# Limiting Factors of Exercise Performance

## Limitierende Faktoren der körperlichen Leistungsfähigkeit

## SUMMARY

Endurance exercise performance depends on several interacting factors, some physiological and some psychological. Important among these is achieving a high rate of O_{2} transport from the air to the muscle mitochondria and at the same a high capacity to metabolize O_{2} for ATP generation. O_{2} transport occurs via an integrated, in series, system of conductances reflecting the lungs (involving ventilation and alveolar-capillary diffusion); the heart and cardiovascular system (involving circulatory transport from lungs to muscle and also affecting O_{2} diffusion equilibration in the lungs and muscle); the blood (via the concentration of hemoglobin and also the shape and position of the O_{2} dissociation curve); and the muscles themselves (involving diffusive O2transport from the microcirculation to the mitochondria). The present analysis combines all of these steps and processes into a single, integrated system to explain how maximal O_{2} transport depends on each and every step of the transport pathway. It further shows how each step individually affects maximal transport similarly in a non-linear fashion - controlling overall O_{2} flow when its conductance is low but having little overall effect when high. Finally, how maximal mitochondrial metabolic capacity to use O_{2} can be considered together with maximal O_{2} transport to set the limits to maximal VO_{2} is shown. Experimental data are presented to confirm this integrated, conceptual approach.

Key words: exercise performance, O_{2}-transport, endurance, cellular metabolic capacity

## ZUSAMMENFASSUNG

Die Ausdauerleistungsfähigkeit wird von diversen miteinander in Wechselwirkung stehenden physiologischen und psychologischen Faktoren beeinflusst. Diese sind sowohl eine hohe O_{2}-Transportrate zwischen der Atemluft und den Mitochondrien als auch eine hohe Kapazität des O_{2}-Metabolismus für die ATPSynthese. Der O_{2}-Transport stellt ein Weiterleitungssystem dar, das aus den Lungen (Ventilation und alveolar-kapillare Diffusion), dem Herz-Kreislauf-System (O_{2}-Transport von den Lungen zum Muskel und dem O_{2}-Diffusionsgleichgewicht in den Lungen und Muskel), dem Blut (Hämoglobin-Konzentration sowie Form und Position der O_{2}-Dissoziationskurve) sowie den Muskeln selbst (O_{2}-Transport aus der Mikrozirkulation in die Mitochondrien) besteht. Die vorliegende Arbeit fasst diese einzelnen Prozesse in einem Modell- System zusammen, anhand dessen die Abhängigkeit der maximalen O_{2}-Transportrate von jedem systemimmanentem Prozess auf dem Transportweg gezeigt werden kann. Weiter zeigt dieses Modell, dass jeder Schritt im System die maximale Transportkapazität auf ähnlich nichtlineare Weise beeinflusst. Ist der O_{2} -Transport niedrig, so ist der Kontrolleinfluss auf die Gesamtsauerstoff-Flussrate hoch; bei hohem O_{2}-Transport hingegen ist der Einfluss der einzelnen Prozesse auf die Gesamtsauerstoff-Flussrate niedrig. Die VO_{2max} wird somit über die maximale mitochondriale metabolische Kapazität und damit über die Sauerstoffnutzung und über die maximale Sauerstofftransport limitiert. Die integrierte konzeptionelle Herangehensweise des vorgestellten Modell-Systems kann mit experimentell ermittelten Daten bestätigt werden.

Schlüsselwörter: Leistungsfähigkeit, O_{2}-Transport, Ausdauer, zelluläre Stoffwechselkapazität

## INTRODUCTION

While the assigned title refers to exercise performance, this brief review focuses on one aspect of performance: attainment of maximal oxygen consumption (VO_{2max}). Endurance exercise performance depends on several factors in addition to VO_{2max} itself, such as motivation, tolerance for pain and dyspnea, development of neuromuscular fatigue, and the intensity of exercise that can be attained before lactate levels rise significantly. It would be beyond the scope of this review to attempt discussing and integrating all of these factors.

Oxygen consumption requires two interacting systems: the O_{2} transport system that delivers O_{2} from the air to the muscle mitochondria, and the cellular metabolic processing system that uses the O_{2} to generate energy in the form of ATP through the mitochondrial respiratory chain. Individual components of both systems are very well known. What remains incompletely understood is how maximal O_{2} transport itself depends on several tissues and organs in an integrated manner, and how O_{2} transport integrates with O_{2} metabolic utilization to set VO_{2max}.

The purpose of this review is to explain how these systems in fact integrate and set VO_{2max} under any set of circumstances.

## O2 TRANSPORT

Transport of O_{2} from the air to the muscle mitochondria involves the lungs and chest wall, the heart and cardiovascular system, the blood, and the muscle itself (9). In the lungs, ventilation first brings fresh O^{2} from the air to the alveoli. Diffusion then transports the O_{2} from alveolar gas across the alveolar-capillary membrane into the pulmonary capillary blood. The next step is perfusion–transport of the O_{2} in the blood through the pulmonary capillaries, back to the left heart and then to the muscles via the systemic arterial tree.

The final step is the unloading of O_{2} from Hb within the muscle microvascular red cells, and diffusion from there out of the microvessels, into the myocytes, and to the mitochondria. It is critical to appreciate that this system is an in series, or “bucket brigade” system:

A given O_{2} molecule must pass through each of the above steps in sequence. An important property of such an in series system is that every step affects maximal throughput (5, 8). A second important property of such an in series system is that each step can affect the performance of all other steps. One clear example is that when blood flow is increased, it may inherently limit O_{2} transfer at the diffusion-based steps in the lungs and muscle. This risk occurs simply because high blood flow may reduce gas exchange transit time.

Figure 1 brings together the several steps in the O_{2} transport pathway, showing blood flow bringing O_{2} to the muscle vascular bed (a convective process), and subsequently, diffusion allowing O_{2} to move from the red blood cells to the mitochondria, as shown in panel A. In panel B, the amount of O_{2} given up by the blood per unit time as it flows through the muscle bed is formulated according to the well known Fick principle of mass conservation: The amount of O_{2} lost from the blood per minute is the product of muscle blood flow rate (Q.) and the O_{2} concentration difference between arterial and muscle venous blood. Arterial O_{2} concentration is denoted CaO_{2}; that for venous blood CvO_{2}: Note that CaO_{2} (arterial O_{2} concentration), already reflects the influence of ventilation, alveolar-capillary diffusion in the lungs and blood flow through the pulmonary vascular bed. In panel C, the diffusive process for O_{2} moving from the muscle microvascular red cells to the mitochondria is defined by the laws of diffusion, also an expression of mass conservation: The amount of O_{2} transferred by diffusion per minute is the product of the diffusing capacity of the muscle for O_{2} (D in Figure 1) and the difference between the red cell PO_{2} (PcapO_{2}) and the mitochondrial PO_{2} (PmitoO_{2}). Here P_{CAP}O_{2} is the mean capillary PO_{2}, averaged along the capillary length.

To simplify the concepts, we will assume that mitochondrial PO_{2} during maximal exercise is so low it can be ignored compared to PcapO_{2}. This is reasonable as the former is no greater than 3-4 mm Hg (2) while the latter is 40-50 mm Hg (4). For purposes of presentation, we will also assume that mean capillary PO_{2} is proportional to PO_{2} in the muscle venous blood. That is, as muscle venous PO_{2} (PvO_{2}) rises or falls, so too does mean capillary PO_{2}.

This assumption allows us to replace PcapO_{2} in panel C of Figure 1 by k x PVO_{2} where k is a constant (that happens to be about 2.0). The reason we make this reasonable (4) assumption becomes clear if we compare the equation in Figure 1 panel B with that in Figure 1 panel C:

Panel B: VO_{2}=Q x [CaO_{2}–CvO_{2}] (1)

Panel C: VO_{2}= D x [PcapO_{2}– PmitoO_{2}] = D x k x PvO_{2} (2)

The key concept is that while equation 1 reflects the convective transport process based on blood flow and while equation 2 reflects the diffusive transport process, both equations must describe the same quantitative flow rate of O_{2}. Thus, VO_{2} in both equations must be the same. What is more, both equations contain PvO_{2} (or its equivalent, CvO_{2}, which is defined by PVO_{2} and the Hb dissociation curve) and PvO_{2} must also be the same in both equations.

This is better discussed in the framework of a figure that shows both equations (7). This is done in Figure 2, Panel A where VO_{2} is plotted against PvO_{2}. The curved line of negative slope traces equation 1. The open square represents the amount of O_{2} delivered to the muscle (product of blood flow and arterial O_{2} concentration) and would be the VO_{2} if all O_{2} delivered to the muscle vasculature could be made available by diffusion to the mitochondria, such that none was left in the venous blood. The closed square represents both VO_{2} and muscle venous PO_{2} if no O_{2} at all was taken out of the muscle blood flow: zero VO_{2} and a venous PO_{2} equal to that in the inflowing arterial blood. Neither of these extremes occurs in live muscle, but the curved line between them shows the only combinations of VO_{2} and PvO_{2} that satisfy mass conservation (equation 1).

The straight line of positive slope traces equation 2, and shows the only combinations of VO_{2} and PvO_{2} that satisfy equation 2. The critical concept is that the point of intersection of the two lines, marked by the closed circle, is the only point on the entire figure where both equations are simultaneously satisfied, and thus marks the actual VO_{2} and PvO_{2} that must be present.

It should be evident that as the slope of the line for equation 2 (i.e., the muscle O_{2} diffusing capacity) changes, so too will the point of intersection of the two lines even if the other line remains unchanged. Symmetrically, as the determinants of the curved line for equation 1 change, this line (and thus point of intersection of the two lines) will also shift. The determinants of the line for equation 1 are arterial PO_{2} (and concentration, which reflects mostly arterial PO_{2} and [Hb]) and muscle blood flow, as equation 1 shows. In turn, arterial PO_{2} depends on ventilation, and alveolar-capillary diffusion. Taken together, it should now be clear that the point of intersection depends on lung, cardiovascular, blood, and muscle function. If the values for blood flow, [Hb], arterial PO_{2} and muscle diffusing capacity are those at maximal exercise, the VO_{2} defined by the intersection of equations 1 and 2 must be VO_{2max}.

How changes in the key determining variables – arterial PO_{2} (and O_{2} concentration), muscle diffusing capacity, and muscle blood flow – individually affect VO_{2max} is shown in Figure 2, panels B, C and D respectively. In panel B, progressive hypoxia reduces arterial PO_{2} (closed squares) from normal (~95 mm Hg) to (in these particular examples) 40 and then 30 mm Hg, simultaneously decreasing arterial O_{2} saturation and thus [O_{2}] as indicated by the open squares. Maximal VO_{2} must fall linearly with PvO_{2} as arterial PO_{2} is reduced. In panel C, reduction in diffusing capacity means a decrease in the slope of the diffusing capacity line as shown. V O_{2} max must fall, while PvO_{2} must rise. In contrast, when muscle blood flow is reduced, VO_{2max} again falls, but so too does PvO_{2}, and along the same line as in panel B. These predictions are borne out by many different studies, reviewed in (6).

## CELLULAR METABOLIC CAPACITY

The preceding discussion has made another important assumption: That the mitochondria have the capacity to use all of the O_{2} that can be transported according to Figure 2. However, it can be imagined that oxidative enzyme levels in, for example, very inactive subjects, may be low enough that the O_{2} transport system can deliver more O_{2} to the mitochondria than they can use. This potential metabolic limitation on VO_{2} maxcan be incorporated into the scheme of Figure 2, and this is done in Figure 3. In Panel A, the concept of maximal mitochondrial oxidative capacity is shown on a plot of Wilson et al’s data (10) relating VO_{2} of a mitochondrial suspension to PO_{2} in the medium. At PO_{2} values below about 2 mm Hg, there is an essentially proportional relationship where VO_{2} depends on PO_{2}, but at higher PO_{2} values, VO_{2} plateaus at a maximal value that cannot be increased by further raising PO_{2}. This behavior is predictable, based on the equation for oxidative phosphorylation:

0.5O_{2} + 3ADP + 3Pi + NADH + H^{+} → 3ATP + NAD^{+} + H_{2}O

Because O_{2} is a reactant on the left side of the equation, the velocity of the forward reaction will be particularly affected by [O_{2}] when [O_{2}] is low, but essentially not at all when [O_{2}] is high, and the other reactants now become limiting.

The maximal value of metabolic capacity to use O_{2} is shown in Figure 3 as a horizontal line depicting that maximal possible VO_{2} for two hypothetical scenarios (panel B, where maximal metabolic capacity exceeds maximal O2transport capacity at all three arterial PO_{2} values shown by the three negatively sloped lines taken from Figure 2, panel B), and panel C, where maximal metabolic capacity is much lower and is less than maximal O_{2} transport capacity at the two higher arterial PO_{2} values.

In both panels, actual VO_{2max} must be the lesser of maximal O_{2} transport capacity and maximal metabolic capacity. Thus, in panel B, where transport < metabolic capacity, the VO_{2max}/PvO_{2} relationship follows the linear, proportional line of Figure 2; in panel C, the relationship remains proportional to PvO_{2} below maximal metabolic capacity (i.e., in hypoxia) but, as hyperoxia is imposed, becomes completely independent of PvO_{2} at the VO2equal to metabolic capacity. Panel D shows, with data from trained normal subjects (3) and untrained, sedentary subjects (1), that training appears to change the relationship from one limited mostly by metabolic capacity to one limited entirely by O_{2} transport capacity.

In summary, maximal VO_{2} is one (but not the only) importantdeterminant of maximal endurance exercise capacity. Maximal VO_{2} is set by the interplay between two systems: 1) that for O_{2} transport from the air to the mitochondria, involving the lungs, heart, blood and muscle, and 2) that for mitochondrial metabolic use of delivered O_{2}. The way in which all of these factors come together to determine VO_{2max }is conveniently understood from a diagram that combines the mass conservation principles of both convection and diffusion of O_{2} with that of oxidative phosphorylation. This analysis shows that there is no single determinant of VO_{2max} – it depends on conditions and the values of the above variables. In particular, all involved variables contribute to setting VO_{2max} through their interactions as a system.

Competing interests: None.

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Dr. Peter D. Wagner

Division of Physiology, Department of Medicine

University of California, San Diego

9500 Gilman Drive, DEPT 0623A

La Jolla, CA, 92093-0623A USA

E-Mail: pdwagner@ucsd.edu