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Die Deutsche Zeitschrift für Sportmedizin behandelt die klinische Praxis und deren angrenzende Felder im Sinne translationaler Forschung, die den Einfluss von körperlicher Aktivität, Bewegung, Training und Sport sowie Bewegungsmangel von gesunden Personen und Patienten aller Altersgruppen erforscht. Dies umfasst die Auswirkungen von Prävention, Diagnose, Therapie, Rehabilitation und körperlichem Training sowie das gesamte Feld der Sportmedizin und sportwissenschaftliche, physiologische und biomechanische Forschung.

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REVIEW
LIMITING FACTORS OF EXERCISE PERFORMANCE

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 O2 transport from the air to the muscle mitochondria and at the same a high capacity to metabolize O2 for ATP generation. O2 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  O2 diffusion equilibration in the lungs and muscle); the blood (via the concentration of hemoglobin and also the shape and position of the O2 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  O2 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 O2 flow when its conductance is low but having little overall effect when high.  Finally,  how  maximal  mitochondrial  metabolic  capacity  to  use  O2 can  be considered together with maximal O2 transport to set the limits to maximal VO2 is shown. Experimental data are presented to confirm this integrated, conceptual approach.

Key words: exercise performance, O2-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  O2-Transportrate  zwischen  der  Atemluft  und  den Mitochondrien als auch eine hohe Kapazität des O2-Metabolismus für die ATPSynthese. Der O2-Transport stellt ein Weiterleitungssystem dar, das aus den Lungen (Ventilation  und  alveolar-kapillare  Diffusion),  dem  Herz-Kreislauf-System  (O2-Transport von den Lungen zum Muskel und dem O2-Diffusionsgleichgewicht in den Lungen und Muskel), dem Blut (Hämoglobin-Konzentration sowie Form und Position der O2-Dissoziationskurve) sowie den Muskeln selbst (O2-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  O2-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 O2 -Transport niedrig, so ist der Kontrolleinfluss auf  die  Gesamtsauerstoff-Flussrate  hoch;  bei  hohem  O2-Transport  hingegen  ist der  Einfluss  der  einzelnen  Prozesse  auf  die  Gesamtsauerstoff-Flussrate  niedrig. Die VO2max 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,  O2-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  (VO2max).  Endurance  exercise  performance depends on several factors in addition to VO2max 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 O2 transport  system  that  delivers  O2 from the air to the muscle mitochondria, and the cellular metabolic processing system that uses  the  O2 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  O2 transport  itself  depends  on  several tissues and organs in an integrated manner, and how O2 transport integrates with O2 metabolic utilization to set VO2max.
The purpose of this review is to explain how these systems in fact integrate and set VO2max under any set of circumstances.

O2 TRANSPORT

Transport of O2 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 O2 from the air to the alveoli. Diffusion then transports the O2 from alveolar gas across the alveolar-capillary membrane into the pulmonary capillary blood. The next step is perfusion–transport of the O2 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  O2 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 O2 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 O2 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 O2 transport pathway,  showing  blood  flow  bringing  O2 to  the  muscle  vascular bed (a convective process), and subsequently, diffusion allowing O2 to move from the red blood cells to the mitochondria, as shown in panel A. In panel B, the amount of O2 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 O2 lost from the blood per minute is the product of muscle blood flow rate (Q.) and the O2 concentration difference between arterial and muscle venous blood. Arterial O2 concentration is denoted CaO2; that for venous blood CvO2: Note that CaO2 (arterial O2 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 O2 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 O2 transferred by diffusion per minute is the product of the diffusing capacity of the muscle for O2 (D in Figure 1) and the difference between the red cell PO2 (PcapO2) and the mitochondrial PO2 (PmitoO2). Here PCAPO2 is the mean capillary PO2, averaged along the capillary length.
To simplify the concepts, we will assume that mitochondrial PO2 during maximal exercise is so low it can be ignored compared to PcapO2. 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 PO2 is proportional to PO2 in the muscle venous blood. That is, as muscle venous PO2 (PvO2) rises or falls, so too does mean capillary PO2.
This assumption allows us to replace PcapO2 in panel C of Figure 1 by k x PVO2 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: VO2=Q x [CaO2–CvO2] (1)

Panel C: VO2= D x [PcapO2– PmitoO2] = D x k x PvO2 (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 O2. Thus, VO2 in both equations must be the same. What is more, both equations contain PvO2 (or its equivalent, CvO2, which is defined by PVO2 and the Hb dissociation curve) and PvO2 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 VO2 is plotted against PvO2. The curved line of negative slope traces equation 1. The open square represents the amount of O2 delivered to the muscle (product of blood flow and arterial O2 concentration) and would be the VO2 if all O2 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 VO2 and muscle venous PO2 if no O2 at all was taken out of the muscle blood flow: zero VO2 and a venous PO2 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 VO2 and PvO2 that satisfy mass conservation (equation 1).

The straight line of positive slope traces equation 2, and shows the only combinations of VO2 and PvO2 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 VO2 and PvO2 that must be present.
It  should  be  evident  that  as  the  slope  of  the  line  for  equation 2 (i.e., the muscle O2 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  PO2 (and  concentration,  which  reflects  mostly arterial PO2 and [Hb]) and muscle blood flow, as equation 1 shows. In turn, arterial PO2 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 PO2 and muscle diffusing capacity are those at maximal exercise, the VO2 defined by the intersection of equations 1 and 2 must be VO2max.

How changes in the key determining variables – arterial PO2 (and  O2 concentration),  muscle  diffusing  capacity,  and  muscle blood  flow  –  individually  affect  VO2max is  shown  in  Figure  2,  panels B, C and D respectively. In panel B, progressive hypoxia reduces arterial PO2 (closed squares) from normal (~95 mm Hg) to (in these particular examples) 40 and then 30 mm Hg, simultaneously decreasing arterial O2 saturation and thus [O2] as indicated by the open squares. Maximal VO2 must fall linearly with PvO2 as arterial PO2 is reduced. In panel C, reduction in diffusing capacity means a decrease in the slope of the diffusing capacity line as shown. V O2 max must  fall,  while  PvO2 must  rise.  In  contrast,  when  muscle blood flow is reduced, VO2max again falls, but so too does PvO2, 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 O2 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 O2 transport system can deliver more O2 to the mitochondria than they can use. This potential metabolic limitation on VO2 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 VO2 of a mitochondrial suspension to PO2 in the medium. At PO2 values below about 2 mm Hg, there is an essentially proportional relationship where VO2 depends on PO2, but at higher PO2 values, VO2 plateaus at a maximal value that cannot be increased by further raising PO2. This behavior is predictable, based on the equation for oxidative phosphorylation:

0.5O2 +  3ADP  +  3Pi  +  NADH  +  H+ → 3ATP  + NAD+ + H2O

Because O2 is a reactant on the left side of the equation, the velocity of the forward reaction will be particularly affected by [O2] when [O2] is low, but essentially not at all when [O2] is high, and the other reactants now become limiting.
The maximal value of metabolic capacity to use O2 is shown in Figure 3 as a horizontal line depicting that maximal possible VO2 for two hypothetical scenarios (panel B, where maximal metabolic capacity exceeds maximal O2transport capacity at all three arterial PO2 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 O2 transport capacity at the two higher arterial PO2 values.
In both panels, actual VO2max must be the lesser of maximal O2 transport  capacity  and  maximal  metabolic  capacity.  Thus,  in panel B, where transport < metabolic capacity, the VO2max/PvO2 relationship follows the linear, proportional line of Figure 2; in panel C, the relationship remains proportional to PvO2 below maximal metabolic capacity (i.e., in hypoxia) but, as hyperoxia is imposed, becomes completely independent of PvO2 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 O2 transport capacity.

In summary, maximal VO2 is one (but not the only) importantdeterminant of maximal endurance exercise capacity. Maximal VO2 is set by the interplay between two systems: 1) that for O2 transport from the air to the mitochondria, involving the lungs, heart, blood and muscle, and 2) that for mitochondrial metabolic use of delivered O2. The way in which all of these factors come together to determine VO2max is conveniently understood from a diagram that combines the mass conservation principles of both convection and diffusion of O2 with that of oxidative phosphorylation. This analysis shows that there is no single determinant of VO2max – it depends on conditions and the values of the above variables. In particular, all involved variables contribute to setting VO2max through their interactions as a system.

Competing interests: None.

REFERENCES

  1. Cardus J, Marrades Rm, Roca J, Barberá Ja, Diaz O, Masclans Jr, Rodriguez-Roisin R, Wagner Pd: Effects of FIO2 on leg VO2 during cycle ergometry in sedentary subjects. Med Sci Sports Exerc 30 (1998) 697 - 703.
  2. Richardson Rs, Noyszewski Ea, Kendrick Kf, Leigh Js, Wagner Pd: Myoglobin O2 desaturation during exercise: evidence of limited O2 transport. J Clin Invest 96 (1995) 1916 - 1926.
  3. Richardson Rs, Grassi B, Gavin Tp, Haseler Lj, Tagore K, Roca J, Wagner Pd: Evidence of O2 supply-dependent VO2max in the exercise-trained human quadriceps. J Appl Physiol 86 (1999) 1048 - 1053.
  4. Roca J, Gavin T, Jordan M, Siafakas N, Wagner H, Benoit H, Breen E, Wagner PD: Angiogenic growth factor mRNA responses to passive and contraction-induced hyperperfusion in skeletal muscle. J Appl Physiol 85 (1998) 1142 - 1149.
  5. Wagner Pd: Algebraic analysis of the determinants of VO2max. Respir Physiol 93 (1993) 221 - 237.
  6. Wagner Pd, Hoppeler H, Saltin B: Determinants of maximal oxygen uptake. In: THE LUNG: Scientific Foundations, chapt. 5.6.3, ed. RG Crystal and JB West et al. Raven Press Ltd., New York, pp. 1585-1593 (1994).
  7. Wagner Pd: Determinants of maximal oxygen transport and utilization. Annu Rev Physiol 58 (1996) 21 - 50.
  8. Wagner Pd: A theoretical analysis of factors determining VO2max at sea level and altitude. Resp Physiol 106 (1996) 329 - 343.
  9. Weibel Er: The Pathway for Oxygen. Structure and Function in the Mammalian Respiratory System. Cambridge, MA: Harvard University Press, 1984.
  10. Wilson Df, Erecinska M, Drown C, Silver Ia: Effect of oxygen tension on cellular energetics. Am J Physiol 2 (1977) 135 - 140.
Corresponding Address:
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
 
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