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Muscular exercise requires transitions to and from metabolic rates often exceeding an order of magnitude above resting and places prodigious demands on the oxidative machinery and O2-transport pathway. The science of kinetics seeks to characterize the dynamic profiles of the respiratory, cardiovascular, and muscular systems and their integration to resolve the essential control mechanisms of muscle energetics and oxidative function: a goal not feasible using the steady-state response. Essential features of the O2 uptake (VO2) kinetics response are highly conserved across the animal kingdom. For a given metabolic demand, fast VO2 kinetics mandates a smaller O2 deficit, less substrate-level phosphorylation and high exercise tolerance. By the same token, slow VO2 kinetics incurs a high O2 deficit, presents a greater challenge to homeostasis and presages poor exercise tolerance. Compelling evidence supports that, in healthy individuals walking, running, or cycling upright, VO2 kinetics control resides within the exercising muscle(s) and is therefore not dependent upon, or limited by, upstream O2-transport systems. However, disease, aging, and other imposed constraints may redistribute VO2 kinetics control more proximally within the O2-transport system. Greater understanding of VO2 kinetics control and, in particular, its relation to the plasticity of the O2-transport/utilization system is considered important for improving the human condition, not just in athletic populations, but crucially for patients suffering from pathologically slowed VO2 kinetics as well as the burgeoning elderly population. © 2012 American Physiological Society. Compr Physiol 2:933-996, 2012.
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Oxygen Uptake Kinetics
David C. Poole*1 and Andrew M. Jones2
ABSTRACT
Muscular exercise requires transitions to and from metabolic rates often exceeding an order
of magnitude above resting and places prodigious demands on the oxidative machinery and
O2-transport pathway. The science of kinetics seeks to characterize the dynamic profiles of the
respiratory, cardiovascular, and muscular systems and their integration to resolve the essential
control mechanisms of muscle energetics and oxidative function: a goal not feasible using the
steady-state response. Essential features of the O2uptake ( ˙
VO2) kinetics response are highly con-
served across the animal kingdom. For a given metabolic demand, fast ˙
VO2kinetics mandates a
smaller O2deficit, less substrate-level phosphorylation and high exercise tolerance. By the same
token, slow ˙
VO2kinetics incurs a high O2deficit, presents a greater challenge to homeostasis
and presages poor exercise tolerance. Compelling evidence supports that, in healthy individuals
walking, running, or cycling upright, ˙
VO2kinetics control resides within the exercising muscle(s)
and is therefore not dependent upon, or limited by, upstream O2-transport systems. However,
disease, aging, and other imposed constraints may redistribute ˙
VO2kinetics control more prox-
imally within the O2-transport system. Greater understanding of ˙
VO2kinetics control and, in
particular, its relation to the plasticity of the O2-transport/utilization system is considered impor-
tant for improving the human condition, not just in athletic populations, but crucially for patients
suffering from pathologically slowed ˙
VO2kinetics as well as the burgeoning elderly population.
C
2012 American Physiological Society. Compr Physiol 2:933-996, 2012.
Introduction
As a scientific expedient, physiological processes are often
studied under “steady-state” conditions which may be approx-
imated at rest and during moderate (below lactate threshold,
LT) or even heavy (>LT) intensity exercise. Whilst undoubt-
edly valuable, it may be argued that this steady-state of ex-
ercise is a laboratory contrivance. For, whilst awake, humans
and animals transition frequently among different metabolic
rates as we, for example, get up from a chair, climb stairs, run
to catch a bus or train, or engage in activities such as physi-
cal labor and recreational or professional sports and activities
(Fig. 1). Because of the very limited nonoxidative muscle
energy stores, at the transition from rest to exercise there
must be a coordinated pulmonary, cardiovascular, and mus-
cular system response to increase rapidly the flux of O2from
atmosphere to muscle mitochondria allowing aerobic ATP
production (See Section Integration of Dynamic Responses
in the Pathway for O2). Thus, the transitory phase(s), prior to
achievement of any steady state, provides a window into the
fundamental processes of muscle energetics and metabolic
control that are otherwise not accessible. Indeed, that ˙
Vo2
does not rise immediately to its steady-state suggests that a
finite metabolic capacitance may have evolved as a crucial fea-
ture of the energy transfer pathways. Unlike ˙
Vo2max which
may be limited by the capacity of the O2-transport system in its
entirety (review 50, 648, 586, 744) the locus of control of ˙
Vo2
kinetics is believed to be sited principally in the muscle mito-
chondrion [see Section Site(s) of Limitation of ˙
Vo2Kinetics:
Oxygen Delivery Versus Cellular Respiration]. For the major
forms of whole-body exercise such as walking, running, and
cycling it is only disease and other system dysfunctions (aging
and possibly very low fitness levels) that displace this locus
of control upstream into the O2-transport pathway (Fig. 2).
Figure 3 portrays the key systems in the O2-transport pathway
and emphasizes intramuscular energetic control rather than a
more proximal limitation in O2flux.
Whilst acknowledging the complexity and importance of
understanding pulmonary, cardiovascular, and muscle-control
mechanisms in facilitating O2flux to the mitochondria (see
Section Integration of Dynamic Responses in the Pathway
for O2) this review focuses on the ultimate end product as
it is expressed in the ˙
Vo2kinetics. In particular, the lively
controversy regarding the role of O2delivery versus intra-
muscular metabolic control takes center stage [see Section
Site(s) of Limitation of ˙
Vo2Kinetics: Oxygen Delivery Ver-
sus Cellular Respiration] (182, 273, 275, 280, 363, 370, 589,
728). Whereas it is acknowledged that impediment at any
upstream site (lungs, cardiac, vascular, and microvascular)
can, if sufficiently severe, ultimately slow ˙
Vo2kinetics and
impair exercise performance (see Section Disease States),
*Correspondence to poole@vet.ksu.edu
1Departments of Kinesiology, Anatomy, and Physiology, Kansas State
University, Manhattan, Kansas
2School of Sport and Health Sciences, University of Exeter, Exeter,
Devon, United Kingdom
Published online, April 2012 (comprehensivephysiology.com)
DOI: 10.1002/cphy.c100072
Copyright C
American Physiological Society
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20
40
0
40
20
0
40
20
0
0 150 300 450 600
Time (s)
VO
2
(ml min
–1
kg
–1
)
Figure 1 Profiles of children’s (6-10 year olds) ˙
V
O2during free
ranging spontaneous activity. These have been ranked as low, mod-
erate, and heavy activity for (A) (female), (B) (female), and (C) (male),
children respectively. Horizontal line denotes the gas exchange thresh-
old, GET. Redrawn, with permission, from Bailey et al. (22).
compelling evidence will be presented that, in healthy young
humans cycling or running and horses (424, 425), the speed
of the ˙
Vo2kinetics at exercise onset is limited predominantly
by some intramuscular process(es) (most likely oxidative en-
ergy system inertia) rather than bulk muscle O2delivery per se
(Fig. 2). However, the balance of control may change with dif-
ferent modes (e.g., leg vs. arm, see Section Effects of Exercise
Modality on ˙
Vo2Kinetics) and intensities (i.e., moderate and
heavy vs. severe) of exercise, within different fiber-type popu-
lations (see Section Influence of Muscle Fiber Type and Motor
Unit Recruitment on ˙
Vo2Kinetics), with aging (see Section
Maturation and Aging), in different experimental perturba-
tions (e.g., hypoxia) and also for diseases that compromise
O2transport such as heart failure and chronic obstructive pul-
monary disease (see Section Disease States). Whereas there
are many acute and chronic perturbations that slow ˙
Vo2ki-
netics, primarily via reduced O2transport and the dependence
of metabolic control on microvascular and intramyocyte O2
pressures (74, 372, 511, 512), there is an extraordinary de-
gree of plasticity in both directions. Exercise training causes
a speeding of the primary ˙
Vo2kinetics within very few train-
ing bouts and the ˙
Vo2slow component ( ˙
Vo2sc) is reduced by
exercise training and often by improved muscle O2delivery
(See Section Slow Component of ˙
Vo2Kinetics: Mechanistic
Bases and Exercise Training and Performance). Because ˙
Vo2
and therefore ˙
Vo2kinetics is measured most conveniently via
pulmonary gas exchange and yet, in most forms of exercises,
the predominant response is driven by the muscles perform-
ing the work, it is essential to know how closely the temporal
profile of pulmonary ˙
Vo2matches that across the contracting
muscles. This crucial perspective is broached in Section Re-
lationship Between Pulmonary and Exercising Muscle ˙
Vo2
Responses.
Where possible throughout this review, emphasis is placed
on experimental evidence from humans performing voluntary
exercise. However, experiments in animals and animal mus-
cles will be featured in so far as they have made important con-
tributions to our understanding of ˙
Vo2kinetics (see Section
Comparative Physiology of ˙
Vo2Dynamics). This is particu-
larly true with respect to determining the dynamic matching of
O2delivery-to- ˙
Vo2and the control of microvascular O2par-
tial pressures (Pmvo2) within contracting muscle(s) (see Sec-
tion Relationship Between Pulmonary and Exercising Muscle
˙
Vo2Responses) as well as extending the range of O2flux
(˙
Vo2max) achievable from <10 to 240 ml min1kg1.Key
points and questions raised in the preceding sections are sum-
marized in section Conclusions paying particular attention to
points of controversy and pressing directions for future sci-
entific efforts. A modicum of redundancy is retained as an
expedient to facilitate ease and convenience of “dipping” into
discrete sections.
Brief Historical Perspective
The study of ˙
Vo2and ˙
Vo2kinetics has its historical foun-
dations deep within the broader fields of physiology and
exercise physiology. Atmospheric O2was first created as a
byproduct by simple unicellular prokaryocytes that harnessed
photosynthesis as an energy source. Over billions of years
Earth’s atmosphere increased to 10% to 30% O2and pow-
ered the mitochondrial energetics of complex multicellular
creatures in the Cambrian explosion (542-488 million years
ago) (719). In the 17th century, Polish apothecary Michael
Sendivogius [1566-1636] produced O2by heating saltpeter
(potassium nitrate) (717) and Dutch engineer/inventor Cor-
nelis Drebbel [1572-1633] used purified O2for life sup-
port in his submarine. In 1621, Drebbel demonstrated to
King James I and a host of onlookers that this submarine
could remain submerged whilst 12 men rowed the 7 miles
from Westminster to Greenwich (717). However, it was left
to the great 18th-century French chemist Antoine Lavoisier
[1743-1794] to name oxygen (oxygine)1777 for its acid-
forming properties and demonstrate quantitatively O2s role in
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O2 delivery
-independent zone
O2 delivery
-dependent zone
Disease
Tipping point
Faster
01
Time (min)
VO2 (increase above baseline)
23
Slower
( τ)
( τ)
VO2 time constant (
τ
p)
SlowFast
Muscle O2 delivery
IncreaseDecrease
Figure 2 With respect to the speed of ˙
V
O2kinetics there are O2-delivery-dependent and -independent regions.
Note that when O2delivery falls below the “tipping point” ˙
V
O2kinetics becomes progressively slowed as evidenced
by increasing τ(see inset for graphical portrayal of altered τ). In young healthy individuals conventional locomotory
activities such as walking, running, and cycling lie to the right of the tipping point. Many diseases such as chronic
heart failure, emphysema [chronic obstructive pulmonary disease (COPD)] and type II diabetes (see Section Disease
States) as well as healthy aging (see Section Maturation and Aging) move the individual leftward into the O2-delivery-
dependent region.
muscular exercise and ( ˙
VCO2)CO
2production thereby defin-
ing the respiratory quotient (review 16, 87, 191, 394, 577,
763). Working with Pierre-Simon LaPlace [1749-1827] and
Armand Seguin [1767-1835], Lavoisier developed what was
likely the world’s first calorimeter and, using it to measure
heat production in guinea pigs, recognized that respiration was
...nothing but a slow combustion of carbon and hydrogen
similar in all aspects to that of a ...lighted candle” (472, 526).
Gas-blood
barrier
Blood-myocyte
barrier
Mitochondrial
reticulum
dVO2/dt
Vo2
VCO2
O2O2
CO2CO2
Vo2
.
.
.
.
Figure 3 The pathway for O2from lung to skeletal muscle mitochondria.
For healthy humans performing large muscle mass exercise (e.g., cycling and
running) ˙
V
O2kinetics at exercise onset are controlled by the capacity for mi-
tochondrial O2utilization (right-most arrow) rather than upstream perfusive
or diffusive flux limitations (larger arrows, left and middle) as is the case for
˙
V
O2max [see Section Site(s) of Limitation of ˙
V
O2Kinetics:Oxygen Delivery
Versus Cellular Respiration for more details).
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Figure 4 Two of the foremost pioneers in the field of exercise metabolic control and ˙
V
O2kinetics. Left
panel: Nobel laureate Archibald Vivian Hill in 1927. Right panel: Brian J. Whipp in 2002.
Lavoisier mistakenly considered that respiration took place in
the lungs and it was up to Lazaro Spallanzani [1729-1799]
and later Carl von Voight [1831-1908], Gustav Magnus [1802-
1870], and Edward Pfleuger [1829-1910] to correctly site O2
utilization and ˙
VCO2within the muscles and distal organs
(191, 763). In the 19th century, German physiologists Nathan
Zuntz [1847-1920], Geppert and colleagues (263, 811-815)
revolutionized our understanding of pulmonary gas exchange
and metabolism based upon their measurements of ˙
Vo2and
˙
VCO2in exercising humans and animals. With technical im-
provements, by the late 1800s, it was possible for Johansson to
follow the rapidity of the heart rate (HR) response of the rabbit
to spontaneous movement (i.e., 20 b·min1increase within
1.5 s; reference 383 as chronicled by Secher and Ludbrook,
680) and interest was stimulated in other dynamic responses.
Subsequently, the Nobel laureates August Krogh [1874-1949]
and Archibald Vivian Hill [1886-1977] Fig. 4, left panel) and
their colleagues (345-347, 452, 453) quantified the dynamics
of HR (see also Benedict and Cathcart, 78) and ˙
Vo2at ex-
ercise onset and recognized the importance of the metabolic
transition in defining the O2deficit. With his strong mathemat-
ical training, Hill described the exponential nature of the ˙
Vo2
kinetics as a linear and (to a certain degree) symmetrical sys-
tem (i.e., on- vs. off-transient symmetry). Though Franklin M.
Henry [1904-1993] and Janice Demoor (329; see also Henry,
328) and also Rodolfo Margaria [1901-1983], Paolo Cerretelli
and Pietro di Prampero (references 496-498) investigated the
exponential nature of ˙
Vo2following the on- and particularly
the off-transition their overriding focus was on “lactacid” and
“alactacid” components and analysis of the so-called O2debt.
Hence the groundwork laid by Krogh and Lindhard (452,
453) and Hill and colleagues (references 345-347) would
not be substantially improved upon for several decades un-
til the development of rapidly responding gas analyzers and
breath-by-breath determination of pulmonary gas exchange.
Hill was an avid runner who studied energetic and thermody-
namic processes in isolated animal muscles to gain insights
into respiratory control and muscular performance in humans
(341-344, 348). In particular, Hill demonstrated the simulta-
neous contribution of anaerobic and aerobic processes to mus-
cle contractile energetics (review 49). His lectures at Cornell
University in 1926 led to the foundation of the Harvard Fa-
tigue laboratory at Harvard University which brought Rodolfo
Margaria (University of Milan), H.T. Edwards and David
Bruce Dill together to embark on the study of metabolism
during exercise. These events signaled the inception of exer-
cise physiology as a legitimate academic discipline (722).
Capitalizing on the early development of breath-by-breath
gas exchange technology, in the late 1960s and early 1970s,
three different groups helped establish and develop the then-
embryonic field of ˙
Vo2kinetics: Notably, physician scientist
Karl Wasserman and the brilliant Welshman, Brian J. Whipp
(1937-2011) (Fig. 4, right panel), and their team at Harbor-
UCLA Medical Center in Los Angeles, USA, Rodolfo Mar-
garia, Paolo Cerretelli, and Pietro di Prampero in Milan, Italy,
and Leon Farhi in Buffalo, USA.
Today the kinetic response of ˙
Vo2following the onset
of exercise is recognized as a sentinel parameter of aerobic
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function and its measurement is becoming standard in labora-
tories around the World. In view of the relationship between
physical performance and ˙
Vo2kinetics (287, 386, review 638)
development of therapeutic strategies aimed at speeding ˙
Vo2
kinetics and reducing the size and/or progression of the ˙
Vo2sc
offer hope for improving exercise tolerance and the quality of
life for aged and patient populations. This consideration and
the scientific prerogative to understand metabolic control dur-
ing exercise have helped establish and drive the burgeoning
scientific interest in the field of ˙
Vo2kinetics.
Systems Control of Pulmonary
˙
V
O2Kinetics
Within seconds-to-minutes following the onset of severe-
intensity exercise, pulmonary ˙
Vo2may increase from a
resting value of 0.25 liters·min1(or somewhat higher,
0.5-1.0 liters·min1for “unloaded” cycling, Fig. 5) up to
its maximum value for the individual (Fig. 5) which, in the
extreme, may exceed 5 to 6 liters·min1. For skeletal muscle
the dynamic range is even greater with ˙
Vo2rising over 60-
fold from <10 ml min1kg1at rest to 600 ml min1kg1
during maximal knee-extensor exercise (5, 31, 455, 628).
As early as 1922, Hill and colleagues (345-347, review
771, and see also 328) demonstrated that, following the onset
of moderate intensity exercise [i.e., <LT or the gas exchange
threshold (GET)], pulmonary ˙
Vo2as a function of time, t,
increases as an exponential process (Fig. 6):
˙
Vo2(t)=˙
Vo2ss(1 ekt),(1)
Moderate
Heavy
Severe
Extreme
.
Time
(
s
)
V
O
2
(liters.min
–1
)
.
V
O2
max
–120 0 120 240 360
0
2
4
CP
GET
Figure 5 ˙
V
O2response following the onset of moderate (<gas ex-
change threshold, GET), heavy (>GET<critical power, CP), severe
(>CP leading to ˙
V
O2max), and extreme (>severe such that fatigue
ensues before ˙
V
O2max is achieved) exercise. Note that for moder-
ate exercise a steady state is achieved rapidly; for heavy exercise the
steady state is delayed; for severe exercise no steady state is evident
but ˙
V
O2projects to ˙
V
O2max which is achieved before fatigue ensues
(arrows). Both heavy and severe exercise may evince a slow component
(i.e., ˙
V
O2sc see Section Slow Component of ˙
V
O2Kinetics:Mechanistic
Bases). For extreme exercise, fatigue ensues prior to reaching ˙
V
O2max.
Adapted, with permission, from Wilkerson et al. (788).
VO2(t) = ss (1 – e-t/Tp )
Time (min)
0123456
VO2
.
I, cardiodynamic
II, primary, p
III, steady state
.VO2
.
2τ
BL
Error signal
3τ4τ
τss
VO2
Δ Δ
Δ
Figure 6 Top: breath-by-breath alveolar ˙
V
O2response following
the onset of moderate intensity cycle ergometer exercise. Phases I (car-
diodynamic), II (primary), and III (steady-state) are designated and
fit by an appropriate exponential model (see text). Bottom: schematic
demonstrating fundamental properties of the single component ex-
ponential response. Note that the imposition of a time delay feature
(omitted here for clarity) is required to improve the model fit and ac-
count for Phase I (see Eq. 5). The rate of ˙
V
O2increase is quantified
by the time constant (τ) of the exponential (40 s for this example)
where BL signifies baseline ˙
V
O2and the increase or amplitude of
˙
V
O2above baseline (right vertical arrows, 2 liters·min1for this ex-
ample). For each multiple of τ˙
V
O2increases by 63% of the difference
between that value at the previous τand the required steady state.
Thus, after 2τ(80 s) ˙
V
O2has risen to 86%[1.00.63 =0.37;
(0.37 ×0.63) +0.63 =0.86], 3τ’s (120 s) =95%,4τ’s (160 s)
=98%.τpdesignates the time constant of the primary component
response. Also shown is the metabolic error signal [difference between
˙
V
O2(t)andthat drives the increase of ˙
V
O2] which decreases with
each increment of τ.TheO
2deficit is the area from exercise onset
(time =0) bounded by the actual ˙
V
O2profile and the asymptotic ˙
V
O2
projected backward to time 0.
where tis the time elapsed from exercise onset and ˙
Vo2ss
is the steady-state increase of ˙
Vo2above baseline (typically
expressed as liters·min1). The rate constant, k, is independent
of ˙
Vo2ss across a broad range of metabolic demands (771).
This relationship is consistent with the existence of an initial
error signal (i.e., the difference between the instantaneous and
required value and a feedback response that aims to eliminate
the error, Fig. 6, bottom) and can also be expressed as:
˙
Vo2(t)=˙
Vo2ss(1 et/τ),(2)
where τis the time constant (i.e., 1/kdenoting the time to
reach 63%˙
Vo2ss) which may span a broad range from 10
to >100 s. Importantly, at these exercise intensities, the off-
transient (Eq. 3) is symmetrical to the on-transient (551):
˙
Vo2(t)=˙
Vo2(0)et/τ.(3)
The faster ˙
Vo2ss can be achieved (i.e., the more rapid the
˙
Vo2kinetics) the better, in part, because this incurs a smaller
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O2deficit (Fig. 6) for any given increase in ˙
Vo2, and intra-
cellular perturbations (e.g., [H+], [lactate], and [PCr])
will be minimized. The O2deficit for moderate exercise is
most easily calculated as the area between the actual ˙
Vo2and
the required ˙
Vo2(i.e., baseline +steady state) which is
calculated according to:
O2deficit =˙
Vo2·τ.(4)
Thus, τ˙
Vo2is a fundamental parameter of aerobic per-
formance (765, 769) and differences in τ˙
Vo2(i.e., the speed
of ˙
Vo2kinetics) may help explain the broad range of physi-
cal/athletic capabilities and exercise tolerance across popula-
tions (110, 386, review 638). Accordingly, trained endurance
athletes exhibit extremely fast ˙
Vo2kinetics (see Section Ex-
ercise Training and Performance) whereas detraining, aging
(see Section Maturation and Aging) and the predations of
many chronic disease conditions (see Section Disease States)
slow ˙
Vo2kinetics. Thus, at the transition to exercise, elite
cyclists (43, 442, 445) and marathon runners (395) as well as
horses (467, 593) and Greyhounds (593) may achieve near-
constant exercising ˙
Vo2’s within 30 to 40 s (i.e., 4 ×τ).
In contrast, aged individuals or those suffering from chronic
heart failure (CHF) or pulmonary disease may require several
minutes or more to reach steady state and will consequently,
for a given increase in ˙
Vo2, incur a much larger O2deficit
which is associated with premature fatigue (see Sections
Maturation and Aging and Disease States).
When exercising work rate is taken as the system input and
pulmonary ˙
Vo2(t) as the corresponding output Eqs. 1 to 4
characterize a dynamic linear first-order system that, as such,
should be described by a unique transfer function. The rele-
vance here is that, if pulmonary ˙
Vo2kinetics reflects closely
muscle ˙
Vo2, the most straightforward (Occam’s razor) con-
clusion is that the ATP-muscle ˙
Vo2coupling is rate-limited
by a single first-order reaction (review 638, 771) and that
˙
Vo2kinetics is not limited by O2transport per se [see Section
Site(s) of Limitation of ˙
Vo2Kinetics: Oxygen Delivery Versus
Cellular Respiration]. Riggs (630) concept of superposition,
can be used across different work forcings to test the presump-
tion that muscle ˙
Vo2kinetics is governed by such a system
(review 638, 771). Thus, considering the pulse/impulse as the
input function, which has as its first integral the step and its
second integral the ramp, across these different work forcings
the parameters of the ˙
Vo2(output) (i.e., τ, mean response
time, MRT; gain, G, i.e., ˙
Vo2/Watt) should be identical.
Tests of superposition have verified that pulmonary ˙
Vo2re-
sponds generally as a linear first-order system; at least in the
moderate domain. Specifically, following a high work rate
“impulse” [e.g., 0 500 (10 s) 0 Watts] ˙
Vo2rises al-
most instantaneously to a value that is proportional to the
impulse area and then declines exponentially to baseline. For
the “step” (e.g., 0 50 Watts) in the moderate domain ˙
Vo2
increases exponentially, after a brief delay, to the steady state.
Finally, in the “ramp” the ˙
Vo2increase lags by 1τbehind
the expected steady-state response for each given work rate.
Across all forcing profiles the parameters are invariant with
the exception that the Gdetermination is problematic for the
impulse.
Experiments in muscles contracting in vitro (frog sarto-
rius, 344, 488-491) and in situ (dog gastrocnemius, 580) have
supported the characterization of ˙
Vo2as a linear first-order
system. Because, during large muscle mass exercise, ˙
Vo2
of the contracting muscles overwhelms that of other tissues
(606) pulmonary ˙
Vo2reflects changes of muscle(s) ˙
Vo2(and
high-energy phosphates, e.g., 640, 641) with high fidelity (31,
285, 455). This is true despite the interposition of transit de-
lays and alterations of O2stores (primarily in the lungs and
venous blood) as detailed in Sections Site(s) of Limitation
of ˙
Vo2Kinetics: Oxygen Delivery Versus Cellular Respi-
ration and Relationship Between Pulmonary and Exercising
Muscle ˙
Vo2Responses. However, whereas with appropriate
modeling techniques and parameterization of the response
a close facsimile of muscle ˙
Vo2kinetics can be extracted
from pulmonary data in the moderate exercise intensity do-
main, system nonlinearities [i.e., manifestation of the ˙
Vo2sc
(see Section Slow Component of ˙
Vo2Kinetics: Mechanistic
Bases), and asymmetry of ˙
Vo2on- versus off-kinetics (455,
551, 645)] occurring at work rates in the heavy and severe-
intensity domains dispute the linear first-order characteriza-
tion of the ˙
Vo2response.
Exercise Intensity Domains
In a given individual, the profile of ˙
Vo2following the onset
of constant-work-rate exercise may be defined with respect
to the exercise-intensity domain in which the exercise is per-
formed which, in turn, is determined by the cluster of common
metabolic (i.e., ˙
Vo2and [lactate]) responses evoked (Figs. 5
and 7, references 174, 258, 350, 749, 751, 788). Specifically,
for moderate intensity (<LT or GET, Figs. 5 and 6, top) exer-
cise pulmonary ˙
Vo2begins to increase within the first breath
(Phase I or cardiodynamic component), there is then a brief
surcease prior to the appearance of the exponential increase
of ˙
Vo2some 15-20 s later [i.e., Phase II, fundamental or pri-
mary component, p (latter used herein)] to the steady state
(Phase III). This response is best modeled as a time delay
(TDp, 10-20 s) followed by an exponential (769, 771):
˙
Vo2(t)=˙
Vo2(1 etTDp/τp).(5)
With respect to the Phase I ˙
Vo2response, as for ˙
Ve(see
Section Integration of Dynamic Responses in the Pathway for
O2), this is believed to be driven by the increase in pulmonary
blood flow in the absence of altered arterial or venous O2
contents (but see 129). The rapidity of the Phase I cardiody-
namic response is attributed most convincingly to the almost
instantaneous cardiac output increase which is initiated by
vagal withdrawal and the mechanical pumping action of the
contracting muscles (review 461, 462, 522).
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Comprehensive Physiology Oxygen Uptake Kinetics
05 10
Time (min)
0
2
4
Moderate
Heavy
Severe
05 10
Time (min)
Blood [lactate] (mM)
0
5
10
Moderate
Heavy
Severe
V
O
2
(liters.min
–1
)
.
Figure 7 Left panel: schematic representation of the ˙
V
O2response to constant-work-rate exercise in the moderate, heavy, and severe domains.
Note presence of ˙
V
O2slow component (hatched area) for heavy and severe exercise. Arrow denotes exercise curtailed by fatigue. Right panel:
schematic representation of the blood [lactate] response to constant-work-rate exercise in the moderate, heavy, and severe domains. Arrow
denotes exercise curtailed by fatigue. Note correspondence between [lactate] and ˙
V
O2responses within domains.
Figure 6 (bottom) demonstrates some of the pertinent
properties of a simple exponential response, in particular, the
approach of ˙
Vo2to its steady state value within about 2 to
3 min in a healthy young individual. For cycle ergometry G
or amplitude of the response is 9 to 11 ml O2min1W1
(e.g., 39, 255, 315, 492, 597, 751, 769, 778). In the heavy-
intensity domain, which encompasses all metabolic rates be-
tween LT/GET and critical power (CP) a secondary ˙
Vo2ele-
vation (i.e., the ˙
Vo2sc, see Section Slow Component of ˙
Vo2
Kinetics: Mechanistic Bases), becomes apparent after 90 to
120 s and is superimposed on the faster primary (p) response
(Fig. 7, left panel; 258, 330, 589, 606, 646, 771, 780). CP is the
asymptote of the power-duration curve for high-intensity ex-
ercise (i.e., notionally the highest work rate or, more properly,
˙
Vo2that can be sustained for a prolonged period (528, 532;
Fig. 5). CP therefore represents the highest submaximal ˙
Vo2
that can be stabilized (i.e., the ˙
Vo2sc rise can be curtailed, ref-
erence 610) which corresponds to the maximal lactate steady
state (79, MLSS, depicted in the heavy domain of Fig. 7, right
panel, see Section Slow Component of ˙
Vo2Kinetics: Mecha-
nistic Bases); both occurring typically at 50% of the GET-
˙
Vo2max obtained on the ramp/incremental exercise test (618,
696). CP also constitutes the highest metabolic rate at which
intramuscular [creatine phosphate] and [H+] stabilize (review
400). Given that CP (rather than GET/LT) represents a crucial
demarcator of metabolic stability its relevance with respect
to understanding exercise tolerance and exhaustion cannot be
overemphasized. Fitting the ˙
Vo2response in the heavy do-
main requires a more complex model that includes additional
delay (TDsc) and exponential (τsc) components related to the
˙
Vo2sc:
˙
Vo2(t)=˙
Vo2(1 etTDp/τp)
+˙
Vo2sc(1 etTDsc/τsc).(6)
Whereas it is possible to fit a third exponential component
to describe Phase I (e.g., 285, 675; Fig. 6, top) this practice
wields a double-edged sword: it improves the overall fit math-
ematically but it may over burden the parameterization which
reduces confidence in the individual parameter estimation
(772). There is thus a solid argument, in any given instance,
for judicious selection of the simplest model that adequately
characterizes the response for the parameters of most interest.
It is crucial to acknowledge that the ˙
Vo2sc, the exponentiality
of which is by no means certain (see Section Slow Component
of ˙
Vo2Kinetics: Mechanistic Bases), represents an additional
O2cost which increases the ˙
Vo2G(>11 ml min1W1)
effectively reducing work efficiency and delaying attainment
of the ˙
Vo2steady state for as long as 15 min or more (330,
610, 780). At yet higher work rates in the severe intensity
domain (i.e., >CP,Fig.5) ˙
Vo2may either rise rapidly and ex-
ponentially to ˙
Vo2max or, alternatively, evince a ˙
Vo2sc that
increases systematically as a function of time, driving ˙
Vo2
to ˙
Vo2max: either profile heralding imminent fatigue once
˙
Vo2max is attained (350, 610). For severe exercise blood
[lactate] rises inexorably to the point of fatigue (Fig. 7, right
panel) and there is evidence that the primary component ˙
Vo2
Gmay be reduced (389, 616, 673). For heavy and severe exer-
cise where the ˙
Vo2sc is present, ˙
Vo2changes as a function of
time and not work rate. Thus, in these domains the common
practice of describing exercise intensity as % ˙
Vo2max is
indefensible. Finally, there exists a still higher exercise
intensity domain, termed “extreme,” where the work rate is
so great that fatigue intervenes in approximately <140 s (i.e.,
<4τ’s) before ˙
Vo2max can be achieved (Fig. 5, 350, 394,
397, 589).
The exercise intensity domain schematism described
above (i.e., moderate-heavy-severe-extreme, Scheme 1,
Figs. 5 and 7) is not the only one proposed. Specifically,
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Whipp and Rossiter (638, 772) have proposed a moderate-
heavy-very heavy-severe domains classification (Scheme 2).
The principal discrimination between the two schemes may be
summarized as follows: Scheme 1 is defined by the achieved
˙
Vo2profile in that all work rates that achieve the indepen-
dently determined ˙
Vo2max are considered to reside within
the severe domain—irrespective of whether ˙
Vo2projects to
˙
Vo2max via the primary or slow component of the response.
Scheme 2 discriminates very heavy from severe exercise on
the basis of whether or not the primary component is predicted
to project below (very heavy) or above (severe) ˙
Vo2max.
Notwithstanding the uncertainties of predicting the ˙
Vo2cost
at these high intensities and resolving the mechanistic bases
for the ˙
Vo2sc, Scheme 2 makes no provision for work rates
that are too high to elicit ˙
Vo2max (i.e., the extreme domain in
Scheme 1). Accordingly, this review will utilize the moderate-
heavy-severe-extreme classification (Scheme 1).
˙
V
O2Responses Following Exercise
Compared with the on-response the recovery kinetics has re-
ceived less recent attention and yet they can help facilitate
mechanistic interpretation of the on-transient, the effects of
priming exercise and possibly exercise intolerance. However,
the early O2deficit—O2debt concept lent itself to mecha-
nistic overinterpretation (256) which forced renaming of the
so-called “O2debt” to the functionally descriptive “excess
postexercise O2consumption” or EPOC (21, review 256).
As with the on-responses described above, although the off-
transient kinetics return ˙
Vo2toward baseline with a temporal
profile resembling closely the primary on-kinetics in some
cases, there is a certain domain dependency that dictates the
off-kinetics (i.e., presence of a ˙
Vo2sc or not) and symme-
try/asymmetry with the on-kinetics. In the moderate domain,
and, in accordance with the linear first-order nature of ˙
Vo2
kinetics discussed above, the on- and off-responses are sym-
metrical (394, 551, 561). However, for heavy exercise the
˙
Vo2sc present during the on- is absent from the off-transient.
In the severe domain a ˙
Vo2sc may be apparent for both the
on- and off-transient whereas for extreme exercise there is
no ˙
Vo2sc during the on- but one emerges during the off-
transient (551, review 638). ˙
Vo2kinetics in the off-transient
will reflect the lumped temporal characteristics of many phys-
iological processes as the homeostasis of the resting condition
is restored. These include: dynamics of cardiac output, mus-
cle blood flow, and muscle(s) ˙
Vo2(locomotory, respiratory,
cardiac, and accessory), partial refilling of O2stores in ve-
nous blood and muscle, and energetic costs associated with
hormonal, thermal, and metabolic derangements (review 256,
638). As such, and keeping in mind that the primary and slow
components, which may be temporally displaced 1 to 2 min at
exercise onset, are conflated at the off-transient, interpretation
of off-transient ˙
Vo2kinetics is challenging. Notwithstanding
this consideration, in healthy muscle the off-transient mus-
cle blood flow kinetics are slowed in comparison to that of
˙
Vo2(239) permitting elevation of microvascular Po2’s (70,
510, 511) and presumably aiding oxidative recovery. Impaired
vascular control in disease may compromise this process (see
Kemps et al. references 413-416 and Section Disease States).
The coherence between exercising muscle(s) PCr and pul-
monary ˙
Vo2kinetics (see Section Site of Limitation of ˙
Vo2
Kinetics) during the exercise on-transient is found also during
recovery (638, 645) and this is consistent with the correla-
tion of PCr recovery kinetics with muscle oxidative capacity
(508). Moreover, there isan emergent body of evidence which
suggests that recovery of muscle (162) and pulmonary (413)
oxidative processes are both more reproducible and a more re-
liable indicator of dysfunction, for example, in CHF, than the
on-transient kinetics. Given the above, the recent demonstra-
tion that there may be a dissociation between muscle(s) and
pulmonary ˙
Vo2kinetics following exercise (455) suggests
caution is required when interpreting ˙
Vo2recovery data.
Integration of Dynamic Responses
in the Pathway for O2
The dynamics of the O2-transport systems upstream of the
contracting myocytes—pulmonary, cardiovascular, and mus-
cle microvascular—are such that ventilation ( ˙
Ve), cardiac
output, and skeletal muscle vasomotor control ensure that O2
is delivered to the exercising muscle as fast, or even faster,
than ˙
Vo2can increase (Figs. 2 and 3, references 31, 64, 285,
455). Whereas the ultimate control mechanisms for each of
these systems are discussed in detail elsewhere in this volume,
it is pertinent to consider them here as a foundation for un-
derstanding why, in health, they may not pose a limitation to
˙
Vo2kinetics but how specific organ and system dysfunction
can often shift the site of ˙
Vo2limitation upstream (see Fig. 2
and Section Disease States).
Pulmonary system
Rather than regulating arterial O2levels per se, the cardinal
function of the exercise hyperpnea (i.e., increased ˙
Ve) in hu-
mans is to facilitate CO2removal at rates which increase from
0.2 liters·min1at rest to, in the extreme, over 6 liters·min1
during maximal exercise so as to prevent, or at least constrain,
the magnitude of any perturbation in arterial blood gas and
acid-base status. Mass balance considerations require that ˙
Ve
be a determinant of measured gas exchange (review 752).
Thus, across the range of work rates achievable, ˙
Veis cou-
pled closely to CO2exchange (133, 209, 750, review 752,
767) and increases according to:
˙
VE=863 ˙
VCO2/[PaCO2(1 VD/VT)].(7)
Where 863 is the product of barometric pressure, temper-
ature, and water vapor corrections required to express ˙
Veat
body temperature and pressure, saturated (BTPS), ˙
VCO2at
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Comprehensive Physiology Oxygen Uptake Kinetics
Rest Exercise
I, cardiodynamic
II, primary
III, steady state
Time (s)
200150100500
% response
0
50
100
τpVO2= 30 s
.
τpVCO2= 50 s
.
τpV
E= 54 s
.
HR
(b/min)
V
.
E
(liters.min–1)
V
.CO2
(liters.min–1)
Time (min)
40
50
150
0
0
0
50
2
2
REST – 100 watts
V
.
E