Medicine & Science in Sports & Exercise:
Basic Sciences: Symposium: New insights into the control of human muscle blood flow and metabolism in vivo Recent Advances
Human muscle blood flow and metabolism studied in the isolated quadriceps muscles
RICHARDSON, RUSSELL S.; SALTIN, BENGT
Section Editor(s): Richardson, Russell S. Chair
University of California, San Diego, Department of Medicine, 0623A, La Jolla, CA 92093-0623; and The Copenhagen Muscle Research Center, Rigshospitalet, section 7652, DK-2200, Copenhagen, DENMARK
Submitted for publication March 1997.
Accepted for publication April 1997.
Muscle blood flow (Q) and metabolic response to exercise can very within species and may depend upon whether measurements were made in vivo or in situ. It has been suggested that to some extent these variations in muscle Q and metabolism may be the result of a reduction in muscle performance after the surgery of in situ preparations. In contrast, the development of the novel human in vivo preparation often described as dynamic knee-extensor exercise by Andersen and Saltin in 1985 is only minimally invasive. This preparation has revealed human muscle Q which far exceed those previously measured and allows the metabolic response of a single dynamically exercising muscle group to be studied. The use of this human exercise model was not the focus of this symposium, but each contributing author has worked extensively with this and other preparations to investigate muscle blood flow and metabolism in exercise. Thus, the purpose of this symposium was to bring together these new insights into muscle Q and metabolism in exercising muscle studied in vivo and in situ.
The following papers were presented in a symposium entitled “New insights in the Control of human Muscle Blood flow and Metabolism Studiedin Vivo” (held at the 1995 Annual Meeting of the American College of Sports Medicine (ACSM)). The goal of this symposium was to present recent developments in our understanding of skeletal muscle metabolism and perfusion during exercise. The use of the one-legged knee extensor exercise model (2) as a tool to provide these insights was not the focus of this symposium, but this innovative human exercise model has been most useful and has influenced each author's work. Each author has had extensive experience with both the knee-extensor model and other human and animal models that have enabled the extensive study of metabolism and blood flow in vivo during exercise.
The introduction of the human knee-extensor model in 1985(3) allowed a relatively small but functionally significant muscle group (the quadriceps) to be studied in an isolated preparation with minimal instrumentation and disruption of the system. This is made possible by the selection of an exercise which isolates the quadriceps, the insertion of an arterial catheter and a femoral venous catheter, and the use of the thermodilution technique to measure blood flow. With determinations of the arterial-venous differences, it is possible to quantify fluxes for a variety of metabolites and nutrients across a functionally isolated exercising muscle in man. The isolation of the work performed by the quadriceps muscles is achieved by using an ergometer with a fixed free wheel against which the quadriceps extend the lower leg and overcome the resistance applied to the flywheel. Flexion of the knee is passive and produced primarily by the inertia created by the heavy flywheel but also by gravity(2,31). This simple but unique model has advanced our knowledge of human physiology, raised questions, and allowed the study of issues that, until its development, were extremely difficult to address.
Thus, it is most fitting that embedded in this introduction to the symposium are some of the perspectives offered by Dr. Bengt Saltin, a founder of this exercise model and participant in the symposium. Here we will get a perspective of how and why this model was developed, the methodology employed, validations performed in response to criticisms, the use of this model to study vasoactive metabolites and the limitations to muscle O2 uptake, and finally a brief comparison of the physiology behind knee-extensor exercise and conventional cycle ergometry.
The one-legged kicking model was first utilized about 15 years ago at a time when we performed experiments studying skeletal muscle metabolism. The goal was to estimate precisely the contribution of substrates such as carbohydrates and lipids from the blood compared with those stored inside the skeletal muscle. At that time we and others had made these measurements over an exercising limb while pedaling a bicycle or walking on the treadmill(1,10,13). However, we did not have adequate knowledge of the exact muscle mass engaged in the exercise, nor did we know which part of which muscle was preferentially recruited. There was a need for an isolated muscle group model in which we could accurately determine both the size and recruitment pattern of the muscle involved. This would then allow for precise estimates of the role of various substrates.
In the beginning we performed several studies to determine whether our expectations of the new isolated skeletal muscle model were correct. Initially, subjects exercised at a given work load for 60 min during which we measured quadriceps blood flow. We found as expected that, after a rise in blood flow at the start of exercise, blood flow reached a constant level(≈3 min) and was quite stable during this prolonged exercise test(38). The a-vO2 difference was smaller at the beginning of exercise, but widened and then remained constant during the rest of the exercise period (41). Using these stable values for both blood flow and a-vO2 difference, we were able to calculate O2 uptake. As the power output was known, the mechanical efficiency could be calculated, and we observed a value of ≈25%(3). This was very close to what had typically been found in conventional cycle exercise (4) and thus added to the validity of this model. However, we went one step further. Being able to estimate quite precisely the contribution of metabolic substrates (muscle glycogen, blood glucose, free fatty acid uptake, and utilization of triglycerides, as well as glycerol and lactate release) we could compare these data with the O2 uptake measurements. The comparison was a favorable one. The energy turnover by the vascular measurements of O2 uptake was very close to those estimated from the substrate and metabolite data(Table 1, ref. 38). Moreover oxygen uptake and metabolic costs matched power output. These findings convinced us that the model allowed for absolute quantification of not only muscle blood flow and oxygen uptake, but also of substrate supply and utilization.
Having come this far, we continued with the muscle metabolic studies as expected; however, we also became trapped by another problem. When we expressed the blood flows per unit muscle mass involved in the exercise, we obtained values much higher than previously reported in man(9,15). There was a linear increase in blood flow with work intensity, and at exhaustive exercise we measured values ≈200-250 mL·100 g-1·min-1 (3). These values were 2-3 times higher than previously reported in man using other techniques (plethysmography, 133Xe clearance; 9, 25; for ref. see also 26). Since these initial measurements, the knee-extensor model has reproducibly delivered blood flow values this high or higher, with values ranging up to 300-375 mL·100 g-1·min-1 (34,35,37). This disparity in blood flows measured in a small muscle mass versus flows previously measured in large muscle mass exercise certainly rekindled the old question of how blood flow is regulated during physical exercise. However, before discussing this issue it would be useful to look at the methodologies employed in measuring limb or “muscle blood flow.” Although man has a maximal cardiac output often exceeding 25 L·min-1 during conventional whole body exercise (6), we are still arguing with some physiologists who consider that 80 mL·100 g-1·min-1 is the peak muscle blood flow for human muscle. This does not seem possible based on the following: If we assume that 15 kg of muscle is active during maximal cycling, then muscle blood flow would account for 12 L·min-1 of maximal cardiac output (with 3 L·min-1 supplying vital organs), but 10 L·min-1 is still left unaccounted for. Moreover, maximal oxygen uptake cannot be accounted for because with 25 L·min-1 in cardiac output maximal oxygen uptake would be 4 L·min-1. A muscle blood flow of ≈150 mL·100 g-1· min-1 is needed unless an excessively large muscle mass involvement in the exercise is assumed. Critics suggest that the recent blood flow values are a reflection of a) the fact that the thermodilution methods are an improper method for determining blood flow, b) the blood flow measured does not originate from the muscles studied, or c) the mass of muscle engaged in the exercise is underestimated. These issues have been addressed and indicate that such criticisms, although healthy, are not valid. With the thermodilution technique, the criticism of cooling down the tissue or the arterial blood in the neighboring vessels is often levied. However, if we measure the temperature in the artery, proximal and distal to the infusion site, there is evidently no change during the infusion of the ice-cold saline. Additionally, if we look at the temperature measured by thermocouples placed around the femoral vein, temperature values are also very stable until about 22-24 s after the start of the infusion. It is evident that some degree of cooling may take place over the 20 s (typical infusion time), but the magnitude is not large enough to be a source of error. To go a step further, we have compared the thermodilution with the dye-dilution technique, and they compare very well (18). The two methods also have similar coefficients of variation between 5 and 10%(Table 2). With regard to the concern about contamination from other veins that are draining the leg, the principal one is the saphenous vein adjoining the femoral vein proximal to the site of blood flow measurements. To address this criticism we have measured the limb blood flow both proximal and distal to the merge of the saphenous vein. There can be a difference, especially in a very hot environment. However, it is less than half a L·min-1 and in a neutral environment usually close to 0.1 L·min-1. We have also directly measured the flow in the saphenous vein in a few subjects who had large veins, making it possible to insert a catheter (Alonso et al., unpublished data). In these subjects we saw blood flows of 300 mL· min-1 when they were exercising in a hot environment compared with 5000-7000 mL·min-1 in the femoral vein and below 100 mL·g-1·min-1 in a cool temperature at the same work rate. Thus, it can be concluded that there is a contamination, but it represents only a small fraction of the total flow being measured in a hot environment and a negligible fraction, if any, in a neutral or cool environment (18,42).
Now, we turn to the issue of muscle mass recruitment. Biomechanics indicate that only the knee extensors need to be recruited to perform this exercise correctly. We can measure the size of this muscle group rather well, but is this truly the only muscle mass involved in the exercise? To answer this question we have analyzed the muscular recruitment patterns of the leg during knee-extensor exercise with both surface electromyography(2) and T2 weighted magnetic resonance imaging(signal intensity changes indicate active muscles; 31). Both methods revealed excellent isolation of recruitment to the quadriceps muscles. Again, we have gone one step further by studying subjects who have performed the exercise through electrical stimulation of only the knee extensors (18). The kicking exercise works quite well under these conditions, and we saw very similar physiological responses elicited here as in the voluntarily performed exercise. In fact, if anything, we tended to record slightly higher blood flows during the exercise performed by electrical stimulation of only the quadriceps muscles(Table 2). It seems clear that the preponderance of evidence indicates that the quadriceps muscle group, when exercised alone, is able to achieve very high mass specific levels of perfusion.
In an attempt to better understand the mechanism that allows this large vasodilatation, we have recently examined the effect of adenosine and nitric oxide (NO) in this model using both the thermodilution and the ultra-sound Doppler techniques (to attain a faster time resolution) to measure blood flow changes (30). Quite a dramatic increase in flow is observed at rest within 5 s of infusing a small dose of adenosine. Remembering that some of this adenosine is taken up by the red cells, it is apparent that adenosine, even in small quantities, is a very potent vasodilator. Indeed, limb blood flows similar to that observed during exercise may be elicited by an adenosine infusion. The time response is also similar. An elevation in blood flow with adenosine can be elicited not only at rest, but also during exercise (29). This raises the question of what role the endogenous adenosine plays in allowing elevated levels of perfusion in skeletal muscle. The literature suggests that adenosine may be present in the micromolar range (24). This appears to be the case based on in vivo measurements using the microdialysis technique in dynamically contracting skeletal muscle (22). Sufficient quantities are produced in the interstitial space. Moreover, cell culture studies support the notion of its formation in the interstitial space, brought about by ectodermal breakdown of AMP by 5′ nucleotidase located on the outer surface of the sarcolemma. To be able to draw a final conclusion about the role of adenosine, it is necessary to document the link between adenosine and vasodilatation by using a blocker. However, a specific blocker does not yet exist. Theophylline or caffeine reduces most of the effect of adenosine at rest, but only a fraction of the effect of the contraction-induced increase in blood flow. Thus, it is too early to conclude that in the normal situation adenosine plays a major role in causing the vasodilatory response to exercise. However, it is a strong candidate.
Now what about nitric oxide? We infused nitroprusside (a nitric oxide donor) into the femoral artery under conditions of constant blood flow(29). As with adenosine, NO promotes an increase in blood flow related to dosage, but blood flow levels off with elevated doses of NO at a much lower level than adenosine. To block the NOS we gave L-NMMA which is both specific and quite complete, and we found during exercise no effect either on the rate of blood flow elevation or on peak blood flow although the resting blood flow level was halved. By increasing the level of NO available in the muscle vascular bed with L-arginine, blood flow is again increased. Thus, even for NO there are the expected indications that it may play a role in controlling blood flow, but we cannot state that it is the critical controlling factor in human skeletal muscle.
Another interesting issue is that the level of perfusion recorded during human knee-extensor exercise (2-4 L·kg-1·min-1) cannot be supported by the human heart (40). Thus, if more muscle mass is involved in the exercise, the maximum muscle blood flow and ˙VO2peak must be reduced. It seems somewhat logical that if you are exercising with just one small muscle group and then superimpose other muscle groups, there should be a reduction in limb blood flow to maintain blood pressure since the heart cannot supply all capillary beds with a sufficient flow. This was in fact shown in 1977 by Secher et al.(44) in a classic study in which the subjects exercised with two legs for 10 min and then added arm exercise. The work was close to maximal, especially when the arms were added. Secher et al.(44) measured cardiac output and leg blood flow and demonstrated that with the increased exercising muscle mass there was an increase in cardiac output, but it was not sufficient to perfuse the upper body and the arms. Thus, there was an active vasoconstriction in the legs despite the fact that the subjects continued at exactly the same workload. We and others have tried to repeat this phenomenon, but it has been difficult to confirm that this redistribution of cardiac output always takes place(32,45). However, with the use of beta blockers to reduce the capacity of the heart or in heart failure, it is easy to demonstrate the dependence of muscle mass on perfusion(23,28). It is disturbing that we cannot reproduce this in healthy humans. An explanation may be that the experimental design is critical. Typically, workloads selected for combining arm and leg exercise have been reduced to allow the subject to continue the exercise long enough for the cardiovascular measurements to be performed. A better experimental model would be to have the subjects exercise close to maximally with their legs and then add intense upper body work. This design would need a very quick method of measuring blood flow (ultra-sound Doppler) as the exercise could not be continued for long (the subject may fatigue in 30-60 s). Here we would expect an immediate vasoconstriction in the legs. The thermodilution blood flow method does not offer this time resolution, but the ultra-sound Doppler does. An alternative is to do as Secher et al. (27) have done. They did not measure blood flow but determined the size of the diameter of the peripheral arteries, which became reduced in the face of this type of challenge.
From our increasing knowledge of small muscle mass exercise, it is probably not its blood flow that is a limiting factor for muscle O2 uptake and peak power output. By enlarging the mass involved in the exercise, the convective delivery of O2 may now be a limitation. There is also evidence that muscle ˙VO2max may be limited by diffusional conductance of O2 from the blood to muscle(33,47) and/or at the mitochondrial level(39). Addressing the latter of these issues, subjects have been studied during knee-extensor exercise. Others found that the concentration of the citric acid cycle enzymes obtained by muscle biopsy was linearly related to the peak ˙VO2 (7). More interesting than these relationships was the fact that the estimated maximum flux rate for various citric acid cycles gave 2- to 20-fold higher rates than the independently measured muscle ˙VO2 calculated by the direct Fick method except for the oxogluterate dehydrogenase activity which in absolute numbers was in close agreement. This suggests that when a small muscle mass performs maximum exercise (muscle ˙VO2 of 2-400 mL·kg-1·min-1) this step in the citric acid cycle may be working at ˙Vmax and be a limitation. Again, these data relate to situations when a small muscle mass is involved in the exercise(with other possible limitations removed, such as a finite cardiac output) and only here may this ceiling be approached. In fact, based on previous findings in endurance trained subjects (19,35), assuming a value of 7.5% of the fiber volume and a myofibril volume of 80% in the quadriceps (11,12), and a muscle density of 1.06 g·cm-3, we can calculate a mitochondrial volume of 5.7 cm3·100 g-1 and a maximal mitochondrial ˙VO2 of 4.4 mL·O2·min-1·cm-3 for cycling and 10.5 mL·O2·min-1·cm-3 for one-legged knee-extensor exercise. The former being typical of that reported in other species (12) and the latter exceeding even the previous upper range of the hummingbird flight muscles which were calculated to have a mitochondrial rate of 7.1 mL O2·min-1·cm-3 (46). As the O2 uptake of muscle in ordinary bicycle or treadmill exercise is a half, a third, or even only a fourth of what has been measured with the knee-extensor model, it is unlikely that the mitochondrial respiration rate would be a limiting factor in whole body exercise.
We will conclude with a comparison between knee-extensor exercise and conventional cycle exercise (Tables 3a and b and 4). We have already indicated that there is a large difference in the amount of power output that can be performed per unit of muscle mass comparing knee-extensor and ordinary leg exercise. However, the rate of anaerobic energy liberation is similar. The accumulated peak muscle lactate (exhaustion in 4-6 min) increases to levels observed in ordinary bicycle or treadmill exercise. The net release of lactate during that knee-extensor exercise per unit muscle is, however, higher because of the elevated perfusion(5,16). This does result in a very high arterial blood lactate concentration as the total release is low because of the small muscle mass. Thus, there is a marked difference in systemic lactate concentration. With respect to the sympathetic drive, there is also a marked difference in spite of the fact that very intense exercise is performed in both instances. This is indicated by very low plasma levels for epinephrine and norepinephrine when exercising with a small muscle mass. Indeed, the very highest levels are observed in arm-leg exercise as in rowing(14). In short, the sympathetic system is not activated by high intensity dynamic muscular exercise unless the muscle mass involvement is large (32,43). If we consider the nucleotides, ammonia, and creatine phosphate, there are only very minor differences in their utilization or production comparing small and larger muscle mass exercise. In prolonged exercise glycogen utilization is more pronounced with knee-extensor exercise. Blood glucose levels are maintained at levels similar to those in cycle exercise although muscle glucose uptake is enhanced in knee-extensor exercise, but liver storage of glycogen is large enough to support this as the work is confined to a small muscle group(36). With a low catecholamine response and limited sympathetic activation, free fatty acids do not reach very high concentrations in plasma, but because of the high plasma flow they are used to the same extent as seen in conventional cycle exercise (17). Surprisingly enough, insulin falls in both models despite the difference in sympathetic drive (17). Overall, in terms of the commonly measured metabolic variables, knee-extensor exercise differes only in a few distinct aspects from conventional larger muscle mass exercise.
In summary, it is pertinent to highlight some of the advantages of using the one-legged knee-extensor model to study the control of skeletal muscle metabolism and perfusion. Foremost, only the knee-extensors are engaged in the exercise and the various portions of the muscle group are recruited to the same degree. The size of this muscle group is close to 10% of the total muscle mass, and the size is easily measured allowing the calculation of muscle mass specific values. This muscle group is supplied by one feed artery and drained by one main vein (with minimal contamination from other muscles and skin) which facilitates representative blood flow and arterial venous difference measurements. The fact that the muscle group itself is stationary during the exercise allows the study of muscle metabolism by biopsy or magnetic resonance spectroscopy (34). Although there are several useful differences between this small muscle mass model and whole body exercise, it is reassuring that there are also enough similarities to ensure that findings with the knee-extensor model can also be applied to more conventional exercise such as cycling. Of course, since our goal is to understand human physiology, a major advantage of the human knee-extensor model is that is requires little intervention and so offers direct insight into human muscle function studiedin vivo.
Dr. Richardson holds a Parker B. Francis Fellowship in Pulmonary Research and grant funding was provided by NIH 7731. The Copenhagen Muscle Research Center is funded by the Danish National Research Foundation.
The authors would like to offer their sincere thanks to Kuldeep Tagore who was instrumental in the production of this manuscript.
Address for correspondence: Russell S. Richardson, Ph.D., Department of Medicine 0623, 9500 Gilman Drive, University of California, La Jolla, CA 92093-0623. E-mail: firstname.lastname@example.org.
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PERFUSION; NITRIC OXIDE; OXYGEN UPTAKE; KNEE-EXTENSOR EXERCISE
©1998The American College of Sports Medicine
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