Organ-Specific Physiological Responses to Acute

Organ-Specific Physiological Responses to Acute
Physical Exercise and Long-Term Training in Humans
Ilkka Heinonen, Kari K. Kalliokoski, Jarna C. Hannukainen, Dirk J. Duncker, Pirjo
Nuutila and Juhani Knuuti
Physiology 29:421-436, 2014. doi:10.1152/physiol.00067.2013
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PHYSIOLOGY 29: 421– 436, 2014; doi:10.1152/physiol.00067.2013
Ilkka Heinonen,1,2,4
Kari K. Kalliokoski,1
Jarna C. Hannukainen,1
Dirk J. Duncker,4 Pirjo Nuutila,1,3
and Juhani Knuuti1
Organ-Specific Physiological Responses
to Acute Physical Exercise and
Long-Term Training in Humans
Virtually all tissues in the human body rely on aerobic metabolism for energy
production and are therefore critically dependent on continuous supply of
oxygen. Oxygen is provided by blood flow, and, in essence, changes in organ
perfusion are also closely associated with alterations in tissue metabolism. In
1
Turku PET Centre, University of Turku and Turku University
Hospital, Turku, Finland; 2Research Centre of Applied and
Preventive Cardiovascular Medicine, University of Turku and
Turku University Hospital, Turku, Finland; 3Department of
Medicine, University of Turku and Turku University Hospital,
Turku, Finland; and 4Department of Cardiology, Division of
Experimental Cardiology, Thoraxcenter, Erasmus MC, University
Medical Center Rotterdam, Rotterdam, The Netherlands
ilkka.hei[email protected]
response to acute exercise, blood flow is markedly increased in contracting
skeletal muscles and myocardium, but perfusion in other organs (brain and
bone) is only slightly enhanced or is even reduced (visceral organs). Despite
largely unchanged metabolism and perfusion, repeated exposures to altered
hemodynamics and hormonal milieu produced by acute exercise, long-term
exercise training appears to be capable of inducing effects also in tissues
other than muscles that may yield health benefits. However, the physiological
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adaptations and driving-force mechanisms in organs such as brain, liver,
pancreas, gut, bone, and adipose tissue, remain largely obscure in humans.
Along these lines, this review integrates current information on physiological
responses to acute exercise and to long-term physical training in major metabolically active human organs. Knowledge is mostly provided based on the
state-of-the-art, noninvasive human imaging studies, and directions for future
novel research are proposed throughout the review.
The decision to commence physical movements
is made in the motor cortex in the brain (74).
Simultaneously with voluntary activation of skeletal muscle movement, central command activates sympathetic nervous system and depresses
the parasympathetic branch to coordinate the
associated cardiovascular and ventilatory responses resulting in increased cardiac output
and thus oxygen supply via blood flow to contracting myocardium and skeletal muscles, but
also to skin, to dissipate excess heat, whereas
vasoconstriction occurs in other organs, especially in splanchnic vascular beds (91). A decrease
in peripheral resistance is the result of an increase
in diameter of small arteries (100 –300 ␮m) and
especially arterioles (⬍100 ␮m), whereas the increase in diameter of conduit arteries does not
contribute significantly. Immediately after initiation of exercise, afferent inputs from contracting
skeletal muscles, but also from other organs, fine
tune the hemodynamic responses to meet the
increased metabolic requirements produced by
exercise. To facilitate oxygen supply, a small increase in arterial hemoglobin occurs. In most
1548-9213/14 ©2014 Int. Union Physiol. Sci./Am. Physiol. Soc.
animal species, splenic contraction-induced release of erythrocyte-rich blood contributes to the
increase in hemoglobin (91). In contrast, in humans, the increase in hemoglobin is negligible and
is principally the result of hemoconcentration due
to an extravasation of fluids (120). Arterial supply
of energy substrates remains relatively constant
and close to resting levels as exercise initiates. This
response is triggered and maintained by lowered
circulating insulin and elevated glucagon and epinephrine levels, with simultaneous elevation in hepatic glucose production that corresponds to the
utilization of glucose in actively exercising tissues
(18, 44, 78, 79). However, muscle glycogen and
fatty acid storages are also being used, and as exercise intensity increases, there is an elevation in
circulating lactate levels and an increased contribution of lactate to energy metabolism. With increasing exercise duration, the utilization of freefatty acids released from adipose tissue also
increases substantially. After the cessation of exercise, limb blood flow remains elevated above resting levels 1) to restore metabolic debts and wash
out accumulated metabolic by-products, and 2) to
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The focus of this review will be mostly on adaptations in healthy humans. However, in view of the
high prevalence of obesity in modern society,
stemming from an imbalance of physical activity
and energy consumption (49, 174, 176, 178), which
causes predisposition to increased risk of cardiovascular disease, we will occasionally also discuss
the impact of obesity on exercise (training) responses when appropriate. For review of epidemiological evidence of physical activity against that of
drug therapies and associated molecular mediators, readers are referred to a recent comprehensive review article in this journal (28). Furthermore,
knowledge in this review is mostly provided based
on the state-of-the-art, noninvasive human imaging studies, mostly PET imaging. PET is a molecular imaging method based on radioactive isotopes,
of which general and exercise-related principles
have been described in excellent reviews (6, 45, 98,
173, 189), and the feasibility is also compared with
other techniques in human exercise investigations
ranging from whole-body to tissue levels (80). For
methodological details, readers are referred to
these previous reviews.
FIGURE 1. Physiological responses to acute endurance exercise
In response to acute endurance-type exercise, triggered from brain, the main physiological adjustments include increased ventilation and pumping function of the heart associated with substantially decreased peripheral vascular resistance in the muscles but largely unchanged or even increased resistance in many other tissues. This facilitates the
delivery of oxygen and nutrients to working muscles, which consume high amounts of oxygen and nutrients, especially
when exercise intensity increases. These organ-specific responses are discussed in detail in the text. 1, Increases; ↔,
no change in response; 2, decreases; ↕, may increase or decrease.
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also likely dissipate exercise-induced excess heat
production (46). These general physiological responses to acute exercise, which are illustrated in
FIGURE 1, can be uniquely studied with the positron emission tomography (PET) method even at
the whole-body level (FIGURE 2), will be discussed
at the organ level in detail. Furthermore, due to
repeated exposures to altered hemodynamics
and hormonal milieu produced by acute exercise, long-term exercise training is capable of
inducing physiological effects in many organs.
Thus consistent long-term physical exercise
training of a sufficient intensity, frequency, and
duration produces numerous adaptations in the
human body, which are generally beneficial for
health and well being (28). Particularly relevant in
today’s aging society is that the resultant improved
functional capacity and fitness will enhance the
independency of people, especially when at a
higher age, and markedly reduce the likelihood of
premature death (88, 114). These adaptations, in
response to mainly endurance-type exercise training, are summarized in FIGURE 3 and are discussed
organ by organ after discussion of acute responses.
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Brain
The Effects of Acute Exercise
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Studies in humans and animals have shown that
brain blood flow remains largely unchanged in response to acute exercise (8, 65, 91). Brain blood
flow may marginally increase from rest to mild
exercise but does not increase with increasing exercise intensity. This means that increased metabolic demands of active brain parts are mostly met
by redistributing oxygen supply from the areas that
were active at rest but are not necessary during
exercise, although changes in oxygen extraction
may also contribute. During exercise, blood flow is
directed to the areas controlling locomotor, vestibular, cardiorespiratory, and visual functions (8, 91),
facilitated by direct communication of neurons
and vascular cells (94, 134). The blood flow redistribution follows the changes in metabolic activity.
With respect to utilization of energy substrates, the
brain is a highly omnivorous organ capable of glucose, fatty acid, and lactate utilization. In general,
an increased fatty acid oxidation is characteristic of
the fasted state, whereas the uptake of glucose is
the preferred substrate that predominates particularly during mild- to moderate-intensity exercise.
However, with increasing exercise intensity, brain
glucose uptake decreases (75) as the uptake and
utilization of lactate is enhanced (65, 139, 182).
Regional differences in brain glucose uptake are
also evident, which is furthermore influenced by
the level of physical fitness. Thus the decrease in
glucose uptake in the dorsal part of the anterior
cingulate cortex during exercise is significantly
more pronounced in subjects with higher exercise
capacity (75), which is illustrated in FIGURE 4. Importantly, however, even with current imaging
techniques, it is not always possible to differentiate
whether observed changes in brain metabolism or
perfusion are due to regional descending feed-forward activation associated with voluntary activation of muscles or rather sensory feedback from
afferent nerves (158). To be able to differentiate
between these responses would certainly deepen
our understanding in brain physiology.
Although basic circulatory and metabolic physiological adjustments to acute physical exercise in
brain appear to be fairly well characterized to date,
several important research areas warrant further
investigation. Acute exercise is, for instance,
known to increase endocannabinoids in peripheral
blood (62, 162) in an exercise-intensity-dependent
manner (141). Endocannabinoids, acting through
CB1 and CB2 receptors, reduce pain sensation
among their other functions. Quantification of
cannabinoid receptors and their functional investigation in humans is currently possible with PET
(119, 194), and to further understand exercise brain
physiology (140) it should be explored whether
acute exercise triggers similar kinds of alterations
in endocannabinoid receptor functions as noted in
certain cannabinoid-dependence disorders (118).
It would also be important to investigate whether
acute exercise blunts the reward circuit activation
known to be altered in obesity (122). This could
provide mechanistic physiological human information to explain why especially acute high-intensity (152, 159), or aerobic rather than
strength-training, exercise (34) suppresses energy intake after a single bout of exercise. Noninvasive imaging approaches for the mapping of
FIGURE 2. Effect of cross-country skiing on glucose uptake in all human organs
Three-dimensional, whole body illustration of the effect
of cross-country skiing on glucose uptake in all human
organs, as investigated by Bojsen-Moller et al. (7) by
positron emission tomography. Double-poling was used
as a skiing technique, which resulted in high glucose uptake, particularly in triceps brachii and abdominal muscles as expected. Note also, however, a high brain
activation and a resultant glucose uptake, as well as
fairly high uptake of glucose in heart.
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protein synthesis, shown to be enhanced by exercise (115), would also be important to better understand neuronal adaptations to exercise. Finally,
recent advances in imaging methods and tracer
development have made it possible that opioid
receptors also can be investigated in the human
brain (61), but the understanding of acute exercise
on opioid receptor expression and function warrants further exploration (6).
The Effects of Long-Term Exercise Training
In contrast to acute exercise, long-term physiological adaptations to exercise training in the human
brain have been fairly poorly characterized to date.
Hence, research in this area could yield a wealth of
physiologically novel and medically relevant information. Although human brain studies have not
yet been performed to repeat training-induced increased capillarity, neurogenesis, and mitochondrial biogenesis reported in animal studies (3, 87,
168, 183), a physically active lifestyle has been
shown to lead to higher cognitive performance and
delayed or prevented neurological conditions in
humans (71, 101, 143, 191). This is likely important
for mental functional capacity complementing improved physical functional capacity. There is also
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FIGURE 3. Long-term adaptations of human organs to repeated exposures of mainly endurance
exercise
Illustrated are the long-term adaptations of human organs to repeated exposures to mainly endurance-type physical exercise, which are discussed in the text in detail organ-specifically in terms of most metabolically active organs. The main physiological and structural adaptations involve increased capacities for blood flow and oxygen
consumption basically in every organ in the human body, especially heart and skeletal muscles. Directly contributing to better aerobic fitness are also larger lung volumes and higher ventilatory capacity of highly endurancetrained subjects, which might be the result of remodeling of the lungs (17) and its vasculature (59), although it
remains unclear whether larger lungs are largely genetically determined or a result of training, since evidence
stems mostly from cross-sectional investigations. A higher fitness level is also facilitated by training-induced increased oxygen-carrying capacity in the form of an increase in red blood cell mass, although hematocrit decreases
slightly due to an even greater increase in plasma volume (129), hence the term pseudoanemia. In addition, favorable changes in circulating serum lipid and amino acid profiles have been documented in physically active adults
(84). Blood vessels also adapt structurally by increasing their diameter to make it possible to accommodate increased total blood delivery capacity (91). However, although flow-mediated dilatation is generally improved by
exercise training in patient populations with endothelial dysfunction, it is usually not enhanced in healthy subjects
and may even be slightly impaired in highly endurance-trained athletes (32, 33). Similarly, resting blood pressure
can be lowered by exercise training in hypertensive subjects but remains normal in normotensive subjects (22) as
factors regulating the tonus of the blood vessels are adjusted to limit a decrease in peripheral resistance. Largely
uncharacterized are the effects on bone, inner organs and brain, which should thus be the focus of the future
studies. 1, Increases; ↔, no change in response; 2, decreases; ↕, may increase or decrease.
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mediate this effect (195). Although irisin may not
exert the exact same effects in humans as in mice
(132, 144, 177), it would be worthwhile to explore,
using noninvasive imaging methods with novel
tracers, whether BDNF is also increased in the
human brain, and if so in what brain regions, following several bouts of exercise. A study in mice
suggests that the formation of BDNF is increased in
hippocampus and cortex (145), and it has been
shown in humans that endurance training enhances BDNF release from the brain (157), which is
likely to promote not only brain health but also
general whole body metabolism (81).
Finally, it is presently unknown whether endurance training leads to reductions in resting brain
blood flow and higher oxygen extraction similar to
what has been observed in many other organs.
This question could be addressed using noninvasive imaging techniques such as PET and MRI (99),
which would have the additional advantage over
arterial-venous determinations of allowing assessment of the regional differences in alterations in
perfusion and oxygen extraction in the brain.
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evidence that brain size, one determinant of cognitive performance, is larger in individuals with
higher exercise capacity (101, 142), suggesting that
training-induced increases in fitness levels may
also enhance brain size. This may also explain why
brain blood flow is well maintained in aerobically
fit but old subjects (2), as brain hypoperfusion is
associated with cognitive performance in elderly
subjects and explained by brain atrophy (136). In
addition to an improved cognitive performance,
exercise training may also produce re-organization
at the synaptic and receptor-level in several areas
of the brain, including those areas controlling satiety and anxiety, which would explain the beneficial effects of regular physical activity on body
weight control and prevention of depression (25),
respectively. Research in this area is mandatory to
advance our understanding of the mechanisms underlying the beneficial effects of low-intensity exercise on anxiety relief and of high-intensity
exercise on appetite control. The results from such
studies will provide the scientific evidence to further support implementation of exercise as a therapeutic tool for these neurological conditions.
For example, it would be interesting to study
whether exercise training, similar to bariatric surgery
(180), can correct abnormal (increased) insulin-stimulated brain glucose metabolism in obesity. This is
likely in view of experimental data showing that prolonged exercise decreases brain glycogen content in
rats (105), a phenomenon classically also observed
in skeletal muscles and liver. Moreover, the same
group of investigators also showed that subsequent
glycogen supercompensation can occur in the
brain (104), possibly as an adaptation to cope with
the increased metabolic demands and glycogen
depletion during prolonged exercise. Since brain
glycogen content can be measured in humans
(130, 131), it would be of great interest to study
whether these observations in animals can be confirmed in humans. This could, for example, aid in
examining the relation between local depletion of
brain glycogen due to high local neural activity and
central fatigue during prolonged exercise (20).
The production of brain-derived neurotrophic
factor (BDNF), a key protein regulating maintenance and growth of neurons, is known to be stimulated by acute exercise (145), which may
contribute to learning and memory. BDNF is
released from brain already at rest but increases
two- to threefold during exercise, which contributes 70 – 80% of circulating BDNF (145). It has recently been shown in mice that exercise-induced
irisin release contributes to the increase in BDNF
levels (195). Although it is likely that the increased
regional neural activity in brain itself stimulates
the production of BDNF, a recent study showed
that overexpression of irisin in the liver could also
FIGURE 4. Voxel-based analysis testing group-by-intensity level interaction regarding regional brain glucose uptake in cycling
Voxel-based analysis testing group-by-intensity level interaction regarding regional
brain glucose uptake in cycling as investigated by positron emission tomography
(PET). A: parametric map shows the region where decrease in glucose uptake between 30% and 75% of V˙O2 max exercise intensities was larger in subjects with higher
exercise capacity. B: visualization of the same result on the MRI template image. Figure and results are reprinted from the study by Kemppainen et al. (75) to illustrate
that the major strength of the PET method is to investigate glucose or fatty acid uptake, blood flow, oxygen extraction and consumption, or receptor densities in different areas within an organ such as brain, and are used with permission.
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Cardiac and Skeletal Muscles
The Effects of Acute Exercise
FIGURE 5. Fusion image of structural MRI and functional PET
A typical fusion image of structural MRI and functional PET blood flow image from the middle thigh region at rest.
Outer layer white areas and in the middle of the legs are subcutaneous adipose tissue and bone marrow, respectively,
and darker areas are muscle tissue. Red spots (highest activity and thus highest blood flow) show the blood flow in
larger artery, and yellow and green colors illustrate moderate to high blood flow within the leg. Blue color depicts
lower blood flow areas relative to the areas with the highest blood flows. MRI and PET fusion images are oftentimes
needed to combine high anatomical and functional imaging insights, respectively. Fusion images enable precise localization and investigations of different limb tissues, such as different muscles, adipose tissue, and bone, which cannot
be differentiated by methods that measure bulk blood flow of the limb. However, in contrast to Doppler ultrasound,
for instance, PET can be mostly applied only to steady-state conditions due to its fairly low temporal resolution, which
limits its use when it is of interest to investigate rapid transitions from rest to exercise and rapid changes with increasing exercise intensities.
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Cardiac and especially skeletal muscles play a central role in determining the level of whole body
metabolism not only at rest but particularly during
exercise. This is best illustrated by the fact that
these tissues receive almost all (85–95%) of the
cardiac output and thus oxygen delivery during
maximal exercise (91). Due to their central role in
body movement and in pumping oxygen and energy substrates to all tissues of the body, skeletal
and cardiac muscle have also been the most intensely investigated organs in exercise physiology.
Here, we will highlight only the main adjustments
to acute exercise.
Although there is some animal and indirect human evidence that sympathetic nervous system
plays an important role in distributing blood flow,
not only to different organs but also between active
and inactive skeletal muscle (48), it was not until
recently that direct human evidence was provided
(60). Using PET, which is capable of measuring
organ perfusion and metabolism noninvasively
(FIGURE 5), it was shown that blood flow is markedly increased in nonactive but not in active muscles during ␣-adrenergic receptor inhibition in
healthy volunteers (60). These findings indicate
functional sympatholysis in contracting muscles
but not in any other tissue such as adipose tissue
or bone (60), highlighting the importance of sympathetic nervous control in controlling organ perfusion during exercise. Distribution of blood flow
within and between active skeletal muscles not
only is of substantial importance for matching of
oxygen delivery and consumption locally in skeletal muscle (80), but it also plays an important role
in matching energy substrate delivery with local
metabolic needs (43, 54, 86). Thus, although glucose uptake is increased in response to exercise
and further enhanced by hypoxia (53), its regional
uptake does not correlate with local muscle perfusion (86). This is particularly true with low-intensity exercise, where regional uptake of free fatty
acids correlates tightly with local muscle perfusion
(43, 86). It is presently unclear whether matching
between glucose uptake and local muscle perfusion improves when exercise intensity increases.
Nonetheless, the uptake of glucose is controlled
among others by nitric oxide during heavy- (12)
but not low-intensity exercise (57), whereas nitric
oxide, on the other hand, regulates muscle oxygen
uptake more robustly in a quiescent rather than an
exercising skeletal muscle (58).
Although glucose uptake increases with increasing exercise intensity in working skeletal muscle
(76) and reaches higher uptake levels in endurance-trained men as the absolute workloads they
can perform are higher (29), glucose uptake in myocardium increases only up to moderate-intensity
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The Effects of Long-Term Exercise Training
Investigations made possible by the needle biopsy
muscle sampling technique several decades ago
have demonstrated that endurance exercise training substantially increases the aerobic respiratory
capacity of the skeletal muscle. This is mainly due
to an increase in mitochondrial mass but also is
due to an increase in mitochondrial enzyme concentrations and activities. In addition, endurance
training can stimulate angiogenesis, leading to
higher muscle capillary densities, which act to facilitate oxygen transport to the mitochondria (24).
The higher capillary density increases mean blood
transit time (154), which facilitates an increase in
oxygen extraction (70), thereby allowing a lower
blood flow at rest and at each level of submaximal
exercise. The enlarged capillary surface area and longer blood transit time similarly facilitate the uptake of
substrates, with the relative contribution of glucose,
free fatty acids, and lactate remaining constant at
corresponding relative exercise intensities in
trained vs. untrained subjects (4, 19). However, it
remains to be demonstrated whether blood transit
time and hence oxygen extraction is enhanced in the
endurance-trained human heart.
At the organ level, substantial structural, functional, and electrical cardiac remodeling occurs in
response to exercise training, as recently reviewed
by Prior and La Gerche (137). However, many of
these differences between elite athletes might be
due to genetic differences and self-selection, since
many conclusions are based on cross-sectional investigations. Furthermore, heavy exercise training,
in terms of durations and intensities, appears to be
required to produce structural cardiac adaptations.
Thus differences in (non-athlete level) physical activity had no influence on cardiac structure in genetically identical twins despite clear effect on
fitness (41). When structural adaptations do occur,
they consist of symmetrical enlargement of all
chambers of the heart (163), with eccentric remodeling (due to lengthening of cardiomyocytes) occurring in response to endurance-type training
and concentric remodeling (due to cross-sectional
cardiomyocyte hypertrophy) when a static muscle
loading component is present (137). However, a
recent study, in fact the first prospective long-term
training investigation, failed to observe cardiac
structural adaptations in response to resistance
training in healthy volunteers (164). Major alterations in the cardiac function due to training are not
evident either (137), but conclusions may be hampered by the fact that most of the comparative
studies were performed at rest, and adaptations
could perhaps have been observed during heavy
exercise, for which the physiological adaptations
are intended.
Insights into the cellular mechanisms of exercise-induced adaptations in the human heart are
sparse, owing to the ethical considerations concerning cardiac biopsies in healthy humans.
However, animal studies have shown that subcellular adaptations, for instance in mitochondrial respiratory capacity and capillary densities
in cardiac muscle, are minimal (91, 128, 155,
161). Also myocardial contractility appears to be
minimally affected (91), although there is some
evidence that exercise training enhances myocardial contractility due to enhanced myofilament
calcium sensitivity and cardiomyocyte calcium
handling (192), whereas there is also an extremely
fast relaxation of already very compliant heart of a
well -trained subject (27, 31, 95, 96). Thus the increased maximum cardiac output in the trained
healthy human appears principally due to an increase in cardiac mass and volume and superior
diastolic performance. This is in striking contrast
with the adaptations in skeletal muscle, which can
be “qualitatively” improved by exercise training
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whole body exercise (76). Strikingly, with higher
exercise intensities, when circulating lactate increases, myocardial glucose uptake returns back
to the level observed at rest (76). This highlights
the role of other energy substrates, mainly or
solely lactate (100, 166, 167), increasing their
contribution serving as energy substrates for
heavily working myocardium, whereas uptake of
glucose correlates inversely with circulating free
fatty acids at the low exercise intensities (76). In
contrasts to glucose uptake, cardiac blood flow,
however, increases with increasing exercise intensity and is lower in endurance-trained subjects at
the same absolute, but not with the same relative,
exercise intensity compared with untrained subjects (85). The aforementioned is known regarding
the left ventricle, but there is a lack of very basic
physiological knowledge from healthy human volunteers as to what happens in the right ventricle in
response to acute exercise. Also unknown is
whether regional ventricular blood flow or energy
substrate uptake changes from rest to exercise.
Novel imaging data software now allow fairly detailed physiological investigations also at the regional level (from base to apex and different walls
of the left ventricle) (117), making it possible to
elucidate whether blood flow or glucose uptake
heterogeneity decreases with increasing exercise
intensity also in myocardium as it does in skeletal
muscle (54, 55). In addition, this approach would
allow determination of whether endurance training alters the distribution of blood flow and its
changes from rest to exercise, as one might expect
if blood flow were to follow the changes in mechanical contraction found to be altered especially
in apex in fit subjects (170).
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insulin resistance ameliorated by physical activity
(149), fitness affects insulin sensitivity differently in
skeletal and cardiac muscle (123). Insulin-stimulated whole body and skeletal muscle glucose uptake at rest is namely substantially higher in
endurance-trained but not resistance-trained subjects (172), compared with untrained controls, but
is markedly reduced in myocardium on both
groups, likely due to decreased wall stress and energy requirements or the use of alternative fuels
(123). Exercise is also known to potentiate insulinstimulated glucose uptake in skeletal muscle but
more so in already insulin-sensitive subjects (124).
When continued as regular physical activity, improved insulin sensitivity is evident particularly by
lower serum insulin levels, whereas circulating
fasting glucose is also lowered but not to that extent as insulin (103). Improved insulin sensitivity
by physically active lifestyle is the hallmark in the
prevention of Type 2 diabetes in obese risk profile
subjects (179), although exercise training, even
when combined comprehensively with other lifestyle adjustments, does not provide any benefits
for mortality once diabetic (175, 181).
Bone
The Effects of Acute Exercise
Exercise is known for its benefits in strengthening
bone, the tissue that provides the basic framework
for human movements with muscles. The beneficial changes in bone mineral content and structure
are likely made possible by increased acute exercise-induced and recovery phase blood flow that
supplies bone with nutrients in accordance with its
metabolic needs (23, 26, 106). However, as is the
case with basically every organ located deep in the
human body, the study of the regulation of blood
flow to bone in humans has been hampered by
limitations in technology. However, we have recently
begun investigating the responses of femoral bone to
exercise and other physiological perturbations, and
found that human bone is surprisingly active tissue
as its blood flow and glucose uptake clearly increase
in response to acute exercise (51). Nevertheless,
blood flow levels off with increasing exercise loads,
likely due to sympathetic nervous system restraints,
which direct flow to active muscles rather than to
bone and other less active tissues. This phenomenon
appears to be analogous to metabolism in human
tendons (37). Furthermore, human bone also has
substantial capacity for vasodilation (higher than that
induced by exercise), as assessed by direct pharmacological determination, but its blood flow does not
change when humans are challenged with acute systemic hypoxic gas mixture breathing (51). This is
likely due to constrictive stimulation of arterial
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even without an appreciable increase in muscle
mass (e.g., in marathon runners), so that exercisetrained skeletal muscle is capable of performing
more work and consuming more oxygen per unit
mass than that of sedentary muscle. These adaptations are also coupled with enhanced skeletal
muscle vasodilation capacity with increasing fitness (52), whereas coronary adaptations occur
commensurately with, but do not exceed, the degree of hypertrophy produced by exercise training
(39, 56, 69, 90).
Although there are animal data showing lower
myocardial oxygen consumption under resting
conditions in trained animals (91), human data are
scarce. When the metabolic milieu was made comparable between trained and untrained subjects by
producing euglycemic hyperinsulinemia, endurance-trained heart showed lowered cardiac oxygen
consumption per unit mass (171), which appeared
as the result of exercise-induced bradycardia since
other determinants of oxygen consumption were
unaltered (171). However, whether oxygen consumption is also lowered in the trained heart without insulin stimulation remains uncertain, since
substrate utilization is well known to affect cardiac
energetics (110, 126, 160). It is possible that a lower
oxygen consumption in the trained heart is not as
pronounced in the basal fasting state. Thus, in
contrast to skeletal muscle, utilization of energy
substrates in the heart is principally determined by
their availability in arterial blood (5, 30, 193). In
view of the higher levels of circulating free fatty
acids and lower insulin levels in trained subjects,
the resultant increase in free fatty acid utilization
will result in slightly higher levels of oxygen consumption per high energy phosphate produced
(110, 126, 160), thereby mitigating the lower oxygen consumption in trained subjects. Paradoxically, this condition resembles obesity, where there
is an excessive myocardial uptake of free fatty acids, although it can, however, be corrected by
weight loss (186).
Additionally, although studies on structural adaptations of the right ventricle have emerged (137,
163), basic adaptations of right ventricular blood
flow and oxygen utilization in response to acute
exercise and long-term training warrant further investigation. Such studies would be particularly relevant in view of emerging evidence suggesting that
the right ventricle may undergo remodeling in response to physical training to an even larger extent
than the left ventricle (137). Several PET tracers are
also available for the investigation of neural innervations of heart (92), enabling the study of possible
modification by exercise training due to exposure
to high levels of stress hormones during exercise.
Finally, although higher fitness is well known to
be associated with higher insulin sensitivity and
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The Effects of Long-Term Exercise Training
Although repeated exposure to exercise-induced
mechanical stress improves the physical characteristics of bone, we are not aware of any studies that
have investigated the effects of exercise training on
blood flow or metabolism of human bone. Such
studies would be particularly timely and important
because a role for bone in influencing whole body
metabolism is increasingly being recognized (72,
111, 198). The bone plays an important role in
releasing (vascular) precursor cells into the circulation, and there is evidence that exercise can enhance this mobilization of stem cells from bone
marrow, possibly through nitric oxide (89). However, studies in humans are still scarce. Similarly,
the effects of exercise training on vascularity and
its integrity in bone marrow remain largely unstudied in humans. Such studies would be important
since exercise training could potentially correct
vascular impairments and attenuate endothelial
progenitor cell release observed in bone marrow in
disease states such as diabetes (125, 190). Taken
together, exercise-induced physiological adaptations in bone (marrow) have remained largely ill-
studied in humans to date, and many of these
issues should clearly be the subject of future
studies.
Liver, Pancreas, and Gut
The Effects of Acute Exercise
Although we are not aware that tissue perfusion in
liver, pancreas, and gut has been determined in
response to acute exercise in humans, there are
studies that have elucidated that arterial inflow in
arteries supplying these organs is decreased (79,
133, 153). These studies also support the concept
that overall metabolism, as estimated from total
oxygen consumption, of these splanchnic organs is
unaffected by exercise. Blood flow can, however,
be reduced to as low as 20% of its resting value,
but, at least up to moderate-intensity exercise, this
is more apparent in splanchnic organs other than
gut (133), which may help to prevent intestinal
hypoperfusion. Nevertheless, when exercise intensity further increases, it may lead to gut hypoperfusion and gastrointestinal compromise, which
could have a negative impact on exercise performance and subsequent recovery (184). Furthermore, epithelial integrity and gut wall barrier
function might also be compromised with repeated exposure to strenuous physical stress (184),
which may explain why some subjects may have to
avoid intense exercise (184).
Although the overall level of metabolism does
not change in response to acute exercise, especially
pancreas and liver perform important functions
during exercise. Thus, although the production of
insulin from pancreatic ␤-cells is blunted mainly
by sympathetic stimulation, there is an increased
production of glucagone from pancreatic ␣-cells.
The latter allows maintenance of blood glucose
levels and effective mobilization of free fatty acids
and their utilization, particularly during prolonged
exercise. The capacity of the liver for gluconeogenesis from lactate and branched-chain amino acids
during exercise is also well recognized. Conversely,
the mechanism by which the uptake of energy
substrates, mainly glucose and free fatty acids,
changes in these tissues themselves in response to
acute exercise remains poorly understood. In the
fasting state, the liver consumes mainly free fatty
acids and amino acids, but from the total amount
of free fatty acid oxidation, the liver uses only a
small portion of fatty acids for its own intrinsic
metabolic processes (112). Future studies are required to investigate the effects of exercise on substrate uptake and utilization.
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chemoreceptors that predominate over a local hypoxic vasodilation in bone.
It is likely that exercise-induced enhanced bone
perfusion is also responsible for enhancing the efflux of stem cell from bone marrow. As recently
reviewed by Schuler et al. (156), acute physical
exercise has been shown to mobilize stem cells
such as endothelial precursors from bone marrow.
The mechanism underlying this recruitment appears to be principally through endothelial nitric
oxide synthase-derived nitric oxide (89), although
sympathetic nervous system may also contribute
(73). However, it remains to be established to what
extent these exercise-mobilized stem cells are capable of incorporating into the vascular wall and
contribute to end-organ adaptations (138). Moreover, we have recently investigated that, although
nitric oxide synthase inhibition reduces bone
blood flow at rest, it does not affect bone blood
flow during exercise even when combined with
inhibition of prostanoids, whereas the inhibition of
adenosine receptors reduces bone blood flow during exercise significantly (Heinonen I, Saltin B,
Kaskinoro K, Knuuti J, Boushel R, Hellsten Y, Kalliokoski KK, unpublished observations). Adenosine
receptors are known to be expressed in bone and
adenosine acting as primary signaling molecule
(35), and in future mechanistic studies that could
be performed in humans it might be fruitful to try
to relate exercise- and inhibition-induced changes
in bone blood flow with simultaneous sampling of
peripheral (femoral) venous blood to gain insights
into their possible associations.
The Effects of Long-Term Exercise Training
Increasing insulin resistance due to physically inactive lifestyle is likely not only due to augmented
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Adipose Tissue
The Effects of Acute Exercise
There are two types of adipose tissue in humans,
white and brown adipose tissue. White adipose tissue
is distributed mainly subcutaneously throughout the
entire body and in most of the subjects has the capacity to undergo expansion when energy is in surplus. Nevertheless, when the largely genetically
determined capacity of subcutaneous fat storage is
exceeded, fat starts to accumulate in a form of
white fat around and within organs and as visceral
fat, the phenomenon that is associated with impaired health and metabolic diseases (135, 174).
Conversely, brown adipose tissue is localized only
in special small depots, mostly in the neck area,
and is activated by cold exposure (187). In contrast
to white fat, which stores fat, brown fat burns
energy, which is released as heat. Interestingly, it
was recently proposed that brown fat in adult humans may not be exactly similar to the brown fat
found in small animals such as mice, and hence
has been named “beige” fat (196). In contrast, in
human infants, the brown fat does closely resemble the brown fat of rodents (97), suggesting that
not species differences but also age differences in
expression exist. In humans, brown or beige fat has
also been proposed to play a role in body weight
control (197). As mentioned, cold stress is capable
of inducing the activation of this fat, but it is currently unknown whether acute physical exercise
can activate brown fat depots in humans.
It is well known that lipolysis in white fat is
activated by exercise (176), which releases free fatty
acids into the circulation to be consumed by other
tissues, a phenomenon that is particularly pronounced when the duration of exercise increases.
During prolonged exercise, lipolysis and associated
changes in adipose tissue blood flow (13–16) are
driven largely by a decrease in plasma insulin and
circulating catecholamines (165), particularly epinephrine (21). However, although adipose tissue
blood flow increases from rest to light- and moderate-intensity exercise (47), it has been speculated
that a reduction in adipose tissue blood flow during high-intensity exercise results in decreased free
fatty acid release (150) at a time when it is energetically no longer efficient to burn energy from
fat. This phenomenon might be mediated by sympathetically mediated vasoconstriction in white
adipose tissue, since norepinephrine reduces adipose blood flow acutely, both at rest and during
exercise (60). Sympathetically mediated vasoconstriction is also likely to contribute to hypoxiainduced adipose tissue blood flow reduction
during exercise (50). Adipose blood flow is also
regulated by nitric oxide (58), but only at rest,
whereas adenosine regulates adipose blood flow
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insulin resistance in skeletal muscles but also in
the liver, where insulin no longer normally suppresses the production of glucose. Although exercise training effectively improves insulin sensitivity
in muscles (149), it remains incompletely understood whether training similarly ameliorates insulin resistance in the liver. This question is
important since hepatic insulin sensitivity plays a
pivotal role in controlling whole body metabolism.
Hence, it is likely, but remains to be investigated,
that exercise leads to improvements in liver insulin
sensitivity that are similar to those produced by
bariatric surgery in obese and diabetic subjects
(66). This same holds true for pancreas and gut,
where insulin resistance is also present in obesity
(9, 64, 185). In the gut, insulin resistance develops
even before the deterioration of systemic glucose
tolerance (64), and it is plausible that physical activity could maintain the normal metabolic state of
this important tissue for early absorption of food
and handling of pathogens and immunity.
Interestingly, endurance-trained subjects show
increased free fatty acid uptake in skeletal muscle
but lower uptake in the liver during hyperinsulinemia (67). This exercise-induced reduction in free
fatty acid uptake in the liver was also observed in
twins who were discordant for recreational physical activity, and who showed no difference in free
fatty acid uptake in skeletal muscle (42). Furthermore, liver free fatty acid uptake was associated
with body fat percentage (38), whereas liver and
pancreatic fat percent was also found to be lower
in the active twin (38), and pancreatic fat was associated with a subject’s fitness, insulin resistance,
and hepatic fat content (38). These findings, together with findings regarding physical activity and
liver fat (146), clearly support the concept that
accumulation of ectopic fat in visceral organs is
generally unhealthy, whereas excess adiposity in
these organs can be prevented by regular physical
activity.
By using PET for noninvasive measurement of
renal blood flow (83), it has been demonstrated
that renal blood flow is reduced in response to
acute (static) exercise (108, 109). It has also been
shown that chronic endurance training decreased
renal sympathetic nervous activity in sedentary
normotensive men, which was associated with a
decrease in renal (but not cardiac) vascular resistance (107). To the best of our knowledge, no study
has addressed whether perfusion of adrenal glands
is altered in response to training. Alterations would
be plausible since repeated exposures to extremely
high blood flow (⬃300 ml·min⫺1·100 g⫺1) are common during high-intensity exercise (102), co-existing with a higher epinephrine secretion capacity in
endurance-trained individuals compared with sedentary subjects (77).
REVIEWS
during exercise (47). Other factors, such as natriuretic peptides released from the heart, are also
likely to contribute to adipose tissue blood flow
regulation (176).
The Effects of Long-Term Exercise Training
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Although it is well known that exercise training can
lead to reductions in fat mass and associated biological adaptations (176), including an increase in
capillary density due to fat cell size reduction, the
elucidation of physiological adaptations to longterm physical activity in adipose tissue is still in its
infancy. This is the case, for instance, in regard to
adipose blood flow at rest and during exercise
(176). As an endocrine organ, adipose tissue can,
however, secrete various adipokines (176) that can
trigger important physiological functions in various other tissues in the body, which can be modulated by endurance training (11). Recent animal
studies suggest that training can modulate several
aspects of metabolism within the fat tissue (169).
In humans, both glucose (188) and free fatty acid
(40) uptake were shown to be higher in visceral
than in subcutaneous fat. However, subcutaneous
fat contributed more to circulating levels of free
fatty acids owing to its larger total mass (40). Interestingly, aerobic endurance exercise-induced
improvement in insulin-stimulated glucose uptake
was confined to skeletal muscle, with no detectable
change in glucose uptake in adipose tissue (147).
The latter may have been due in part to the reduction in adipose mass, which occurred to a similar
extent in subcutaneous and visceral depots. Although adipose tissue is likely not the main tissue
mediating the amelioration of systemic insulin resistance as a result of exercise training, it may
participate in maintaining and prolonging postexercise oxygen consumption and therefore overall
energy metabolism leading to weight loss. In this
respect, it would be important to investigate
whether endurance training can change the phenotype of white fat to a more beige or even brown
phenotype. Recent investigations in animals support this concept (10, 148), but recent studies in
humans either did not see any signs of browning
(151) or only saw signs to a minimal extent (121).
Moreover, browning of white fat, and to a substantial extent, would be needed to show physiologically relevant effects on whole body metabolism, as
a recent human investigation has shown that
purely brown fat thermogenesis can only account
for energy consumption of ⬍20 kcal/day (113).
This amount of energy consumption can be
achieved by performing moderate physical exercise, such as brisk walking or moderate-intensity
running, for only 2 min (113), highlighting the potential of physical activity per se in burning excess
calories and preventing and treating associated
metabolic diseases.
Finally, although obesity is generally considered
unhealthy, it has been postulated over the years
that being physically fit protects against the associated consequences (93). Furthermore, during recent years, a concept of “metabolically healthy
obesity” (MHO) has emerged, meaning that, despite increased body weight and adiposity, classical cardiovascular risk factors remain normal.
Questions, however, remain, such as whether
MHO is just an incomplete clinical characterization (inflammatory status, etc.) of subjects or a
transition phase (1). Recent studies suggest that,
although MHO is associated with lower risk for
Type 2 diabetes (63), risk for cardiovascular diseases and all-cause mortality is elevated compared
with metabolically healthy normal-weight individuals (63, 82). Nevertheless, one recent study, however, also importantly suggests that higher physical
fitness is a characteristic of MHO, since once fitness is accounted for, MHO appears as a benign
condition (127). Furthermore, a recent study in
weight-discordant monozygotic twins suggests
that sport activity (but not necessarily other physical activity disciplines) is important in MHO, since
sport activity appeared to be one of the few protective lifestyle factors against fatty liver (116).
However, physical activity and fitness are not only
important characteristics of MHO but are protective also in subjects with clustered metabolic abnormalities (36). This effect is likely mediated by
physiological responses other than influence on
conventional risk factors (68), supporting exercise
as an important lifestyle behavior, particularly in
primary prevention of cardiovascular diseases.
Conclusions
Based on the available evidence obtained in human subjects, we conclude that many of the main
regulatory aspects, especially in cardiac and skeletal muscles, in response to acute exercise and longterm physical training have been fairly well
characterized. In contrast, many important issues
pertaining to perfusion and metabolism in brain,
bone, adipose tissue, and splanchnic organs have
been comparatively sparsely investigated and
hence remain to be elucidated. Although the state
of general metabolism does not change substantially in nonmuscular tissues during acute exercise,
it is nonetheless conceivable that the alterations in
central (blood pressure that is transmitted to the
periphery) and local (shear stress) hemodynamics,
as well as changes in energy substrate and hormonal milieu, produce adaptations in these tissues. These intriguing organs should therefore
be the focus of future research to even more
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431
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comprehensively enhance our understanding of
the physiological adaptations to voluntary physical
exercise in humans. A deeper understanding of the
exercise training-induced adaptations will hopefully ultimately enable us to improve health and
well being of the general population as well as a
wide variety of patient populations. 䡲
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This review was conducted within the Centre of Excellence in Molecular Imaging in Cardiovascular and Metabolic Research, supported by the Academy of Finland,
University of Turku, Turku University Hospital and Åbo
Akademi University. The studies performed at the Turku
PET Centre and reviewed here have been financially supported by the Ministry of Education of the State of Finland,
the Academy of Finland, the Finnish Cardiovascular Foundation, the Finnish Cultural Foundation, and its SouthWestern Fund, the Finnish Sport Research Foundation,
and the Hospital District of Southwest Finland.
No conflicts of interest, financial or otherwise, are declared by the author(s).
Author contributions: I.H., K.K.K., J.C.H., D.J.D., P.N.,
and J.K. conception and design of research; I.H. prepared
figures; I.H. drafted manuscript; I.H., K.K.K., J.C.H., D.J.D.,
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