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Advan. Physiol. Edu. 27: 183-191, 2003; doi:10.1152/advan.00038.2003
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ADV PHYSIOL EDUC 27:183-191, 2003
© 2003 American Physiological Society

APS REFRESHER COURSE REPORT

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

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: rrichardson{at}ucsd.edu)

Abstract

Exercise 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 (V·O2 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.

Key words: review; cardiovascular; metabolism; exercise; blood flow

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.), 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).

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 influenced 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).

Whether maximal O2 uptake (V·O2 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)."

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).

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.

Measurements.
Skeletal muscle V·O2 during KE was determined via blood samples taken from the radial 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 {approx}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 {approx}20%, was then administered (total CO administered = 312 ± 25 ml) (6, 26).

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).

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 V·O2 was calculated as the product of arterial-venous [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.

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 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.



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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.

 
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 mmHg), but was closely linked to reductions in arterial oxyhemoglobin.

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 single-leg 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.



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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.

 
O2 SUPPLY AND DEMAND AT MAXIMAL EXERCISE

The maximal metabolic rate or V·O2 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 V·O2 max. Many studies (7, 8, 22, 30, 34) now support the theoretical construct that V·O2 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).

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 V·O2 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 V·O2 max from A to D or E, respectively. Letters F, G, H, and I represent the effect on V·O2 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 = V·O2 max (i.e., 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 V·O2 max would now equal zero (i.e., none of the O2 delivered to the muscle was utilized).



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  		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 (V·O2 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 O2supply and demand at maximal exercise).

 
Finally, to gain a complete understanding of this model of the determinants of V·O2 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 V·O2 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 V·O2 max) and join the y-axis at 40 mmHg (left-shifted O2 dissociation curve) or pass through C (elevated V·O2 max) and join the y-axis at 160 mmHg (right-shifted O2 dissociation curve).

DETERMINANTS OF MAXIMAL EXERCISE: EXPERIMENTAL EVIDENCE

Role of central and peripheral limits in determining V·O2 max.
Although it is likely that there will always be disagreement on the factors that limit muscle V·O2 max, in addition to the currently highlighted findings several recent studies have provided evidence supporting the concept that O2 supply rather than biochemical limitation (4) sets V·O2 max. Specifically, despite using a similar optical technique to that of Stainsby et al. (32), Duhaylongsod et al. (3) reported 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 V·O2 max with a hypoxically induced reduction in intracellular PO2. These data provide support for the concept that maximal respiratory rate (V·O2 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 V·O2 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 V·O2 max was increased by 8% in hyperoxia (100% O2) and reduced by 30% in hypoxia (12% O2).

As illustrated in Fig. 4, a clear indication that O2 supply governs muscle V·O2 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 V·O2 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).



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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 V·O2 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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  		FIG. 5 Similar relationship between V·O2 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).

 
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 V·O2 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 V·O2 in humans (Fig. 5), is limited by O2 supply, not O2 demand.

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 V·O2 max (dictated by the interaction of O2 delivery with O2 utilization (D·O2; Fig. 5) (22). Here, it should be recognized that O2 extraction (e) is not a pure reflection of "peripheral" factors (i.e., D·O2) as it incorporates other "central" factors (namely blood flow (Q) and the shape of the O2 dissociation curve (ß) [O2 extraction = 1 - e-D·O2/(ß · 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 V·O2 max with changes in muscle O2 delivery. Hence, in KE, despite an increased D·O2 and a similar relationship between O2 extraction and V·O2 (27), O2 extraction at V·O2 max appears to be attenuated by high muscle blood flows.

Diffusion of O2 as a determinant of V·O2 max.
It has been demonstrated that an increase in O2 delivery can increase V·O2 max (2, 11, 21, 35), which suggests that O2 supply limitation does exist. However, it has also been shown in the isolated canine gastrocnemius preparation that this is not the unique determinant of V·O2 max (33). The principal observation in this animal study is that, under conditions of constant convective arterial D·O2, an increase in P50 allowed exercising skeletal muscle to achieve a greater V·O2 max (Fig. 6). This provided evidence that V·O2 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 V·O2 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 V·O2 max, if DmO2 is an important determinant of V·O2 max. This experimental approach (using RSR13 to right-shift the O2 dissociation curve) revealed an increase in V·O2 max and no substantial change in DmO2 (Fig. 6) (28).



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  		FIG. 6 Unchanged relationship between V·O2 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 V·O2 max.

 
V·O2 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 important role of Hb affinity in determining O2 extraction.

DISCLOSURES

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).

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.

[The PowerPoint slides from this Refresher Course presentation at Experimental Biology 2002 are available through the Archive of Teaching Resources at www.apsarchive.org].

Acknowledgments

I thank all collaborators and subjects involved in these studies.

Received for publication August 27, 2003. Accepted for publication August 28, 2003.

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