JOURNAL OF PHYSIOLOGY AND PHARMACOLOGY 2006, 57, Suppl 10, 53–65
www.jpp.krakow.pl
B. GRASSI
OXYGEN UPTAKE KINETICS:
WHY ARE THEY SO SLOW? AND WHAT DO THEY TELL US?
Department of Science and Biomedical Technologies,Università degli Studi di Milano,
Milano, Italy; Institute of Bioimaging and Molecular Physiology, CNR, Milano, Italy
·
V O2 kinetics and O2 deficit are important determinants of exercise tolerance. In
"normal" conditions convective and diffusive O2 delivery to skeletal muscle fibers do
·
not represent important determinants of V O2 kinetics, whose limiting factors seem
mainly located within muscle fibers. Whereas a limiting role by PDH has not been
confirmed, the role of inhibition of mitochondrial respiration by NO needs further
·
investigations. Important determinants of skeletal muscle V O2 kinetics likely reside in
the interplay between bioenergetic mechanisms at exercise onset. By acting as high-
capacitance energy buffers, PCr hydrolysis and anaerobic glycolysis would delay or
attenuate the increase in [ADP] within muscle fibers following rapid increases in ATP
demand, preventing a more rapid activation of oxidative phosphorylation.
The
·
different
V O2max
"localization"
offers
the
of
opportunity
the
to
main
limiting
perform
a
factors
functional
for
·
V O2
evaluation
kinetics
of
and
oxidative
metabolism at two different levels of the pathway for O2, from ambient air to
mitochondria.
cardiovascular
Whereas
system
·
to
V O 2max
deliver
is
O2
mainly
to
limited
exercising
by
muscles,
the
by
capacity
analysis
of
of
·
the
V O2
kinetics the functional evaluation is mainly related to skeletal muscle. In pathological
conditions the situation may be less clear, and warrants further investigations.
Key
w o r d s : gas exchange kinetics, skeletal muscle oxidative metabolism, bioenergetics
INTRODUCTION
·
The notion that at the onset of constant-load exercise the increase in O2 uptake
(VO2) lags behind the increase in mechanical power output has been around since
the pioneering works by Nobel laureates August Krogh (1) and A.V. Hill (2).
From the results of these studies, and of many others which followed, emerged
54
the concept of the "O2 deficit" (see e.g. 3, 4), the amount of energy that at the
onset of a constant-load exercise must necessarily be derived from substrate level
phosphorylation. The finite rate of adjustment of oxidative phosphorylation to
·
sudden increases in energy demand has been termed "VO2 kinetics". Sudden
changes in work output are frequently encountered in sports as well as during
·
many activities of everyday life. Faster VO2 kinetics (observed, for example, after
exercise
training
disturbance
of
(see
5))
e.g.
cellular
and
are
associated
organ
with
homeostasis
a
lower
O2
(lower
deficit,
less
degradation
of
phosphocreatine and glycogen stores, lower accumulation of lactate and H ), with
+
positive consequences on exercise tolerance and muscle fatigue.
·
The interest in studies on VO2 kinetics derives also from the fact that such
research gives valuable insight into basic mechanisms of metabolic control during
muscular contraction. Whereas metabolic steady-states provide a stable scenario
to gather data, it is indeed in the transient responses where the best insights into
system control can be obtained. The issue of the limiting, or regulating, factor(s)
·
for VO2 kinetics has been a matter of debate and controversy for many years,
·
mainly between those in favor of the concept that the finite kinetics of VO2
adjustment to workload increases is attributable to delayed metabolic activation,
or to an intrinsic slowness, of intracellular oxidative metabolism to adjust to the
new
metabolic
requirement
("metabolic
limitation",
or
"oxidative
inertia"
hypothesis) (6 - 10), and those who suggest that an important limiting factor
resides
in
the
finite
kinetics
of
O2
delivery
to
muscle
fibers
("O2
limitation", or "O2 availability" hypothesis) (11, 12).
delivery
The first purpose of the present paper is to review some experimental evidence
·
pointing to a delayed metabolic activation as the main limiting factor for VO2
kinetics, and to discuss some of the mechanisms or factors possibly involved.
·
Secondly, possible inferences deriving from VO2 kinetics analysis in normal
subjects and in patients will be briefly discussed.
For the sake of simplicity the present paper will not discuss about the so-called
"slow
component"
of
·
VO2
kinetics,
that
is
the
additional
increase
in
·
VO2
described after a few minutes of constant-load exercise carried out above the "gas
exchange threshold" (13, 14).
·
VO2 KINETICS: WHY ARE THEY SO SLOW?
Some studies have approached the problem of the identification of the limiting
·
factor(s) of VO2 kinetics by defining whether the adjustment of O2 delivery to
skeletal muscle was indeed faster than that of O2 utilization, as suggested many
years ago by the study by Piiper et al. (15), conducted on the isolated dog
·
gastrocnemius preparation in situ. The kinetics of O2 delivery and VO2 in humans
at the level of exercising limbs were determined (16 - 18). A common finding
deriving
from
these
studies
was
that,
during
the
first
·
seconds
of
exercise,
increases in O2 delivery were faster than increases in VO2, whereas for the
55
ensuing part of the transition the results were less unequivocal and may lead to
·
different interpretations. Moreover, these studies were limited by the fact that VO2
measurements were carried out across exercising limbs, so that transit delays
from the sites of gas exchange to the measurements sites confounded the overall
picture, as demonstrated by Bangsbo et al. (16), who estimated such delays by
dye injection into the arterial circulation.
More
recently,
another
series
of
studies
"got
inside
the
muscle",
during
metabolic transitions, by utilizing different techniques, such as the intravascular
phosphorescence quenching technique for the determination of microvascular
PO2 (see e.g. 19) or near-infrared spectroscopy (NIRS) for the determination of
tissue oxygenation (see e.g. 20). A common denominator among these techniques
lies in the fact that the determined variables allow to evaluate the balance (or the
·
lack thereof) between O2 delivery and VO2 in the area of interest, being therefore
conceptually
similar
to
O2
extraction,
or
to
arterio-venous
O2
concentration
difference [C(a-v)O2]. The observation of an increased microvascular PO2, or an
increased oxygenation during the initial phase of the transition would indicate a
faster
adjustment
of
O2
delivery
that
vs.
·
of
VO2,
thereby
providing
indirect
evidence against the "O2 delivery limitation" hypothesis. Conversely, a decreased
·
microvascular PO2 or oxygenation, suggesting a faster adjustment of VO2 vs. that
of O2 delivery, would provide indirect evidence in favor of the "O2 delivery
limitation" hypothesis. The obtained results, however, suggested an unchanged
(or only slightly decreased) O2 extraction for several seconds after the increase in
work rate, reflecting a tight coupling, during that period, between O2 delivery and
·
VO2 (19, 20). The immediate and pronounced increase in muscle blood flow
(associated with vasodilation) at the onset of exercise is well-known (see e.g. 21).
The studies mentioned above (19, 20) suggest that such rapid and pronounced
·
increase in O2 delivery at the transition allows VO2 to increase even in the
presence of an unchanged O2 extraction. Only after this initial delay the increased
O2 extraction at the muscle level would contribute, together with the ongoing O2
delivery
increase,
suggested
by
the
to
the
further
increase
above-mentioned
·
in
studies
VO2.
(19,
The
20)
is
O2
extraction
very
similar
pattern
to
that
indicated by the C(a-v)O2 measurements carried out across exercising legs in
humans (17, see also Fig. 2 in 22) and across the isolated dog gastrocnemius
preparation in situ (23), and is also similar to the time-course described by Hogan
(24) for intracellular PO2 (determined by phosphorescence quenching) in an
isolated amphibian muscle fiber model.
In any case, the tight coupling between the increased O2 delivery and the
·
increased VO2 does not allow to exclude, per se, that an enhanced O2 delivery
could,
in
theory,
lead
to
a
faster
·
VO2
response.
Moreover,
the
experiments
mentioned above did not allow to make much inferences, in terms of limiting
factors,
for
demonstrate
significant
the
phases
whether
limiting
of
O2
the
transition
beyond
delivery/availability
factor
for
·
VO2
the
does
kinetics,
initial
(or
does
experiments
~10
not)
seconds.
To
represent
showing
that
a
a
56
significantly faster than normal or an enhanced O2 delivery was (or was not)
·
associated with faster than normal VO2 kinetics were needed.
Convective and diffusive O2 delivery
This issue was approached by a series of studies conducted by our group on
the isolated dog gastrocnemius preparation in situ. The experiments were carried
out in the laboratories of Drs. Peter D. Wagner and Michael C. Hogan (University
of
California,
San
Diego)
and
L.
Bruce
Gladden
(Auburn
University).
Advantages and limitations of this model, as far as the study of O2 kinetics) have
been previously discussed in detail (23, 25 - 28). As mentioned above, the same
·
experimental model had been utilized to study muscle VO2 kinetics by Piiper et
·
·
al. (15). These authors determined muscle blood flow (Qm) and muscle VO2
kinetics,
muscle.
but
In
did
our
adjustment
of
not
experimentally
studies
the
convective
·
first
O2
manipulate
approach
delivery
to
was
to
O2
muscle,
delivery
eliminate
by
to
all
the
working
delays
pump-perfusing
in
it
the
at
a
constantly elevated Qm, at rest and throughout the transition, as well as by the
concurrent administration of a vasodilatory drug. These interventions did not
speed
·
the
VO2
kinetics
during
transitions
to
~60%
of
·
VO2peak
(25),
and
determined only a relatively minor speeding during transitions to ~100% of
·
VO2peak (27). In further experiments we enhanced peripheral O2 diffusion, by
hyperoxic breathing and by the administration of a drug (methylpropionic acid,
RSR13,
Allos
Therapeutics)
which
shifted
to
the
right
the
oxy-hemoglobin
dissociation curve, thereby reducing the affinity of hemoglobin for O2. Also in
this
case,
we
described
no
effects
on
·
VO2
kinetics
during
transitions
to
submaximal loads (26). Taken together, these studies provide evidence that, in
"normal" conditions (e.g. normoxia, no impediments to O2 delivery, absence of
pathological conditions (11, 12, 14, 29)) convective and diffusive O2 delivery to
skeletal muscle fibers do not represent important determinants of the kinetics of
adjustment
of
oxidative
phosphorylation
following
increases
in
metabolic
demand, pointing to a delayed metabolic activation, or to an intrinsic slowness, of
intracellular oxidative metabolism to adjust to the new metabolic requirement.
Which could be the cause(s) responsible for this delayed metabolic activation,
or
intrinsic
slowness
of
oxidative
phosphorylation,
compared
to
the
other
mechanisms of energy provision in skeletal muscle cells, that is phosphocreatine
(PCr) hydrolysis and anaerobic glycolysis?
Pyruvate dehydrogenase
There
are
several
possible
rate-limiting
reactions
within
the
complex
oxidative pathways, and some studies had pointed to acetyl group availability
within mitochondria and to the activation of pyruvate dehydrogenase (PDH) as
·
possible metabolic limiting factors for VO2 kinetics. PDH is localized within the
inner mitochondrial membrane, and catalyzes the decarboxylation of pyruvate to
57
acetyl-CoA, committing pyruvate to entry into the trycarboxylic acids cycle and
to
oxidation.
Experiments
conducted
in
ischemic
dog
muscles
(30)
and
in
humans during transitions from rest to submaximal exercise (31) pointed to PDH
as
one
of
the
sites
where
the
delayed
metabolic
activation
of
oxidative
phosphorylation may occur. These authors observed, following activation of
PDH and stockpiling of acetyl groups at rest, obtained by the administration of
the drug dichloroacetate (DCA) (32), less phosphocreatine (PCr) degradation
and less lactate accumulation in muscle, associated with less fatigue during
submaximal contractions. They hypothesized that the attenuation of anaerobic
energy production during the transition, that is the lower O2 deficit, could be
explained by a faster adjustment of oxidative phosphorylation. In none of these
·
studies, however, were VO2 kinetics determined. We tested the hypothesis in the
isolated dog gastrocnemius in situ (23). DCA infusion resulted in a significant
activation
of
PDH,
but
it
did
not
significantly
affect
"anaerobic"
energy
provision (PCr hydrolysis, muscle lactate accumulation, calculated substrate
·
level phosphorylation) and VO2 kinetics (23). Thus, in this experimental model,
PDH activation status did not seem to be responsible for the delayed metabolic
activation of oxidative phosphorylation. Similar conclusions were drawn by
another
study
conducted
on
humans,
in
which
the
authors
determined
·
VO2
kinetics across the exercising limb during leg extension exercises (33). Rossiter
et
al.
(34)
confirmed
that
·
PDH
activation
by
DCA
does
not
determine,
in
humans, faster pulmonary VO2 kinetics, nor faster kinetics of PCr hydrolysis.
These authors, however, observed after DCA, for the same workload, a lower
·
amplitude of VO2 and PCr responses and less blood lactate accumulation. The
·
lower amplitude of the VO2 response determined a lower O2 deficit even in the
presence
of
unchanged
·
·
VO2
kinetics.
For
the
same
power
output,
lower
amplitudes of the VO2 and PCr responses and less blood lactate accumulation
suggest a lower energy cost of contractions. Interestingly enough, a lower energy
cost of contractions after DCA was also observed by our group in the dog
gastrocnemius
in
situ:
in
the
presence
of
less
·
muscle
fatigue
(higher
force
production), we indeed observed unchanged VO2 and no significant differences
in terms of substrate level phosphorylation (23). "Closing the circle", then, the
·
lower energy cost of contractions and the lower amplitudes of the VO2 and PCr
responses after DCA could explain, at least in part, the PCr "sparing" described
·
by Timmons et al. (30, 31), with no need to hypothesize faster VO2 kinetics. A
lower energy cost of contractions after DCA could be explained, at least in part,
by a drug-induced preferential utilization of carbohydrates as energy sources (3).
·
In the presence of a lower energy cost of contractions, for the same VO2 more
ATP can be generated and a higher force can be sustained (23), or, conversely,
·
for the same power output less VO2 is needed to sustain ATP needs (34). An
indirect confirmation of this hypothesis derives from the direct inotropic effect
on the heart obtained by DCA (32, 35).
58
Inhibition of mitochondrial respiration by nitric oxide
The
delayed
metabolic
activation
of
skeletal
muscle
oxidative
phosphorylation at exercise onset might be related, at least in part, to a regulatory
role of nitric oxide (NO) on mitochondrial respiration. Amongst a myriad of
·
functions, which comprehend vasodilation, NO competitively inhibits VO2 in the
electron transport chain, specifically at the cytochrome c oxidase level (36).
·
Through its combined effects of vasodilation and VO2 inhibition, NO may serve
as part of a feedback mechanism aimed at increasing O2 delivery and reducing the
·
reliance on O2 extraction to meet the increase in muscle VO2; by this mechanism,
NO would work in the direction of maintaining higher intramyocyte PO2 levels
during exercise (37). In exercising horses, inhibition of NO synthases by the
administration
·
of
the
arginine
analogue
L-NAME
determined
indeed
faster
pulmonary VO2 kinetics, both during heavy (37) and moderate intensity exercise
·
(38). Faster pulmonary VO2 kinetics after L-NAME have also been described in
humans during transitions to moderate intensity exercise (39), heavy intensity
·
exercise (40) as well as supramaximal exercise (41). Faster muscle VO2 kinetics
after L-NAME administration, on the other hand, was not observed in a recent
study conducted by our group in the isolated dog gastrocnemius preparation in
situ (28). Possible explanations for the conflicting results between our study (28)
and those mentioned above (37 - 41) are detailed in letters recently published on
·
the Journal of Physiology (42, 43). Compared to conventional pulmonary VO2
kinetics determination (37 - 41), our experimental model had an advantage,
·
particularly relevant for the study in question, that is the possibility to keep Qm
constantly elevated during the transition from rest to contractions. As mentioned
above, NO elicits vasodilation and inhibits mitochondrial respiration. Thus, NO
·
synthases inhibition could have opposing effects on VO2 kinetics: inhibition of
·
vasodilation could restrict O2 delivery and slow VO2 kinetics, whereas relief of
mitochondrial inhibition could speed the kinetics. By pump-perfusion, we kept
·
Qm constantly elevated, so that we were better suited (compared to the studies
·
based upon conventional pulmonary VO2 kinetics analysis, see 37 - 41) to see
effects of NO synthases inhibition on mitochondrial respiration. Nonetheless, we
·
saw no effect on VO2 kinetics. In our opinion, the role played by the NO-induced
inhibition of mitochondrial respiration on the delayed metabolic activation of
oxidative
phosphorylation
at
exercise
onset
needs
clarification
and
warrants
further investigations (28, 43).
PCr hydrolysis as an "energy buffer"
At exercise onset PCr hydrolysis acts as a high-capacity temporal buffer,
which would delay or attenuate the increase in (ADP) within muscle fibers
following rapid increases in ATP demand, thereby "buffering" a more rapid
activation
buffering
of
of
oxidative
(ADP)
phosphorylation
increases
at
(44).
exercise
A
onset
similar
would
role
be
of
played
temporal
by
ATP
59
provision by anaerobic glycolysis, as proposed by Cerretelli et al. (5) some
decades ago with the "early lactate" concept. The interplay between the various
mechanisms of energy provision at exercise onset suggests that pharmacological
interventions aimed at blocking PCr hydrolysis and/or glycolysis could speed the
rate of adjustment of oxidative phosphorylation. This seems indeed to be the
case, as demonstrated by studies conducted on isolated amphibian myocytes
after blocking creatine kinase (CK) and PCr hydrolysis by iodoacatemide (44),
or in isolated rabbit hearts after blocking glycolysis by iodoacetic acid (45). A
·
more rapid VO2 response to an elevation in metabolic demand has also been
·
demonstrated in cardiac muscle of CK-knockout mice (46). Faster VO2 kinetics
after
CK
blocking
preliminary
data
by
iodoacetamide
obtained
by
our
have
group
in
been
the
recently
isolated
confirmed
dog
by
gastrocnemius
preparation in situ (47).
·
V O2 KINETICS: WHAT DO THEY TELL US?
"Normal" conditions
As discussed above, in "normal" conditions (e.g. normoxia, no impediments to
O2 delivery, absence of pathological conditions (see 11, 12, 14, 29 and below)),
convective and diffusive O2 delivery to skeletal muscle fibers does not represent
an
important
determinant
of
the
kinetics
of
adjustment
of
oxidative
phosphorylation following increases in metabolic demand. Thus, in "normal"
·
conditions, the limiting factors for VO2 kinetics seem to be mainly located within
muscle fibers. On the other hand, it is generally accepted that the main limiting
·
factor for maximal aerobic power (maximal O2 consumption, VO2max) resides in
the
capacity
by
the
cardiovascular
system
to
deliver
O2 (by
convection
and
diffusion) to muscle fibers (see e.g. 48). The different "localization" of the main
·
·
limiting factors for the two variables, VO2 kinetics and VO2max, offers to exercise
physiologists the opportunity to perform a functional evaluation of oxidative
metabolism at two different levels of the long pathway covered by O2, from
ambient air to the mitochondria of exercising muscles. In other words, according
·
to a presumably oversimplified scenario: by measuring VO2max we primarily
evaluate the functional capacity by the cardiovascular system to deliver O2 to the
exercising
evaluation
muscles,
is
whereas
mainly
aimed
when
at
we
analyze
skeletal
·
VO2
muscle
kinetics
oxidative
the
functional
metabolism.
In
accordance with this concept, it has been demostrated that the two variables can
respond differently to external perturbations such as exercise training: both in
young (49) and in middle-aged subjects (50), indeed, the effects of exercise
·
·
training on VO2 kinetics can occur much earlier than the effects on VO2max. A
dissociation between the two variables has also been recently described by our
group
on
patients
transplantation (51).
followed
during
the
first
couple
of
years
after
heart
60
Pathological conditions
Does the concept outlined above apply also to pathological conditions? It is
·
well known that pulmonary VO2 kinetics are slower than normal in patients
affected by pathologies such as chronic obstructive pulmonary diseases (52),
congestive heart failure (53), peripheral vascular diseases (54), type II diabetes
(55). Does this mean that an impaired capacity by the lungs, heart, blood vessels
to deliver O2 to the exercising muscles can be responsible for slower than normal
·
VO2
kinetics?
diseases,
does
In
other
the
terms,
in
determination
patients
with
of
kinetics
·
VO2
lungs,
heart
mainly
or
blood
offer
a
vessels
functional
evaluation of a limited capacity of O2 delivery to exercising muscles? In a broader
·
view, could VO2 kinetics analysis have a different meaning, in terms of the
functional evaluation of oxidative metabolism, in normal subjects and in patients
with diseases affecting the main systems involved in O2 transport?
The answers to these questions is not straightforward, and the topic definitively
needs further investigations. Evidence in favor of the concept that a limited capacity
·
to deliver O2 to exercising muscles determines slower VO2 kinetics derives from
experiments in subjects exposed to acute hypoxia (56), in subjects performing arm
exercise with the arms above (vs. below) the heart level (18), in subjects performing
leg exercise in the supine (vs. upright) posture (57), in subjects treated with
·
β-
blockers (58). In all these conditions, slower pulmonary VO2 kinetics have been
described, in association with (or as a consequence of) a reduced O2 delivery to the
exercising muscles. On the other hand, it is being increasingly recognized that in
patients with chronic cardiac (59), pulmonary (60), or blood vessel diseases (61), as
well as in diabetic patients (62) skeletal muscles are metabolically altered, and play
a
crucial
recipients
role
in
present
determining
slower
the
reduced
pulmonary
·
VO2
exercise
kinetics
tolerance.
(51,
63
-
Heart
65),
transplant
which,
as
a
consequence of the denervation of the transplanted heart, are associated with slower
heart rate (63) and cardiac output (64) kinetics. Our group has demonstrated that in
heart transplant recipients an acceleration of cardiac output kinetics, obtained by a
·
warm-up exercise, does not obtain a speeding of VO2 kinetics (65). This suggests
that also in these patients a "peripheral" limitation (i.e., occurring at the skeletal
muscle level) is likely superimposed on the limited capacity of O2 delivery to
exercising muscles. In accordance with this concept, we have recently demonstrated
in heart transplant recipients an impairment of the "peak" capacity of O2 extraction
by skeletal muscles (66).
Thus, in all patients mentioned above, limitations deriving from an impaired
oxidative metabolism at the skeletal muscle level appear to be superimposed on
those
related
to
the
impaired
capacity
to
deliver
O2
to
skeletal
muscles,
attributable to the primary pathological condition. The possibility to discriminate,
non-invasively, between the two types of limitations would be of great interest to
clinicians, in order to follow the clinical course of the disease, as well as to choose
and/or
evaluate
specific
rehabilitative
or
therapeutic
interventions.
What
61
·
inferences can then be made, in these patients, upon the analysis of VO2 kinetics?
This topic needs clarification and further studies. Some work has been conducted
on animal models (see e.g. 29, 67, 68). The need for a better understanding
·
derives also from the fact that analysis of pulmonary VO2 kinetics is being
increasingly utilized as a functional evaluation tool in the clinical field (see e.g.
29, 69). Schalcher et al. (70), for example, recently observed that in patients with
·
chronic heart failure pulmonary VO2 kinetics has a stronger prognostic value
·
compared to VO2max.
According
·
to
Poole
&
Jones
(14)
and
Poole
et
al.
(29),
the
relationship
between VO2 kinetics and O2 delivery/availability could be characterized by two
"regions", somehow separated from each other by the "normal" condition: going
from
the
"normal"
condition
towards
·
a
situation
of
increased
O2
delivery/availability, no significant effects on VO2 kinetics would be observed; on
the
other
hand,
going
from
the
"normal"
condition
towards
a
situation
of
decreased O2 delivery/availability (either physiologically induced or attributable
·
to disease states), slower VO2 kinetics could occur. As mentioned above, this
hypothesis clearly deserves further investigations, whose results could enable us
·
to fully exploit the possibility to utilize analysis of VO2 kinetics as a functional
evaluation tool. The exact boundaries of the "normal" condition are one example
of the aspects which need to be better elucidated.
CONCLUSIONS
·
VO2
kinetics
and
O2
deficit
represent
important
determinants
of
exercise
tolerance and sport performance. In "normal" conditions convective and diffusive
O2 delivery to skeletal muscle fibers do not represent important determinants of
·
VO2 kinetics. Thus, in "normal" conditions (e.g. normoxia, no impediments to O2
·
delivery, absence of pathological conditions) the limiting factors for VO2 kinetics
seem mainly located within muscle fibers. Whereas a limiting role by PDH has
not
been
experimentally
confirmed,
the
role
of
inhibition
of
mitochondrial
respiration by NO needs further investigations. Important determinants of skeletal
muscle
·
VO 2
kinetics
likely
reside
in
the
interplay
between
the
various
mechanisms of energy provision at exercise onset. By acting as high-capacitance
energy buffers, PCr hydrolysis and anaerobic glycolysis would delay or attenuate
the increase in (ADP) within the cell following rapid increases in ATP demand,
thereby buffering a more rapid activation of oxidative phosphorylation.
·
·
The different "localization" of the main limiting factors for VO2 kinetics and
VO2max
offers
to
exercise
physiologists
the
opportunity
to
perform,
non-
invasively, a functional evaluation of oxidative metabolism at two different levels
of the pathway covered by O2, from ambient air to the mitochondria of exercising
·
muscles. By measuring VO2max we primarily evaluate the functional capacity by
the cardiovascular system to deliver O2 to the exercising muscles, whereas when
62
·
we determine VO2 kinetics the functional evaluation is mainly related to skeletal
muscle oxidative metabolism. In pathological conditions the situation may be less
clear, and warrants further investigations.
Acknowledgements: Financial support by ASI Contract n. I/007/06/0, OSMA, Work Package
1B-32-1, and by institutional funds (FIRST) from the University of Milano is acknowledged. The
experiments on the isolated dog gastrocnemius preparation in situ preparation were carried out in
the laboratories of Drs. Peter D. Wagner, Michael C. Hogan (University of California, San Diego)
and L. Bruce Gladden (Auburn University).
REFERENCES
1.
Krogh A, Lindhard J. The regulation of respiration and circulation during the initial stages of
muscular work. J Physiol 1913; 47: 112-136.
2.
Hill AV, Lupton H. Muscular exercise, lactic acid, and the supply and utilization of oxygen. Q
J Med 1923; 16: 135-171.
3.
di Prampero PE. Energetics of muscular exercise. Rev Physiol Biochem Pharmacol 1981; 89:
143-222.
4.
Cerretelli P, di Prampero PE. Gas exchange in exercise. In Handbook of Physiology, Section 3,
The Respiratory System, vol. IV, Gas Exchange, LE Fahri, SM Tenney SM (eds.). Bethesda,
MD, USA, American Physiological Society, 1987, pp. 297-339.
5.
Cerretelli P, Pendergast D, Paganelli WC, Rennie DW. Effects of specific muscle training on O2
6.
Cerretelli P, Rennie DW, Pendergast DR. Kinetics of metabolic transients during exercise. In
on-response and early blood lactate. J Appl Physiol 1979; 47: 761-769.
Exercise Bioenergetics and Gas Exchange. P. Cerretelli, BJ Whipp (eds.). Amsterdam, The
Netherlands, Elsevier, 1980, pp. 187-209.
7.
di Prampero PE, Margaria R. Relationship between O2 consumption, high energy phosphates
8.
Margaria R, Mangili F, Cuttica F, Cerretelli P. The kinetics of the oxygen consumption at the
and the kinetics of the O2 debt in exercise. Pflüg Arch 1968; 304: 11-19.
onset of muscular exercise in man. Ergonomics 1965; 8: 49-54.
9.
Whipp BJ, Mahler M. Dynamics of pulmonary gas exchange during exercise. In Pulmonary Gas
Exchange, Vol. II, JB West (ed.). New York, NY, USA, Academic, 1980, pp. 33-96.
10. Grassi B. Delayed activation of oxidative phosphorylation in skeletal muscle at exercise onset.
Med Sci Sports Exerc 2005; 37: 1567-1573.
11. Hughson RL, Tschakowsky ME, Houston ME. Regulation of oxygen consumption at the onset
of exercise. Exerc Sport Sci Rev 2001; 29: 129-133.
12. Tschakovsky ME, Hughson RL. Interaction of factors determining oxygen uptake at the onset
of exercise. J Appl Physiol 1999; 86: 1101-1113.
13. Whipp BJ, Rossiter HB, Ward SA. Exertional oxygen uptake kinetics: a stamen of stamina?
Biochem Soc Trans 2002; 30: 237-247.
·
14. Poole DC, Jones AM. Towards an understanding of the mechanistic bases of V O2 kinetics. In
Oxygen Uptake Kinetics in Sport, Exercise and Medicine. AM Jones & DC Poole (eds),
London, UK, Routledge, 2005 pp. 294-328.
15. Piiper
J,
di
Prampero
PE,
Cerretelli
P.
Oxygen
debt
and
high
energy
phosphates
in
gastrocnemius muscle of the dog. Am J Physiol 1968; 215: 523-531.
16. Bangsbo J, Krustrup P, Gonzalez-Alonso J, Boushel R, Saltin B. Muscle oxygen kinetics at
onset of intense dynamic exercise in humans. Am J Physiol 2000; 279: R899-R906.
63
17. Grassi B, Poole DC, Richardson RS, Knight DR, Erickson BK, Wagner PD. Muscle O2 uptake
kinetics in humans: implications for metabolic control. J Appl Physiol 1996; 80: 988-998.
·
18. Hughson RL, Shoemaker JK, Tschakovsky ME, Kowalchuck JM. Dependence of muscle V O2
on blood flow dynamics at the onset of forearm exercise. J Appl Physiol 1996; 81: 1619-1626.
19. Behnke BJ, Kindig CA, Musch TI, Sexton WL, Poole DC. Effects of prior contractions on muscle
microvascular oxygen pressure at onset of subsequent contractions. J Physiol 2002; 593: 927-934.
20. Grassi B, Pogliaghi S, Rampichini S, et al. Muscle oxygenation and gas exchange kinetics
during cycling exercise on-transitions in humans. J Appl Physiol 2003; 95: 149-158.
21. Radegran G, Saltin B. Muscle blood flow at onset of dynamic exercise in humans. Am J Physiol
1998; 274: H314-H322.
·
22. Grassi B. Skeletal muscle V O2 on-kinetics: set by O2 delivery or by O2 utilization? New insights
into an old issue. Med Sci Sports Exerc 2000; 32: 108-116.
·
23. Grassi B, Hogan MC, Greenhaff PL, et al. V O2 on-kinetics in dog gastrocnemius in situ following
activation of pyruvate dehydrogenase by dichloroacetate. J Physiol 2002; 538: 195-207.
24. Hogan MC. Fall in intracellular PO2 at the onset of contractions in Xenopus single skeletal
muscle fibers. J Appl Physiol 2001; 90: 1871-1876.
25. Grassi B, Gladden LB, Samaja M, Stary CM, Hogan MC. Faster adjustment of O2 delivery does
·
not affect V O2 on-kinetics in isolated in situ canine muscle. J Appl Physiol 1998; 85: 1394-1403.
26. Grassi B, Gladden LB, Stary CM, Wagner PD, Hogan MC. Peripheral O2 diffusion does not
·
affect V O2 on-kinetics in isolated in situ canine muscle. J Appl Physiol 1998; 85: 1404-1412.
·
27. Grassi B, Hogan MC, Kelley KM, et al. Role of convective O2 delivery in determining V O2 on·
kinetics in canine muscle contracting at peak V O2. J Appl Physiol 2000; 89: 1293-1301.
28. Grassi B, Hogan MC, Kelley KM, Howlett RA, Gladden LB. Effects of NOS inhibition by LNAME on oxygen uptake kinetics in isolated canine muscle in situ. J Physiol 2005; 568:
1021-1033.
·
29. Poole DC, Kindig CA, Behnke BJ. V O2 kinetics in different disease states. In Oxygen Uptake
Kinetics
in
Sport,
Exercise
and
Medicine,
AM
Jones
&
DC
Poole
(eds),
London,
UK,
Routledge, 2005 pp. 353-372.
30. Timmons JA, Poucher SM, Constantin-Teodosiu D, MacDonald IA, Greenhaff PL. Metabolic
responses from rest to steady state determine contractile function in ischemic skeletal muscle.
Am J Physiol 1997; 273: E233-E238.
31. Timmons JA, Gustafsson T, Sundberg CJ, Jansson E, Greenhaff PL. Muscle acetyl group
availability is a major determinant of oxygen deficit in humans during submaximal exercise. Am
J Physiol 1998; 274: E377-E380.
32. Stacpoole PW. The pharmacology of dichloroacetate. Metabolism 1989; 38: 1124-1144.
33. Bangsbo
J,
Gibala
MJ,
Krustrup
P,
Gonzalez-Alonso
J,
Saltin
B.
Enhanced
pyruvate
dehydrogenase activity does not affect muscle O2 uptake at onset of intense exercise in humans.
Am J Physiol 2002; 282: R273-R280.
·
34. Rossiter HB, Ward SA, Howe FA, et al. Effects of dichloroacetate on V O2 and intramuscular
P
31
metabolite kinetics during high-intensity exercise in humans. J Appl Physiol 2003; 95: 105-115.
35. Berzin RM, Wolfe C, Kwasman M, et al. Improved hemodynamic function and mechanical
efficiency in congestive heart failure with sodium dichloroacetate. J Am Coll Cardiol 1994; 23:
1617-1624.
36. Brown GC. Nitric oxide as a competitive inhibitor of oxygen consumption in the mitochondrial
respiratory chain. Acta Physiol Scand 2000; 168: 667-674.
37. Kindig CA, McDonough P, Erickson HH, Poole DC. Effect of L-NAME on oxygen uptake
kinetics during heavy-intensity exercise in the horse. J Appl Physiol 2001; 91: 891-896.
64
38. Kindig CA, McDonough P, Erickson HH, Poole DC. Nitric oxide synthase inhibition speeds
oxygen uptake kinetics in horses during moderate domain running. Respir Physiol Neurobiol
2002; 132: 169-178.
39. Jones AM, Wilkerson DP, Koppo K, Wilmshurst S, Campbell IT. Inhibition of nitric oxide
·
synthase by L-NAME speeds phase II pulmonary V O2 kinetics in the transition to moderate
intensity exercise in man. J Physiol 2003; 552: 265-272.
40. Jones AM, Wilkerson DP, Wilmshurst S, Campbell IT. Influence of L-NAME on pulmonary O2
uptake kinetics during heavy-intensity cycle exercise. J Appl Physiol 2004; 96: 1033-1038.
41. Wilkerson DP, Campbell IT, Jones AT. Influence of nitric oxide synthase inhibition on pulmonary
O2 uptake kinetics during supra-maximal exercise in humans. J Physiol 2004: 561: 623-635.
42. McDonough P, Jones AM, Poole DC. Nitric oxide and muscle O2 kinetics. J Physiol 2006; 568:
563-564.
·
43. Grassi B, Hogan MC, Gladden LB. Nitric oxide and skeletal muscle V O2 kinetics. J Physiol
2006; 573. 565-566.
44. Kindig CA, Howlett RA, Stary CM, Walsh B, Hogan MC. Effects of acute creatine kinase
inhibition on metabolism and tension development in isolated single myocytes. J Appl Physiol
2005; 98: 541-549.
45. Harrison GJ, Van Wijhe MH, De Groot B, Dijk FJ, Gustafson LA, Van Beek JHGM. Glycolytic
buffering
affects
cardiac
bioenergetic
signaling
and
contractile
reserve
similar
to
creatine
kinase. Am J Physiol 2003; 285: H883-H890.
46. Gustafson LA, Van Beek JHGM. Activation time of myocardial oxidative phosphorylation in
creatine kinase and adenylate kinase knockout mice. Am J Physiol 2002; 282: H2259-H2264.
47. Grassi B, Hogan MC, Rossiter HB, et al. Effects of acute creatine kinase inhibition on skeletal
muscle O2 uptake kinetics. Med Sci Sports Exerc 2006; 38: S519.
48. di Prampero PE, Ferretti G. Factors limiting maximal oxygen consumption in humans. Respir
Physiol 1990; 80: 113-128.
49. Phillips SM, Green HJ, MacDonald MJ, Hughson RL. Progressive effect of endurance training
·
on V O2 kinetics at onset of submaximal exercise. J Appl Physiol 1995; 79:1914-1920.
·
50. Fukuoka Y, Grassi B, Conti M, et al. Early effects of exercise training on V O2 on- and offkinetics in 50-yr old subjects. Pflüg Arch 2002; 443: 690-697.
51. Borrelli E, Pogliaghi S, Molinello A, Diciolla F, Maccherini M, Grassi B. Serial assessment of
·
·
peak V O2 and V O2 kinetics early after heart transplantation. Med Sci Sports Exerc 2003; 35:
1798-1804.
52. Nery LE, Wasserman K, Andrews JD, Huntsman DJ, Hansen JE, Whipp BJ. Ventilatory and gas
exchange kinetics during exercise in chronic obstructive pulmonary disease. J Appl Physiol
1982; 53: 1594-1602.
53. Sietsema KE, Ben-Dov I, Zhang YY, Sullivan C, Wasserman K. Dynamics of oxygen uptake
for submaximal exercise and recovery in patients with chronic heart failure. Chest 1994; 105:
1693-1700.
54. Bauer TA, Regensteiner JG, Brass EP, Hiatt WR. Oxygen uptake kinetics are slowed in patients
with peripheral arterial disease. J Appl Physiol 1999; 87: 809-819.
55. Regensteiner JG, Bauer TA, Reusch JEB, et al. Abnormal oxygen uptake kinetics in women
with type II diabetes mellitus. J Appl Physiol 1998; 85: 310-317.
56. Engelen M, Porszaz J, Riley M, Wasserman K, Maehara K, Barstow TJ. Effects of hypoxic hypoxia
on O2 uptake and heart rate kinetics during heavy exercise. J Appl Physiol 1996; 81: 2500-2508.
57. MacDonald MJ, Shoemaker JK, Tschakowsky ME, Hughson RL. Alveolar oxygen uptake and
femoral artery blood flow dynamics in upright and supine leg exercise in humans. J Appl
Physiol 1998; 85: 1622-1628.
65
58. Hughson RL. Alterations in the oxygen deficit-oxygen debt relationship with beta-adrenergic
receptor blockade in man. J Physiol 1984; 349: 375-387.
59. Lunde PK, Sjastad I, Schiotz Thorud H-M, Sejersted OM. Skeletal muscle disorders in heart
failure. Acta Physiol Scand 2001; 171: 277-294.
60. Palange P, Wagner PD. "The skeletal muscle in chronic respiratory diseases", summary of the
ERS research seminar in Rome, Italy, February 11-12, 1999. Eur Resp J 2001; 15: 807-815.
61. Hiatt WR, Wolfel EE, Regensteiner JG, Brass EP. Skeletal muscle carnitine metabolism in
patients with unilateral peripheral arterial disease. J Appl Physiol 1992; 73: 346-353.
62. Baldi JC, Aoina JL, Oxenham HC, Bagg W, Doughty RN. Reduced exercise arteriovenous O2
difference in Type 2 diabetes. J Appl Physiol 2003; 94: 1033-1038.
63. Cerretelli P, Grassi B, Colombini A, Caru B, Marconi C. Gas exchange and metabolic transients
in heart transplant recipients. Respir Physiol 1988; 74: 355-371.
64. Cerretelli
P,
Marconi
C,
Meyer
M,
Ferretti
G,
Grassi
B.
Gas
exchange
kinetics
in
heart
transplant recipients. Chest 1992; 101 (Suppl. 1): 199S-205S.
65. Grassi B, Marconi C, Meyer M, Rieu M, Cerretelli P. Gas exchange and cardiovascular kinetics
upon different exercise protocols in heart transplant recipients. J Appl Physiol 1997; 82: 1952-1962.
66. Lanfranconi F, Borrelli E, Ferri A, et al. B. Non-invasive evaluation of skeletal muscle oxidative
metabolism after heart transplant. Med Sci Sports Exerc 2006; 38: 1374-1383.
67. Behnke BJ, Kindig CA, McDonough P, Poole DC, Sexton WL. Dynamic of microvascular
oxygen pressure during rest-contraction transition in skeletal muscle of diabetic rats. Am J
Physiol 2002; 283: H926-H932.
68. Diederich ER, Behnke BJ, McDonough P, et al. Dynamics of microvascular oxygen partial
pressure in contracting skeletal muscle of rats with chronic heart failure. Cardiov Research
2002; 56: 479-486.
69. Jones AM, Poole DC. Introduction to oxygen uptake kinetics and historical development of the
discipline. In Oxygen Uptake Kinetics in Sport, Exercise and Medicine. AM Jones & DC Poole
(eds), London, UK, Routledge, 2005 pp. 3-35.
70. Schalcher C, Rickli H, Brehn M, et al. Prolonged oxygen uptake kinetics during low-intensity
exercise are related to poor prognosis in patients with mild-to-moderate congestive heart failure.
Chest 2003; 124: 580-586.
Received:
October 13, 2006
A c c e p t e d : November 20, 2006
Author’s address: Bruno Grassi, MD PhD, Dipartimento di Scienze e Tecnologie Biomediche,
Universita` degli Studi di Milano, LITA - Via Fratelli Cervi 93, I -20090 Segrate (MI), Italy. Tel.
+39-02-50330421; Fax +39-02-50330414; e-mail: [email protected]