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INVITED EDITORIAL
Division of Physiology, Pulmonary and Critical Care Medicine, University of California, San Diego, La Jolla, California 92093
In this issue of the Journal of Applied Physiology, Mizuno and colleagues (5) report the use of positron emission tomography (PET) in human skeletal muscle (knee extensors) both at rest and at 30 min after exhaustive single-leg cycling. They were able to measure regional perfusion and O2 consumption in five areas situated at an equal distance over a proximal-todistal axis of 
12 cm. Their principal conclusion was that there was heterogeneity of hemodynamic variables both at rest and during recovery from exercise, with perfusion and O2 consumption that was lower distally vs. proximally.
This formidable illustration of the power of almost noninvasive techniques to gather regional functional information is impressive. Although the spatial resolution may still be coarse compared with the size of functional units of muscle (and we do not yet know that), such methods begin to address one of the most fundamental barriers to the understanding of organ function: heterogeneity. In the muscles, it is the distribution of blood flow (
) in relation to local metabolic rate (O2 consumption; 
O2) that constitutes the major form of heterogeneity. It is useful to compare this with the lungs, where it is the distribution of perfusion () in relation to local alveolar ventilation (A) that is of corresponding concern. We have known for some time that, in lung disease, nonuniform distribution of ventilation-to-perfusion ratios (A/) is the most important cause of inefficient pulmonary gas exchange and resulting hypoxemia (1). To make this assertion has required the development of methods for measuring, directly or indirectly, all of the causes of inadequate pulmonary gas exchange: A/ inequality, diffusion limitation of O2, shunting of through unventilated alveoli, and diminished ventilation. We are only now developing such methods for skeletal muscle, and Mizuno's paper is a significant advance in this area.
The muscles, similar to the lungs, are subject to a corresponding set of O2 exchange limitations: they are O2/ inequality, limitation of diffusive transport of O2 from the muscle microcirculation to the mitochondria, shunting of through nonnutrient vessels, and diminished total muscle . Many studies have indirectly suggested that, contrary to most circumstances in the lungs, diffusion limitation is the principal mechanism of O2 unloading limitation, even in healthy controls (2–4, 7), whereas shunts and limited appear to be of much less importance. However, the contribution of O2/ heterogeneity has been largely obscure for lack of direct methods for its measurement. Recently, Richardson and colleagues (6) were able to measure both and phosphocreatine depletion in exercising human calf muscle under steady-state conditions using magnetic resonance imaging technology. They took phosphocreatine depletion to represent O2. They found a level of O2/ inequality that might interfere with O2 exchange to a small degree (8%). Their data, although intriguing, are somewhat preliminary and await better resolution and more direct measures of O2 consumption.
O2 DELIVERY, CONSUMPTION, AND EXTRACTION: THE FICK PRINCIPLE
As a reminder, the well-known Fick principle of mass conservation relates O2 to and the arteriovenous O2 concentration difference (CaO2 – CvO2) as follows
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x CaO2 is commonly referred to as O2 delivery, whereas the term (CaO2 – CvO2)/CaO2 is defined as fractional O2 extraction (CaO2 is arterial O2 concentration and CvO2 is venous O2 concentration); their product yields O2 consumption. Table 2 of the Mizuno paper lists , O2, and fractional extraction before and after exercise. These data are now addressed separately for each condition. PET DATA AT REST BEFORE EXERCISE
Prior to exercise, a systematic decline in perfusion was observed from proximal to distal quadriceps muscle. This was accompanied by a corresponding fall in O2 consumption [Table 2 of Mizuno et al. (5); Fig. 1, A and B of this editorial]. Because O2 and declined similarly, CaO2 – CvO2 must have been essentially constant across the five regions. Because CaO2 is identical across the five regions sampled, fractional extraction should therefore have been essentially identical as well. This was indeed observed (Table 2 of Mizuno et al. and Fig. 1C of this editorial). The lowest value was 0.56 and the highest value was 0.60 in the leg before exercise. Plotting the ratio of O2 to (which also defines CaO2 – CvO2) with the mean group data in Table 2 of Mizuno's paper results in surprisingly little O2/ heterogeneity. Figure 1D of this editorial shows this ratio across the five sites. The highest value is 0.113, and the lowest value is 0.100. The mean is 0.106, and the coefficient of variation of the five values (SD/mean) is just 0.044. This is about one-tenth the amount of heterogeneity of A/ in the normal resting human lung (6). It is true that looking at mean results may underestimate heterogeneity within subjects; however, the use of group data lessens the extraneous impact of random noise. Thus the present analysis, although approximate, is reasonable.
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One must conclude that at rest there may be some systematic regional variation in O2 consumption. However, remains closely matched to O2, and, as a result, there is very little apparent functional heterogeneity defined as the matching of to metabolism. How perfusion is so tightly matched to O2 consumption even at rest remains a major question to be fully resolved.
PET DATA 30 MIN AFTER EXHAUSTING EXERCISE
If there is evidence of only minor inequality at rest, there is even less evidence for O2/ heterogeneity at the time point after exercise at which Mizuno et al. (5) made their measurements. Use of data from Table 2 of their paper results in an undetectable regional variation in blood flow or O2 consumption. Hence the O2- to- ratio and O2 extraction distributions are also uniform (Fig. 1, C and D, of this editorial). It is remarkable how closely and metabolism remain matched.
Thus the conclusion to be drawn from the data of Mizuno et al. (5) on O2/ heterogeneity in resting muscle is that there is incredibly little, both before and after exercise. It is insufficient to significantly affect O2 transport, subject to the major assumption that no greater degree of heterogeneity exists at finer anatomic scales than can currently be resolved. The need for this assumption suggests that improving resolution would be very helpful.
If this finding also reflects conditions during active exercise, it suggests that functional heterogeneity of with respect to metabolic rate in the quadriceps of healthy subjects is minimal. Unfortunately, no measurements were made during exercise; therefore, this hypothesis remains to be tested. Heterogeneity at rest, at least for healthy individuals, is likely of limited functional importance, but, under exercise conditions, heterogeneity is more like to have an impact in limiting O2 availability and thus exercise capacity. The authors are encouraged to adapt their powerful methods to exercise itself to provide answers to this important question.
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FOOTNOTES |
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REFERENCES
O2 max at constant O2 delivery in dog muscle in situ. J Appl Physiol 70: 2656–2662, 1991.This article has been cited by other articles:
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  K. K. Kalliokoski, J. Knuuti, and P. Nuutila Relationship between muscle blood flow and oxygen uptake during exercise in endurance-trained and untrained men J Appl Physiol, January 1, 2005; 98(1): 380 - 383. [Abstract] [Full Text] [PDF]
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 D. C. Clarke Letter to the Editor Advan Physiol Educ, September 1, 2004; 28(3): 128 - 128. [Abstract] [Full Text] [PDF]
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