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OXYGEN TRANSPORT AND UTILIZATION:
AN INTEGRATION OF THE MUSCLE SYSTEMS
R. S. Richardson
Department of Medicine, University of California, San Diego, La Jolla, California 92093
E
ADV PHYSIOL EDUC 27: 183–191, 2003;
10.1152/advan.00038.2003.
Key words: review; cardiovascular; metabolism; exercise; blood flow
inotropic state, and maximal heart rate. Thus cardiac
muscle is a major determinant of the convective delivery of O2; however, the distribution of this O2 is
determined primarily by smooth muscle, which acts
as the middleman between the pumping cardiac muscle and the external work-performing skeletal muscle.
Therefore, governed somewhat by the endothelium,
the vascular smooth muscle plays a pivotal role in
determining the fraction of cardiac output that passes
through the working muscles (predominantly skeletal
muscle, but the crucial delivery to the cardiac muscle
should not be forgotten) and the extent to which
sympathetic vasoconstriction minimizes peripheral
vascular volume (e.g., splanchnic organs).
The integration of the cardiac, smooth, and skeletal
muscle systems is essential for the normal and somewhat complex physiological response to exercise.
Consequently, the physiology of exercise offers an
excellent approach by which to both research and
teach the integrated function of these systems. Therefore, the purpose of this paper is to tie these three
muscle systems together through the response to exercise. Specifically, O2 supply and demand have been
selected as a means by which to integrate these systems. Here this is attempted by a mixture of basic
physiology, experimental data, and modeling.
At the onset of and throughout exercise, the requirement for increased O2 transport is facilitated by an
increase in cardiac output. Maximal cardiac output
results from a combination of constraints to stroke
volume (e.g., filling pressures, pericardial limits, etc.),
Skeletal muscle, at the end of this chain, determines
O2 demand and therefore has a tremendous potential
impact on actual O2 utilization. This impact is influ-
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xercise offers a unique stage from which to study and teach the integration of
physiological systems. In this article, the process of matching O2 transport
from air to its ultimate consumption in the contracting cell is utilized to
integrate the workings of the cardiac, smooth, and skeletal muscle systems. Specifically, the physiology of exercise and the maximal oxygen consumption (V̇O2 max)
achieved through the precise linking of these three muscle systems are utilized to
highlight the complexity and importance of this integration. Smooth muscle plays a
vital “middleman” role in the distribution of blood-borne O2 to the appropriate area
of demand. Cardiac muscle instigates the convective movement of this O2, whereas
skeletal muscle acts as the recipient and ultimate consumer of O2 in the synthesis of
ATP and performance of work. In combination, these muscle systems facilitate the
remarkable 15- to 30-fold increase in metabolic rate from rest to maximal effort in
endurance-type exercise.
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Whether maximal O2 uptake (V̇O2 max) is determined
by O2 supply or O2 demand by skeletal muscle is still
controversial. To highlight the fact that this topic is
still not completely resolved, the following quote is
provided from a reviewer’s comments regarding this
author’s research recently submitted to the American
Journal of Physiology - Heart and Circulatory Physiology:
“The authors also need to be wary of giving the ‘supplier’ (cardiac output) priority over the ‘consumer’ (muscle) since the consumer must drive supply not the other
way around (i.e. increasing supply does not increase
demand, but surely increasing demand requires an increased supply).”
METHODS FOR ANIMAL STUDIES
Exercise model. The functional and vascular isolation
of the left gastrocnemius-flexor digitorum superficialis
muscle complex (referred to as the gastrocnemius) was
achieved as described previously (28). The gastrocnemius was electrically stimulated to elicit maximal exercise at a normal half-saturation pressure (P50) and then
again with the O2 dissociation curve shifted to the right
by the allosteric modifier of Hb (methylpropionic acid,
RSR13; Allos Therapeutics, Denver, CO).
Clearly, not everyone is in agreement regarding these
issues. Unlike this reviewer, the author of the present
manuscript does not dismiss the potential for the
supplier to have priority over the consumer, as there
are, in fact, many studies that suggest that increasing
O2 supply does allow O2 demand/utilization to also
increase (22, 23). The manuscript under review was
accepted and published with mutually acceptable
changes to the text (20).
Measurements. The arterial-venous O2 concentration ([O2]) difference was calculated from the difference in carotid artery and popliteal venous O2 concentrations. This difference was then divided by
arterial concentration to give O2 extraction. Gastrocnemius V̇O2 was calculated as the product of arterialvenous [O2] difference and blood flow. The standard
P50 of the blood was calculated before each exercise
bout by varying the inspired [O2]. The Hill equation
was then used to calculate the P50 and Hill coefficient
of the O2 dissociation curve in both the normal and
right-shifted conditions.
Consequently, this article is presented with the following sections: human and animal methodologies;
endothelium/smooth muscle and exercise; O2 supply
and demand at maximal exercise; experimental evidence for the determinants of maximal exercise; and
a brief summary.
METHODS FOR HUMAN STUDIES
Exercise model. Single-leg knee extensor exercise
(KE) and cycle exercise were utilized during these
studies. In the KE model, subjects lay semisupine on
a padded bed with a knee extensor ergometer placed
in front of them (illustrated in Ref. 25). Exercise was
limited to the quadriceps muscles during KE.
ENDOTHELIUM/SMOOTH MUSCLE AND O2
TRANSPORT DURING EXERCISE
As the middleman between major central components such as the heart and peripheral skeletal muscle, the smooth muscle/endothelium complex plays
an important role in O2 transport. Figure 1 illustrates,
in a simplified schematic form, how the red blood cell
may act as a “chariot” that distributes the bioactivity
Measurements. Skeletal muscle V̇O2 during KE was
determined via blood samples taken from the radial
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artery and femoral vein in conjunction with the measurement of muscle blood flow by the thermodilution
technique, as previously reported (17, 27). This protocol was repeated in room air (21% O2), hypoxia
(12% O2), and hyperoxia (100% O2). To safely provide
a 20% HbCO load, a carbon monoxide (CO) bolus
estimated to increase the amount of CO bound to
hemoglobin (Hb) by ⬇10% was initially administered,
and venous HbCO was measured spectrophotometrically after 20 min from a blood sample. A second CO
dose, calculated on the basis of the response to the
initial bolus to increase HbCO to ⬇20%, was then
administered (total CO administered ⫽ 312 ⫾ 25 ml)
(6, 26).
enced not only by the metabolic capacity and function of the muscle but also by the structural interplay
between O2 delivery and the muscle bed’s capacity to
facilitate O2 movement from blood to cell, or diffusional O2 conductance (DmO2).
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mmHg), but was closely linked to reductions in arterial oxyhemoglobin.
of substances such as nitric oxide (14) and ATP (5)
dependent on O2 availability. This interaction between red blood cells and the relaxation of the vascular smooth muscle implies that the red blood cell
itself plays an important role in the appropriate fall in
vascular resistance and the consequent increase in
blood flow in areas of increased O2 need.
Most recently, we (19) have recognized a difference
in the vascular response to altered O2 availability
between physically active and sedentary subjects.
This suggests a modulation of the endothelium/
smooth muscle regulation of muscle blood flow (Fig.
1) as a consequence of regular exercise and has important implications regarding the mechanisms by
which O2 delivery is matched to changing metabolic
capacity. As a follow-up to these initial cross-sectional
studies, we have since studied a group of sedentary
healthy subjects both before and after 8 wk of singleleg KE training. This research revealed the same increased vascular responsiveness to altered O2 availability as a result of exercise training in a more robust
longitudinal investigation (Fig. 2) (13). In summary,
the link that the endothelial/smooth muscle complex
maintains between the cardiac muscle of the heart
and the skeletal muscle of the periphery is highly
plastic, facilitating important changes in O2 transport
as the whole body responds to exercise and adapts to
exercise training.
The role of O2 availability in the regulation of blood
flow to active skeletal muscle has previously been
studied with acute anemia (12), normobaric hypoxia
(29), and, more recently with CO, to manipulate the
components of arterial O2 content (CaO2) (6). The
work of Koskolou et al. (12) and Roach et al. (29)
involved isovolumetric hemodilution, the resultant
anemia [with no change in arterial partial O2 pressure
(PaO2)] leading to an elevation in limb blood flow
during two-legged KE. The conclusion was that the
regulation of O2 delivery during submaximal skeletal
muscle work was dependent on CaO2 rather than PO2,
which had previously been the dogma. In the more
recent extension of this work by Gonzalez-Alonso et
al. (6), muscle blood flow was documented to be
invariant across a full spectrum of PaO2 (40 –540
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FIG. 1.
Simplified schema of the blood, endothelium, and smooth muscle interactions.
NO, nitric oxide; NOS, nitric oxide sythase; SGCi and SGCa, inactive and active
soluble guanylate cyclase, respectively.
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O2 SUPPLY AND DEMAND AT MAXIMAL
EXERCISE
all O2 delivered to the muscle was utilized). If the Fick
line were to decrease its slope to be zero, the venous
PO2 would equal the arterial PO2 and V̇O2 max would
now equal zero (i.e., none of the O2 delivered to the
muscle was utilized).
The maximal metabolic rate or V̇O2 max attained during exercise is a complex phenomenon; therefore, its
determination is unlikely to be attributed to a single
factor. In fact, as indicated earlier in this article, each
of the muscle systems (cardiac, smooth, and skeletal)
undoubtedly plays a major role in the setting of
V̇O2 max. Many studies (7, 8, 22, 30, 34) now support
the theoretical construct that V̇O2 max is determined
by the interaction between the bulk delivery of O2
(convective element) and the movement of O2 from
hemoglobin to mitochondria (diffusive element).
Finally, to gain a complete understanding of this
model of the determinants of V̇O2 max, it is important
to note that the Fick principle lines are not straight,
because they are directly reflective of the hemoglobin
dissociation curve. Therefore, changes in hemoglobin
O2 affinity will result in the same O2 delivery (constant y-intercept for the Fick principle line), but variations in muscle venous PO2 (x-intercept for the Fick
principle line). A left-shifted hemoglobin dissociation
curve (greater hemoglobin O2 affinity), resulting in a
lower venous PO2, will bisect the Fick law line earlier
and reduce V̇O2 max and vice versa. Although not illustrated in Fig. 3, this would be the equivalent of anchoring the Fick principle line at its origin of 5.0 l/min
and altering its shape to pass through B (reduced
V̇O2 max) and join the y-axis at 40 mmHg (left-shifted
O2 dissociation curve) or pass through C (elevated
V̇O2 max) and join the y-axis at 160 mmHg (rightshifted O2 dissociation curve).
Figure 3 illustrates both schematically (top) and
graphically (bottom) the interaction between the convective and diffusive elements of O2 transport. In Fig.
3, bottom, the initial V̇O2 max (A), determined by these
two interactions, would fall to B and increase to C
with a respective decrease/increase in the convective
element but without a change in the diffusive element
of O2 transport. An increase or decrease in the diffusive element of O2 transport but no change in the
convective element would move V̇O2 max from A to D
or E, respectively. Letters F, G, H, and I represent the
effect on V̇O2 max caused by a change in the diffusive
element of O2 transport with a concomitant change in
the convective element. Thus it can be seen that, if
the slope of the Fick law line were to increase to be
vertical, the venous PO2 would fall to zero, and the
intersection of the Fick principle and Fick law line
would now illustrate that O2 delivery ⫽ V̇O2 max (i.e.,
DETERMINANTS OF MAXIMAL EXERCISE:
EXPERIMENTAL EVIDENCE
Role of central and peripheral limits in determining V̇O2 max. Although it is likely that there will
always be disagreement on the factors that limit muscle V̇O2 max, in addition to the currently highlighted
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FIG. 2.
Effect of exercise training on leg vascular responsiveness to decreased O2 availability. Reduced O2 availability
was achieved by a 20% carbon monoxide load on hemoglobin.
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As illustrated in Fig. 4, a clear indication that O2
supply governs muscle V̇O2 max became apparent with
the introduction of the functionally isolated KE model
by Andersen and Saltin (1). The comparison that we
make here, between data collected from human quadriceps acting as part of whole body (cycle) exercise
(11) and the KE in isolation, confirms a much higher
specific mitochondrial V̇O2 when central limitations
to O2 delivery are not present (Fig. 4). Somewhat
surprisingly, this appears to be the case whether the
subjects are trained or untrained (Fig. 4), perhaps
because not only does the transition from cycle exercise to KE provide greater O2 delivery per unit of
muscle but also the differing perfusion characteristics
may alter (improve) the matching of O2 supply and
demand (Fig. 5) (24).
FIG. 3.
Interactions between the convective (Eq. 1, Fick principle) and diffusive elements (Eq. 2, Fick law) of O2
transport illustrated both schematically (top) and
graphically (bottom). RBC, red blood cells. Movement
from the initial maximal O2 uptake (V̇O2 max; A) to
values labeled B– I illustrate various combinations of
changes in the convective and diffusive elements of O2
transport (explained in detail in O2 SUPPLY AND DEMAND
AT MAXIMAL EXERCISE).
Another major observation from our isolated human
skeletal muscle studies is that, even in an exercise
paradigm where O2 delivery per unit of muscle mass
is very high (KE), an elevated O2 delivery afforded by
breathing 100% O2 results in an increase in V̇O2 max in
trained skeletal muscle (22). These findings provide
evidence that, in trained subjects, normoxic KE,
which has demonstrated the highest mass-specific
skeletal muscle V̇O2 in humans (Fig. 5), is limited by
O2 supply, not O2 demand.
findings several recent studies have provided evidence supporting the concept that O2 supply rather
than biochemical limitation (4) sets V̇O2 max. Specifically, despite using a similar optical technique to that
of Stainsby et al. (32), Duhaylongsod et al. (3) re-
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ported contrasting results in the canine gracilis muscle, where maximal exercise resulted in near-complete reduction of cytochrome aa3. This was
interpreted to reflect deficient O2 provision to this
muscle (3). In humans, Richardson et al. (25) measured in vivo myoglobin desaturation at maximal exercise, as an endogenous probe of intracellular PO2,
and found a proportional fall in muscle V̇O2 max with a
hypoxically induced reduction in intracellular PO2.
These data provide support for the concept that maximal respiratory rate (V̇O2 max) is limited by O2 supply
(25). Indirect pulmonary gas exchange measurements
during whole body exercise have continued to support the importance of O2 supply in determining
muscle V̇O2 max, (15), whereas more direct evidence
attained by blood gas and blood flow measurements
during cycle exercise have also recently been provided by Knight et al. (11). Here, normoxic leg
V̇O2 max was increased by 8% in hyperoxia (100% O2)
and reduced by 30% in hypoxia (12% O2).
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preparation that this is not the unique determinant of
V̇O2 max (33). The principal observation in this animal
study is that, under conditions of constant convective
arterial ḊO2, an increase in P50 allowed exercising
skeletal muscle to achieve a greater V̇O2 max (Fig. 6).
This provided evidence that V̇O2 max at a normal P50 is
not determined by mitochondrial metabolic limits,
but rather by O2 supply: an increase in P50 producing
a steeper O2 gradient (driving force) from capillary to
tissue, providing more O2 and allowing tissue V̇O2 max
to increase (Fig. 6). Thus these experimental findings
support the concept that, for a given O2 delivery, the
amount of O2 that can be extracted and used by the
working muscle is determined by the DmO2 and the
PO2 gradient from the red blood cell to the mitochondria (Fick’s law of diffusion). Theoretically, if the O2
conductance is held constant and DmO2 does not
change, a right-shifted O2 dissociation curve should
decrease the rate at which the capillary PO2 declines,
as O2 is removed by the working muscle, thereby
increasing the capillary-to-tissue PO2-driving gradient
along the capillary length. This rightward shift in the
O2 dissociation curve should then increase V̇O2 max, if
DmO2 is an important determinant of V̇O2 max. This
Recently collected data extend the observation of O2
supply dependence and illustrate that, within either
exercise paradigm (cycle exercise and KE), increased
or decreased O2 delivery results in a similar change in
muscle V̇O2 max (dictated by the interaction of O2
delivery with O2 utilization (ḊO2; Fig. 5) (22). Here, it
should be recognized that O2 extraction (e) is not a
pure reflection of “peripheral” factors (i.e., ḊO2) as it
incorporates other “central” factors (namely blood
flow (Q) and the shape of the O2 dissociation curve
(␤) [O2 extraction ⫽ 1 ⫺ e⫺ḊO2/(␤ 䡠 Q), (16)]. However, it is evident that the interaction of the variables
that constitute O2 extraction appears to be a limitation that constrains changes in muscle V̇O2 max with
changes in muscle O2 delivery. Hence, in KE, despite
an increased ḊO2 and a similar relationship between
O2 extraction and V̇O2 (27), O2 extraction at V̇O2 max
appears to be attenuated by high muscle blood flows.
Diffusion of O2 as a determinant of V̇O2 max. It has
been demonstrated that an increase in O2 delivery can
increase V̇O2 max (2, 11, 21, 35), which suggests that
O2 supply limitation does exist. However, it has also
been shown in the isolated canine gastrocnemius
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FIG. 4.
Large increase in mitochondrial O2 uptake facilitated by changing the exercise paradigm from cycling to knee
extension exercise (KE), where cardiac output and muscle O2 delivery are not limiting. Mitochondrial V̇O2 was
calculated on the basis of an assumed mitochondrial fiber volume of 7.5 and 4% for trained and untrained
subjects, respectively, a myofibril volume of 80%, and a muscle density of 1.06 g/cm (9, 10, 18). Active muscle
mass used in the normalization was 7.5 kg for cycle exercise and 2.5 kg for KE.
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portant role of Hb affinity in determining O2 extraction.
experimental approach (using RSR13 to right-shift the
O2 dissociation curve) revealed an increase in V̇O2 max
and no substantial change in DmO2 (Fig. 6) (28).
SUMMARY
It is apparent that the cardiac, smooth, and skeletal
muscle systems are essential for the normal and complex physiological response to exercise. Consequently, the physiology of exercise offers an excellent
approach for both researchers and teachers to integrate the function of these systems. The specific use
of maximal exercise and its determinants appears to
be an interesting and reasonable method by which to
examine and understand the integration of these muscle systems.
V̇O2 max rose by 20%, with an increase in P50 from 33
to 53 mmHg (Fig. 6), similar in magnitude to the
reduction reported by Hogan et al. (7) with a decrease
in P50 from 32 to 23 mmHg (⫺17%). Here, it is also
pertinent to note that, in addition to the work of
Hogan et al., Schumacker et al. (31) assessed the
effect of a reduced P50 (by sodium cyanate infusions)
on exercise performance in dogs on a treadmill and
found no effect on O2 extraction and exercise performance. In that study (31), because the animals were
only minimally instrumented it was not possible to
control O2 delivery to the exercising muscles at maximum exercise. However, Schumacker et al. did demonstrate that, for the same O2 delivery, less O2 was
extracted during exercise when the O2 dissociation
curve was shifted to the left, consistent with Hogan et
al. (7) and the present study, which suggest an im-
[The PowerPoint slides from this Refresher Course
presentation at Experimental Biology 2002 are available through the Archive of Teaching Resources at
www.apsarchive.org].
I thank all collaborators and subjects involved in these studies.
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FIG. 6.
Unchanged relationship between V̇O2 max and venous
PO2 following methylpropionic acid (RSR13) administration (shifts the O2 dissociation curve to the right),
illustrates that O2 conductance (DmO2) has remained
unchanged and appears to dictate the improvement in
V̇O2 max.
FIG. 5.
Similar relationship between V̇O2 max and O2 delivery
during conventional cycle exercise (11) and KE data
collected in hypoxia, normoxia, and hyperoxia (22).
However, it should be noted that maximal O2 extraction in each maximal KE bout is significantly reduced
compared with the maximal cycle exercise O2 extractions (#P < 0.05).
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This work was made possible by the support of The National Heart,
Lung, and Blood Institute (HL-17731), National Center for Regional
Resources (RR-14785 and RR-02305), a grant-in-aid from the American Heart Association (9960064Y), The Tobacco Related Disease
Research Program (8KT-0081 and 10KT-0335), and The UC San
Diego Academic Senate (RA 889M).
Address for reprint requests and other correspondence: R. S. Richardson, Dept. of Medicine, Medical Teaching Facility, 9500 Gilman
Dr., La Jolla, CA 92093– 0623 (E-mail: [email protected]).
Submitted 27 August 2003; accepted in final form 28 August 2003.
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