric oxide
synthase; NRF, nuclear respiratory factor; ERR, estrogen-related receptor; PPAR,
peroxisome proliferator activated receptor; C/EBPβ, CCAAT-enhancer binding protein β;
CITED4, CBP/p300–interacting transactivator with ED-rich carboxy-terminal domain-4.
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Table 1
Mouse models of physiologic and pathologic growth
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Multiple models of transgenic overexpression or genetic deletion have been subjected to pathologic or
physiologic hypertrophic cardiac growth. In many instances, the models were subjected to both pathologic and
physiologic stimuli. The response of each model is summarized in the table indicating the type and extent of
cardiac hypertrophy.

Model Physiologic Pathologic Reference

C/EBPβ+/- Promotes physiologic growth and markers of Inhibits pathologic remodeling Boström et al., 2010
proliferation following pressure overload

CITED4 cardiac Tg Promotes physiologic growth Protects against l/R injury Bezzerides et al., 2016

miR-222 knockdown Necessary for physiologic growth n.d. Liu et al., 2015

miR-222 cardiac Tg No change in cardiac size Inhibits pathologic remodeling Liu et al., 2015
following l/R injury

caPI3K(p110α) Promotes physiologic growth Inhibits pathologic remodeling McMullen et al., 2007, 2004
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following pressure overload

dnPI3K(p110α) Prevents physiologic growth to swimming Exaggerated pathologic McMullen et al., 2003
remodeling following pressure
overload

Aktl-/- Prevents physiologic growth to swimming Exaggerated pathologic DeBosch et al., 2006
remodeling following pressure
overload

IGF1R cardiac Tg Promotes physiologic growth n.d. McMullen et al., 2004

IGF1R cardiac KO Prevents physiologic growth to swimming n.d. Kim et al., 2008

IR cardiac KO Normal growth, inhibits metabolic adaptation n.d. Boudina et al., 2009

IRS-1/IRS-2 cardiac KO Prevents physiologic growth to swimming n.d. Riehle et al., 2014

ERRB2 cardiac KO Necessary for CM proliferation during n.d. D'Uva et al., 2015
development

ERRB2 cardiac Tg Promotes CM proliferation n.d. D'Uva et al., 2015

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eNOS-/- No impact on physiologic growth Necessary for protective effects de Waard et al., 2010
of wheel running post-MI
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Cell Metab. Author manuscript; available in PMC 2018 May 02.