Respiration Physiology, 811(1990) 113-128
113
Elsevier RESP 01657
Factors limiting maximal oxygen consumption in humans*,** Pietro Enrico di Prampero 1 and Guido Ferretti 2 l lstituto di Biologia, Facolt~t di Medicina, Universit,~ di Udine, Udine, Italy and 2D~partement de Physiologie, Centre M~dical Universitaire, Geneva, Switzerland
(Accepted 22 March 1990) Abstract. The factors limiting~'o2maxin humans are analyzed according to a multifactorial model derived from the 02 conductance equation. In this context, alveolar ventilation (~rA)and lung 02 transfer (GL) are not considered to be limiting,at least at sea level, because changes in VA and/or in GL are not accompanied by changes in Vo2maxdue to the shape of the 02 dissociation curve. Thus, the limits to Vo2max are shared between blood 02 transport (FQ') and a peripheral factor. This last includes tissue 02 transfer (Ft') and mitochondrial 02 utilization (Fm'). In untrained subjects at sea level, blood 02 transport is found to be responsible for ~ 70~o of the overall limits to ~'o2max (FQ' = 0.7), the rest depending on the peripheral factors. FQ', as well as the sum of Ft' and Fm', are unchanged after training or upon return to sea level followingexposure to chronic hypoxia (altitude higher than 5000 m). In the latter condition, however, since tissue 02 transfer, which sets Ft', is facilitated, and mitochondrial 02 utilization, which sets Fm', is impaired, Ft' is reduced and Fm' increased as compared to control condition and/or after training.
Alveolar ventilation; Animal, man; Diffusing capacity, pulmonary; Gas exchange; Hemoglobin; Cardiac output, maximal; 02 consumption, maximal; Muscle morphometry; Blood, 02 dissociation curve
Several physiological variables have been called u p o n as possible determinants of the maximal 0 2 c o n s u m p t i o n ('V'o2max). A m o n g others, ventilation, 0 2 diffusion at the lung level, 0 2 transport by the circulation, peripheral perfusion a n d diffusion, a n d mitochondrial function have been considered. The role played by the above factors in limiting Vo2max has long since been debated. At least for non-athletic subjects at sea level, Vo2max is generally believed to be limited by 0 2 transport by the circulation. However, the mitochondrial function, as well as the 0 2 diffusion at the lung or tissue level, the latter particularly at extreme altitude a n d / o r in athletes, have also been considered as major limiting factors (Dempsey et al., 1984; Kaijser, 1970; West, 1983). Correspondence to: P.E. di Prampero, Istituto di Biologia, Facolt~tdi Medicina, Universitgtdi Udine, Via Gervasutta 48, 33100 Udine, Italy. * Dedicated to Dr. Johannes Piiper on the occasion of his 65th birthday anniversary. ** Presented at the symposium "Factors determining ~'o2maxin Humans", 73rd Annual Meeting of the Federation of American Societies for Experimental Biology,New Orleans LA, March 19-23, 1989.
0034-5687/90/$03.50 © 1990 Elsevier Science Publishers B.V. (Biomedical Division)
114
P.E. DI PRAMPERO AND G. FERRETTI
The present article is devoted to a discussion of the factors limiting 'V'o~max in man during exercise involving large muscle groups. It is divided into two sections. In the first one a general model, allowing a quantitative analysis of the relative weight of (some of) the above factors, will be proposed and discussed. In the second section, the model will be applied to calculate the role played by: (i) the 02 transport by the circulation, (ii) the 02 perfusion and diffusion at the muscle level and (iii)the mitochondrial function in limiting Vo:max after long term endurance training and upon return to sea level after high altitude acclimatization (acute normoxia). The p a t h w a y for o x y g e n
The 02 path from the environment to the mitochondria can be considered equivalent to a cascade of resistances in series, each resistance being overcome by a specific pressure gradient. If this is so, the overall resistance to 02 flow, RT, is the sum of the specific resistances R i, and the maximal 02 flow through the system is set by: ,~o~max = -APT -, RT
(1)
where APT is the overall pressure gradient. Since at steady state the flow through each R i is the same, then: APT RT
AP i
Ri
(2)
where APi is the pressure gradient across the ith resistance R i. This means that the following equalities must also apply at Vo~max: "V'o:max = (PI - PA)/Rv = (PA - Pa)/RL = (Pa - PV)/RQ = (pro _ Pt)/Rt = (Pt - Pm)/Rm = (PI - Pm)/RT,
(3)
where PI, PA, Pa, PV, Pt and Pm indicate the average partial pressures o f O 2 in inspired and alveolar air, arterial and mixed venous blood, the muscle tissue and the mitochondria, respectively. Correspondingly, the overall resistance to 02 flow from environment to mitochondria (RT) has been partitioned in the following five major steps depending on: (i) alveolar ventilation (Rv), (ii)lung perfusion and diffusion (RL), (iii)blood 02 transport (RQ), (iv) peripheral perfusion and diffusion (Rt), and (v) mitochondrial 02 utilization (Rm). Equation (3) can also be written in the equivalent form of the so-called 02 conductance equation (Shephard, 1969): Vo~max = (PI - PA) X G v = (PA - Pa) x GL = ( P a - PV) x GQ = ( P V - Pt) x Gt = ( P t - Pm) x Gm = (P! - Pm) × GT,
(4)
LIMITS OF MAXIMAL 02 CONSUMPTION
115
whereby the following applies: R = 1/G. In all cases G has the dimensions of amount of 02 per unit of time and unit of O z partial pressure, measurable in ml 02 • min - 1. T o r r - 1. Equations (3) and (4) allow to identify the physiological variables that constitute some of the above conductances or resistances: G v = 1/Rv = ~'A" fig GQ = 1/RQ = (~-/~o,
(5a) (5b)
where ~/Ais the alveolar ventilation, fig the transport coefficient in the gas phase at 37 ° C (1.16 ml 02" L - 1 . T o r r - 1 ) , 0 the cardiac output,/To the transport coefficient in the blood, equal to the average slope of the blood 02 dissociation curve. Whereas the conductance terms of eqs. 5a and b are appropriate physiological variables that can actually be measured, GL, G t and G m are not. Indeed, they depend in a complex way on diffusion and perfusion at the lung (GL) and muscle tissue (Gt) level, and on the overall capacity of the mitochondria to utilize 02 (Gin). Equations (3) and (4) show that the fraction of the overall resistance due to any given physiological step (defined as F with the appropriate suffix) is equal to the ratio of the corresponding pressure drop divided by the overall pressure gradient: (PI (PA (Pa (P~ (Pt -
PA)/(PI Pa)/(PI PV)/(PI Pt)/(PI Pm)/(PI -
Pm) = G T / G v = R v / R T = F v Pm) = GT/GL = RL/RT = FL Pm) = GT/GQ = RQ/RT = FQ Pm) = G T / G t = Rt/RT = Ft Pm) = G T / G m = R m / R T - F m
(6a) (6b) (6c) (6d) (6e)
A direct consequence of eq. (6) is that, if the system behaves linearly, the fractions of the total resistance due to the above identified factors can be calculated on the basis of the 02 partial pressures assumed to hold at the different levels of the 02 cascade. These, together with the corresponding F's, are reported in table 1 for maximal aerobic exercise at sea level and at extreme altitude on the top of Mount Everest (8848 m). In table 1, due to the difficulty of establishing reasonable Pt values, Rt and Rm have been considered as a single peripheral resistance (Rp--- Rt + Rm), so that Fp = Ft + F m = (PV - Pm)/(PI - Pm). Table 1 shows that, at sea level ~40~o of RT is located at the lungs, ~ , 4 5 - 5 0 ~ is due to the 02 transport by the circulation, and the remaining fraction represents the sum of peripheral perfusion and diffusion and mitochondrial capacity. The resistance at the lung level is about equally partitioned between ventilatory conductance and 02 transfer from alveoli to capillaries. The ventilatory factor, can be subdivided further into an external ventilation plus a dead space component. This last is equal to the ratio (PE - PA)/(PI - PA), where PE is the 02 partial pressure in mixed expired air. At maximal exercise, it corresponds to ,~ 5 ~ of Rv. The resistance to 02 transfer from alveoli to capillaries plays a progressively greater role at higher work
116
P.E. DI PRAMPERO AND G. FERRETTI TABLE 1
Factors limiting "¢o2maxon the assumption that the 0 2 conductance equation has a linear solution Sea levela
Vo2max L/min PI Torr PA Torr Pa Torr PV Torr Pm Torr Fv=(PI-PA)/(PI-Pm) FL = (PA-Pa)/(PI-Pm) FQ (Pa-Prc)/PI-Pm) FP = (P~-Pm)/(PI-Pm) =
Everest (8848 m)b
Sedentary
Athlete
3.60 150 120 95 20 0 0.20 } 0.17 0.37 0.50 0.13
4.90 150 116 83 18 0 0.23 } 0.22 0.45 0.43 0.12
1.05 43 36 28 15 0 0.16 } 0.19 0.35 0.30 0.35
a From Cerretelli and di Prampero (1987). b From West (1983). intensities, as shown by the widening of the (PA - Pa) pressure gradient. As a consequence, RE turns out greater in athletes than in sedentary subjects (table 1). At extreme altitude the total resistance to 02 transport is about equally partitioned among pulmonary factors, circulatory O z transport, and peripheral 0 2 transfer and utilization (see table 1). This is the result of the fact that at high altitude: (i) An extreme increase in alveolar ventilation leads to a reduction in Rv; (ii)The arterial 0 2 partial pressure is on the steep part of the 0 2 dissociation curve, of which the average slope (fib) is therefore increased, thus leading to a smaller RQ; This is necessarily followed by (iii) a correspondingly larger fraction of the resistance due to the peripheral factors (see table 1). Because of the further drop of the Oz partial pressure in arterial blood upon work onset, during maximal exercise in chronic hypoxia RE plays an even larger role. The advantage of the above described model of the pathway for O2 is its simplicity which somewhat restricts its applicability. Indeed, not all the described resistances to 02 flow correspond to well defined physiological processes. This is particularly evident at the lung level, where the resistance RE takes into account the complex interactions between diffusive and perfusive factors (Piiper and Scheid, 1981), the effects of "~'A/0 inhomogeneities, and the role played by functional and structural shunts in pulmonary circulation. The same applies to the term Rt, which takes into account the passive and facilitated (by myoglobin) diffusion of 02, and muscle perfusion, which is known to be inhomogeneously distributed (Piiper, 1990). In addition, during maximal exercise, not only the muscles, but also other tissues and organs are active, a fact not considered by the simple resistive model described above. Finally, it should be noted that GL and Gt and the corresponding resistances are obtained from alveolar to arterial and from mixed venous to tissue 02 partial pressure differences, respectively. As such, they are larger than the lung and tissue 02 diffusing
LIMITS OF MAXIMAL02 CONSUMPTION
117
capacities which should be obtained on the basis of the average partial pressures of O z in the lung (PEL) and systemic (PEs) capillaries. Indeed, the present analysis is based on the assumption that the O a flow through each resistance in series is the same. Thus, the Oa flow through the circulation ((~/319. (Pa - P~)) must be equal to the immediately upstream (GL. (PA - Pa)) and downstream (Gt- (P~ - Pt)) ones (see eq. 4). If the O 2 pressure differences at the lung and tissue levels in eq. (4) were replaced by PA - PcL and PEs - Pt, respectively, and GL and Gt by the corresponding 02 diffusing capacities, the circulatory conductance (Qflb) would tend to infinity since the corresponding pressure difference (PEL - P~s) would become vanishingly small, an obviously nonsensical conclusion. On Rv and RL as limiting steps Apart from the above limitations, the model shows that Vo2max is not limited by a single factor, but by a series of physiological variables whose limiting role can be quantitatively assessed on the basis of the model itself. In addition, if the system behaves linearly, and if the overall pressure gradient from environment to mitochondria is constant, any given change of the ith resistance will lead to a change in Vo2max proportional to the relative magnitude of the resistance in question (Fi in eq. 6). However, an increase in alveolar ventilation brings about an increase in PA and Pa without sizeables changes in '~/o2max. In fact, the reduction in Rv ensuing from the higher VA is offset by an approximately equal increase in RQ. This is brought about by a concomitant decrease in/5"0, for the increase in Pao2 occurs on the fiat part of the O z dissociation curve and is not associated with sizeable changes in Pvo~. On the contrary, when Pao2 is situated on the steep part of the Oz dissociation curve, as is the case in deep hypoxia, an increase in VA is more effective in increasing Vo:max. Thus, because of the shape of the 0 2 dissociation curve of blood, at the level of the alveolar arterial step, the system is markedly non-linear. Therefore, even if pulmonary ventilation and diffusion are responsible for a large fraction of the overall 0 z pressure gradient, their role as "limiting factors" is very minor indeed: changing their values leads to negligible modifications of the overall 0 2 flow, at least in healthy non athletic subjects at sea level. Sharing the limits to ~/o2max between circulation and muscles Neglecting, therefore, pulmonary ventilation and alveolar-arterial 02 transfer, in the section that follows we will attempt a partition of the resistance to 02 transport downstream from the lung into two fractions: (i) FQ', due to 02 transport and (ii) Fp' due to both capillary 02 diffusion and mitochondria102 utilisation (Fp' = Ft' + Fm'). (Note again that, whereas FQ and Fp refer to the overall 02 cascade, FQ' and Fp' refer to the portion of the cascade downstream from the lung only). FQ' and Fp' will be estimated from data of changes in "qo2max due to measured changes in blood 02 carrying capacity, obtained by acute alteration of either Hb
Blood withdrawal
Ekblom et aL (1972)
Subsequent withdrawals at 2 days intervals of 1 unit of blood Blood withdrawal Blood infusion Induced hypervolemia Cold Heat Induced anemia 3.48 3.80 3.01
5.33 4.85 4.57 4.57 4.40 4.40 4.49 4.49 4.49 4.27 4.27 4.22 3.34 3.70 2.53
5.58 5.11 4.09 4.40 4.79 4.63 4.21 4.03 3.78 4.03 4.61 4.18 1.042 1.027 1.190
0.955 0.949 1.117 1.039 0.919 0.950 1.067 1.114 1.188 1.060 0.926 1.010 20.0 19.8
28.7 28.7 27.4
B
B/A
B
A
I~max (L/min)
X)o2max (L/min)
19.0 18.6
29.5 28.3 29.5
A
151 158 146 146 132 132 149 149 149 154 147
B
Hb (g/L)
163 167 127 132 149 150 133 126 122 138 161
A
4.08
5.92 5.65 5.37
B
t)o 2 (L/min)
3.01
5.46 6.11 5.31
A
0.050 0.061 0.262
- 0.080 - 0.057 0.130 0.096 - 0.129 - 0.136 0.107 0.154 0.221 0.078 - 0.081 -0.011
ARQ'/RQ'
Vo2max, maximal 0 2 consumption; 0 m a x , maximal cardiac output; Hb, blood hemoglobin; I)o2, convective 0 2 flow in arterial blood. For ARQ'/RQ', see the text for details. (B = before; A = after).
Mc Ardle et al. (1976) Rowell et al. (1966) Woodson et al. (1978)
Kanstrup and Ekblom (1982)
Ekblom et al. (1976)
Blood infusion
Buick et al. (1980)
Blood infusion
Conditions
Authors
Average effects on "~o2max and on the blood 0 2 transport system of manipulations that do not alter Rt and Rm, as from the quoted references.
TABLE 2
"t
rn
Z t7
©
'~
.m
oo
LIMITS OF MAXIMAL 0 2 CONSUMPTION
119
concentration (withdrawal or reinfusion of red blood cells or of blood) or 0 m a x (heat or cold exposure). These data are summarized in table 2. Under these conditions, the overall pressure gradient from arterial blood to mitochondria cannot be expected to change (APT = constant). Hence, assuming that the reduced system behaves linearly, the changes in V o m a x must be due to an equal (and opposite) change of the total resistance to O2 flow (RT'; di Prampero, 1985): 9o~max + A~'o~max = APo~/(RT + ART).
(7)
Dividing eq. (7) by eq. (1): 9o2max/(Vo~max + AVo max ) = (RT' + A R T ' ) / R T ' .
(8)
Since, under these conditions, ART = ARQ + ARp, eq. (8) becomes: Vo~max/('¢o:max + A'~'o2max ) = 1 + (ARQ' + A R p ' ) / R T ' .
(9)
Furthermore, according to the definition of F (eq. 6): Ri'/RT' = Fi' × ARi'/Ri'.
(10)
Thus, combining eqs. (9) and (10): Vo2max/('~o~max + AVo2max) = 1 + FQ' × ARQ'/RQ' + Fp' x A R p ' / R p ' .
(11) Since the experiments reported in table 2 were done acutely, the peripheral resistance (Rp') is assumed to remain essentially unchanged. Hence, ARp' = 0, so that eq. (11) reduces to: ~'o~max/('¢o2max + A'V'o~max) = 1 + FQ' x ARQ'/RQ'.
(12)
Therefore, if one plots the '¢o2max ratio (value before over value after) as a function of ARQ'/RQ', a linear relationship is obtained, with a slope equal to FQ' and an intercept equal to 1. Indeed, least squares linear regression of the data shown in table 2 yields: y = 1.01 + 0.70x,
(13)
where y = Vo2max/(~Zo2max + A~Zo2max) and x --- ARQ'/RQ' (r = 0.97; N = 15; P < 0.001), whence FQ' = 0.70 (and eonsequently Fp' = 0.30) (fig. 1). These values are similar to those that can be calculated from table 1 for sea level conditions; FQ' = 0.78; Fp' = 1 - FQ' = 0.22. In table 2, the changes in the resistance to O 2 transport (ARQ'/RQ') were calculated (in 9 out of 15 cases) from the [Hb] changes alone, thus neglecting any eventual changes
120
P.E. DI PRAMPERO A N D G. FERRETTI
~/02max '~'02max+& 1.3
/
1.2 t.I ARQ -0.2, -0.1 RQ 7 ' o ~°
o
o:,
o:2
o:3
0.9
0.8 Fig. 1. Changes in Vo2max(expressed as the ratio between the values before and after the manipulation) induced by any manipulation acutelyaffectingthe 02 transport system, as a functionof the relative changes in the resistance to 02 flowon the circulatoryside (ARQ'/RQ').Points refer to the experimental data shown in table 2. The regression equation is: y = 1.006 + 0.70 x, r = 0.97,n = 15. The slopeofthe line (0.70)is equal to the fractional limits to XTo2maximposed by circulation 02 transport (FQ', see eq. 14).
in Qmax. When measured, these were found to be rather small. If taken into account, they would tend to reduce the calculated value of ARQ'/RQ' thus leading to a larger slope of the regression equation of fig. 1, and hence to a greater value o f F Q ' . In addition, in calculating ARQ/RQ, it was also assumed that the fib changes with increasing [Hb] are proportional to the changes in [Hb] itself. However, because of the shape of the 02 dissociation curve, the changes in fib with increasing [Hb] are larger than the changes in [Hb] itself. Thus, if taken into account, the actual changes in/3b would lead to larger calculated values of ARQ'/RQ' and hence to smaller values of FQ'. It can therefore be concluded that the two approximations used in calculating ARQ'/RQ' in table 2 lead to opposite errors, which can be shown to be equivalent. Thus the above calculated value o f F Q ' ( = 0.70) can be taken to represent indeed the fraction of the total resistance to 02 flow (downstream from the lung) due to the Oz transport system. As stated above, Fp' (= 0.30) is the sum of Ft' plus F m ' . How F p ' is partitioned between Ft' and F m ' , however, is unknown, because the average O z pressure in the muscles, just outside the mitochondria, cannot be determined and is likely to undergo great local variations. For the sake of the present discussion, the arbitrary assumption is made that, in all conditions considered in table 2 and fig. 1, Ft' = F m ' --- 0.30/2 = 0.15 (see di Prampero, 1985, for a more detailed discussion of this topic).
LIMITS OF MAXIMAL02 CONSUMPTION
121
On changing Rt and Rm The above analysis was conducted on data from conditions in which Rt and Rm could be assumed to stay constant. However, conditions such as chronic environmental or exercise stresses, are accompanied by changes in body structures and functions leading to partial adaptation. For example, chronic exercise (training), besides an increased heart activity, induces a development of muscle structures that contributes to increased Vo2max. The reverse occurs in chronic hypoxia, as a consequence of reduced 0 2 availability (Hoppeler et al., 1990). If it is so, it can be assumed that the observed changes in Vo2max resulting from training or chronic hypoxia are the consequence of changes not only in RQ, but also in Rt and Rm. Therefore the fractional limits to Vomax must be estimated by a different procedure from that described in the preceding paragraphs. This problem will be approached by making a direct estimate of the RQ, Rt and Rm changes induced by any chronic environmental stress, starting from the conclusions arrived at in the previous paragraph. Two specific conditions will be treated, one in which Vo2max is increased (training), and one in which Vo:max is decreased (return to sea level after exposure to chronic hypoxia, a condition here defined as acute normoxia). In order to express Rt and Rm quantitatively, they are assumed to be related to muscle capillary density, [NA(C,f)], and to volume density of muscle mitochondria, [Vv(mt,f)], respectively: 1/Rt = Gt = Kt*NA(C,f) 1/Rm = Gm = Km.Vv(mt, f),
(14)
(15)
where Kt and Km are the proportionality constants, necessary to express G in the appropriate units. In addition, the assumption is made that, after training as well as after chronic hypoxia, the fraction of (~ which goes to the active muscles is unchanged. This assumption is supported by the conclusions arrived at by Clausen (1977) after the data obtained by Grimby et al. (1967) during maximal exercise for the post-training conditions. Concerning chronic hypoxia, the data of Cerretelli et al. (1984) showed a decrease in muscle blood flow (vastus lateralis) during submaximal exercise after chronic hypoxia, which is approximately the same as the decrease in 0 observed by Ferretti et al. (1990) in similar experimental conditions.
Training Aerobic exercise training induces an increase in maximal cardiac output (0max) (Saltin et al., 1968a) and hence in the amount of 0 2 transported per unit of time by convection
(t)o2). Training also increases muscle capillary density, muscle mitochondrial mass, and activity of oxidative enzymes (Anderson and Henriksson, 1977; Henriksson and Reitman, 1977). These changes result in an increase in Vo2max up to ~ 20 ~ . Measured values ofVo2max, t)max, capillary density, and of either mitochondrial density or SDH
122
P.E. DI PRAMPERO AND G. FERRETTI
activity (these two can be considered equivalent, Howald et aL, 1990) before and after training are summarized in table 3 from different sources in the literature. The relative changes of the same parameters after training appear in fig. 2. Unfortunately, to our knowledge, no longitudinal study of physical training, in which all the above variables have been determined at the same time on a given group of subjects all performing the same training program, exists in the literature. Therefore, fig. 2 and table 3 are a mixture of data from various subjects in different conditions. The following lines are devoted to an estimate of the fractional limits to Vo2max in trained subjects, calculated from the data appearing in table 3 and fig. 2. The total resistance to the maximal O 2 flow downstream from the lung, R T ' , is equal to the ratio of the 02 pressure gradient, APo2 to Vo2max (3.25 L/min before training), where APo~ is the pressure difference between arterial blood ( ~ 100 Torr) and the 0 2 mitochondrial sink (assumed to have Po2 = 0). Thus, before training, R T ' = 100/3.25 = 30.8 RU (resistance units, Torr.min/L). Since FQ' = 0.7 and Ft' = F m ' = 0.15, RQ' = FQ' x R T ' = 0.7 × 30.8 = 21.56 RU, and Rt' = R m ' , -- 0.15 R T ' = 4.62 RU. After training, RQ', Rt' and R m ' change in inverse proportion to the relative changes of the related parameters. Therefore, as from table 3 and fig. 2, after training, RQ' = 21.56/1.082 = 19.93 RU, Rt' = 4.62/1.212 = 3.81 RU, and R m ' = 4.62/1.353 = 3.41 RU. Thus R T ' , i.e. the sum of the three resistances, will be equal to 27.15 RU. The theoretical maximal 02 flow through the respiratory system
35
3O
/k 1%) 25
20 15
1
IO
n=49
Vo2max
n=23
(~ max
NA(c,f)
SDH or
Vv(mt,f)
Fig. 2. From left to right, relative changes in '~o2max,maximal cardiac output, muscle capillary density, and muscle SDH activity or mitochondrial density after endurance training. Bars indicate standard deviation. Data are from table 3.
8
13
5
7
6
5
Ekblom et al. (1968)
Henriksson and Reitman (1977)
Hoppeler et al. (1985)
Ingjer (1979)
Rowell (1962)
Saltin et al. (1968a)
3.25~3.78 +16.3~
3.30--, 3.81 + 15.5 Yo 3.15 ~ 3.68 + 16.8 Yo 3.27 ~ 3.88 + 18.6yo 3.50 --, 3.85 + 10.0 Yo 2.90 ~ 3.46 + 19.3 Yo 3.42 -o 3.87 + 13.2 ~o 3.30--, 3.91 + 18.5 Yo
Vozmax (L/min)
[Hb] is assumed not to change with training. Symbols as in the text.
Mean A
5
Anderson and Henriksson (1977)
N
21.9~23.7 +8.2~
22.8 -o 23.8 + 4.4Yo 20.0 ~ 22.8 + 11.4~o
22.4 --* 24.2 + 8.0Yo
0max (L/min)
354~429 +21.2~
387~450 +16.3~ 348~438 +25.9~
329~395 +20.1~
N a (c,f) ( m m - 2)
Effects of training on ~'ozmax and its determinants; N, number of subjects.
TABLE 3
+35.3%
9.5~12.5(SDH) +32.6~ 4.8~6.6(Vv) +38.2~
8.6~12.2(SDH) +41.9~
Vv (mt, f)* (Yo), or SDH (U/g)
F_,
Z
ta~
C3 0 Z
t"
©
,-.]
t"
124
P.E. DI PRAMPERO AND G. FERRETTI
amounts then to 100/27.15 = 3.68 L/min, to be compared with a measured ~'o2max after training of 3.78 L/rain, a value only 2.7~o higher than the predicted one. The fractional limits to "qo,max after training turn out to be FQ' = RQ'/RT' = 19.93/27.15 = 0.73; Ft' = R t ' / R T ' = 3.81/27.15 = 0.14; and Fm' = R m ' / R T ' = 3.41/27.15 = 0.13. It can thus be concluded that also in trained subjects, the fractional limits to "qo2max are essentially the same as in untrained individuals, the greatest role being played again by the 0 2 transport system. Most important, however, is to stress once again the multifactorial limits to V.o2max. Were "~'o2max limited by the 02 transport system only, the observed changes in Vo:max should have been equal to the changes in 02 transport by blood !Qo2). This is not the case: indeed fig. 2 shows that the measured percent increase in Vo:max was approximately twice the increase in 0max, and hence, assuming [Hb] to remain unchanged, in 0o2. This is the consequence of reduced resistances to 02 flow also beyond blood circulation, at the muscle level thus allowing greater 02 flows than one could predict on the basis of changes in t)o.- only. Acute normoxia A controversy among physiologists exists about the factor(s) limiting Vo2max after adaptation to chronic hypoxia. On the one hand, ~'o2max is claimed to be limited by reduced 0 2 transport (Saltin et al., 1968b), on the other by deteriorated muscle function consequent to chronic hypoxia (Cerretelli, 1980). In the present section the factors limiting "qo2max in acute normoxia, are discussed on the basis of the multifactorial
32
24
/k (%} 16
8
0
-8
~
m
-16
-24
~/o2max
(~o2
NA{c,f)
Vv(m1',f)
Fig. 3. Same as fig.2 (but with convective02 transport, 002, instead oft)max), after prolongedexposure to chronic hypoxia.Bars indicate standard deviation.From data obtained in acute normoxia and givenin table 4.
LIMITS OF MAXIMAL 02 CONSUMPTION
125
approach presented above. The purpose is to support the hypothesis that also in acute normoxia the limits to Vo2max are set by a combination of central and peripheral factors. To this aim, the data obtained in the course o f a longitudinal study on a group of subjects who participated in the 1986 Swiss expedition to M o u n t Everest will be used (Ferretti et al., 1990; Hoppeler et al., 1990). Vo2max, (~o2, muscle capillary density, and muscle mitochondrial density were assessed before departure and shortly after return from the expedition (altitude exposure longer than 8 weeks). The results of that study are briefly summarized in table 4 and fig. 3. Before the expedition, R T ' = APo2/Vo:max = 100/3.53 = 28.3 RU. For FQ' = 0.7 and Ft' = F m ' = 0.15, RQ' = 19.81 RU, and Rt' = R m ' = 4.25 RU. According to table 4, chronic hypoxia induced a reduction in 0 o 2 and in mitochondrial density, and an increase in capillary density, yielding sizeable inverse changes in the related resistances. Thus, upon return from altitude, RQ' = 19.81/0.87 = 22.77 RU, Rt' -- 4.25/1.15 = 3.68 RU, and R m ' = 4.25/0.66 = 6.38 R U . The total resistance, R T ' = RQ' + Rt' + R m ' amounted then to 22.77 + 3.68 + 6.38 = 32.83 R U , i.e. 16~o greater than before the expedition. Such resistance allows a maximal 0 2 flow of 100/32.83 = 3.05 L/min, to be compared with a measured Vo2max upon return of 3.28 L/min, a value 7.7 ~o higher than the estimated one. The fractional limits to Vo~max turn out to be: FQ' = R Q ' / R T ' = 22.77/32.83 = 0.69; F t ' = R t ' / R T ' = 3.68/32.83 = 0.11, and F m ' = R m ' / R T ' = 6.38/32.83 = 0.19. F r o m the present analysis it can be concluded that, also in acute normoxia, Vo2max is primarily limited by convective 0 2 transport. However, the two peripheral resistances still play a sizeable role, since they account for ~ 30~/o of the overall limits to Vo max. It is noteworthy that in this case the three considered resistances did vary in opposite directions: whereas RQ' and R m ' increased, Rt' decreased. However, the overall readjustment of the 0 2 pathway was such that the fractional limits to "~'o max were essentially the same as in normoxia. These conclusions contradict the opinion that in acute normoxia V o m a x is limited mostly by muscle deterioration. Indeed, muscles are deteriorated, since the mitochondrial mass and the activity of the oxidative enzymes are decreased, as well as the mean TABLE 4 Effects of chronic exposure to hypoxia on ~/o2max and its determinants. "V'o2max (L/min) Before expedition After expedition (A ~)
3.53 3.28 - 7.1
t)o2 (L/min)
N A (c,f) (mm - 2)
Vv (mt,f) (%)
4.19 3.65
468 599 540* + 15.4"
6.28 4.65 4.18* - 33.3*
- 12.9
The data have been obtained in acute normoxia on a homogeneous group of climbers, who participated in the 1986 Swiss Expedition to Mount Everest (Ferretti et al., 1990; Hoppeler et al., 1990). * Values corrected for the effects of reduced muscle mass following chronic exposure to hypoxia.
126
P.E. DI PRAMPERO AND G. FERRETTI
diameter of muscle fibers (Hoppeler et aL, 1990; Howald et aL, 1990). These changes, however, leading to an increased R m ' , imply also that the area of tissue supplied by each capillary is reduced, which in fact lowers Rt' and compensates for the increase in R m ' . In acute normoxia Vo2max is not increased, in spite of the remarkable increase in Hb, because 0 m a x is reduced by an even greater extent. The decrease in 0 m a x may be the result of a reduced maximal "~'o~and maximal work of the heart. The cardiac muscle also may lose contracting elements and mitochondria, as in the case of skeletal muscles. As previously pointed out, the above analysis is conducted on data obtained (Ferretti etaL, 1990) at sea level, shortly after exposure to chronic hypoxia. Its conclusions, therefore, cannot be applied as such to subjects sojourning at altitude. In fact, at altitude, (i) the 02 pressure gradient is reduced, and hence (ii) the average slope of the O z dissociation curve becomes steeper, thus reducing the resistance to 0 2 flow on the circulatory side. In addition, (iii) the resistances on the ventilatory side cannot be neglected, as in the above analysis, since a higher alveolar ventilation increasing Pao2 may cause Cao~ to increase, as discussed previously. This is even more important at extreme altitude ( > 8000 m above sea level), where a tremendous hyperventilation occurs even at rest, thus limiting the possibility to increase ventilation during exercise. Conclusions In conclusion, this paper discusses and supports the hypothesis that the limits to whole body ~'o~max are multifactorial. At least three resistances to maximal 0 2 flow of physiological relevance are proposed, that are provided by (i) convective 0 2 transport by the circulation of blood, (ii) peripheral 02 transfer from the capillaries to the mitochondria, and (iii) O2 utilisation in the mitochondria. Among these resistances, the greatest role as a limiting factor to "Co,max ( ~ 7 0 ~ ) is played by the convective O z transport in all tested conditions. The structural and functional readjustments in the respiratory system, following either endurance training or exposure to chronic hypoxia, do not alter the proportions on which the three resistances are combined in limiting ~/o2max.
References Andersen, P. and J, Henriksson (1977). Capillarysupply of the quadriceps femorismuscle of man: adaptive response to exercise.J. PhysioL (London) 270: 677-690. Buick, F.J., N. Gledhill, A. B. Froese, L. Spriet and E. C. Meyers (1980). Effect of induced erythrocythemia on aerobic work capacity. J. Appl. Physiol. 48: 636-642. Cerretelli, P. (1980). Gas exchangeat altitude. In: PulmonaryGas Exchange,edited by J. B. West. Academic Press, New York, Vol. 2, pp. 97-147. Cerretelli, P., C. Marconi, O. D6riaz and D. Giezendanner (1984). After effects of chronic hypoxia on cardiac output and muscle blood flow at rest and exercise. Eur..I. AppL Physiol. 53: 92-96. Cerretelli, P. and P.E. di Prampero (1987). Gas exchange at exercise. In: Handbook of Physiology. The Respiratory System IV, edited by L.E. Farhi and S.M. Tenney. Bethesda, MD, Am. Physiol. Soc., pp. 555-632. Clausen, J.P. (1977). Effect of physical training on cardiovascular adjustments to exercise in man. Physiol. Rev. 57" 779-815.
LIMITS OF MAXIMAL 02 CONSUMPTION
127
Dempsey, J. A., P.G. Hanson and K. S. Henderson (1984). Exercise-induced arterial hypoxaemia in healthy human subjects at sea level. J. Physiol. (London) 355: 161-175. di Prampero, P. E. (1985). Metabolic and circulatory limitations to Vo2max at the whole animal level. J. Exp. Biol. 115: 319-331. Ekblom, B., P. O. Ostrand, B. Saltin, J. Stenberg and B. Wallstr6m (1968). Effect of training on circulatory response to exercise. J. Appl. Physiol. 24: 518-528. Ekblom, B., A.N. Goldbarg and B. Gullbring (1972). Response to exercise after blood loss and reinfusion. J. Appl. Physiol. 33: 175-180. Ekblom, B., G. Wilson and P.O. Ostrand (1976). Central circulation during exercise after venesection and reinfusion of red blood cells. J. Appl. Physiol. 40: 379-383. Ferretti, G., U. Boutellier, D.R. Pendergast, C. Moia, A.E. Minetti, H. Howald and P.E. di Prampero (1990). Muscular exercise at high altitude. IV. Oxygen transport system before and after exposure to chronic hypoxia. Int. J. Sports Med. 11, Suppl. 1: S15-$20. Grimby, G., E. Haggendahl and B. Saltin (1967). Local xenon L33 clearance from the quadriceps muscle during exercise in man. J. Appl. Physiol. 22: 305-310. Henriksson, J. and J.S. Reitmann (1977). Time course of changes in human skeletal muscle succinate dehydrogenase and cytochrome oxidase activities and maximal oxygen uptake with physical activity and inactivity. Acta Physiol. Scand. 99: 91-97. Hoppeler, H., H. Howald, K. Conley, S.L. Lindstedt, H. Claassen, P. Vock and E.R. Weibel (1985). Endurance training in humans: aerobic capacity and structure of skeletal muscle. J. Appl. Physiol. 59: 320-327. Hoppeler, H., E. Kleinert, C. Schlegel, H. Claassen, H. Howald, S.R. Kayar and P. Cerretelli (1990). Muscular exercise at high altitude. II. Morphological adaptations of human skeletal muscle to chronic hypoxia. Int. J. Sports Med. 11 Suppl. 1 : $3-$9. Howald, H., D. Pette, J.A. Simoneau, A. Uber, H. Hoppeler and P. Cerretelli (1990). Muscular exercise at high altitude. III. Effects of chronic hypoxia on muscle enzyme activities. Int. J. SportsMed. 11 Suppl. 1 : S10-S14. Ingjer, F. (1979). Effect of endurance training on muscle fibre ATP-ase activity, capillary supply and mitochondrial content in man. J. Physiol. (London) 294: 419-432. Kaijser, L. (1970). Limiting factors for aerobic muscle performance. Acta Physiol. Scand. Suppl. 346: 1-96. Kanstrup, I. L. and B. Ekblom (1982). Acute hypervolemia, cardiac performance, and aerobic power during exercise. J. Appl. Physiol. 52:1186-1191. McArdle, W.D., J. R. Magel, G.R. Lesmes and G. S. Pechar (1976). Metabolic and cardiovascular adjustments to work in air and water at 18, 25 and 33 °C. J. Appl. Physiol. 40: 85-90. Piiper, J. and P. Scheid (1981). Model for capillary-alveolar equilibration with special reference to 02 uptake in hypoxia. Respir. Physiol. 46: 193-208. Piiper, J. (1990). Unequal distribution of blood flow in exercising muscle of the dog. Respir. Physiol. 80: 129-136. Rowell, L. B. (1962). Factors affecting the prediction of the maximal oxygen intake from measurements made during submaximal work. Ph.D. Thesis, University of Minnesota. Rowell, L.B., H.J. Marx, R.A. Bruce, R.D. Conn and F. Kusumi (1966). Reductions in cardiac output, central blood volume and stroke volume with thermal stress in normal man during exercise. J. Clin. Invest. 45: 1801-1816. Saltin, B., C.G. Blomqvist, R.C. Mitchell, R.L. Johnson, K. Wildenthal and C.B. Chapman (1968a). Response to exercise after bed rest and after training. Circulation 38 (Suppl. 7): 1-78. Saltin, B,, R.F. Grover, C.G. Blomqvist, L.H. Hartley and R.L. Johnson Jr. (1968b). Maximal oxygen uptake and cardiac output after 2 weeks at 4300 m. J. Appl. Physiol. 25: 400-409. Shephard, R.J. (1969). A non-linear solution of the oxygen conductance equation: applications to performance at sea level and at an altitude of 7,350 ft. Int. Z. angew. Physiol. 27: 212-225. West, J. B. (1983). Climbing Mount Everest without oxygen: an analysis of maximal exercise during extreme hypoxia. Respir. Physiol. 52: 265-279. Woodson, R. D., R. E. Wills and C. Lenfant (1978). Effect of acute and established anemia on 02 transport at rest, submaximal and maximal work. J. Appl. Physiol. 44: 36-43.
113
Elsevier RESP 01657
Factors limiting maximal oxygen consumption in humans*,** Pietro Enrico di Prampero 1 and Guido Ferretti 2 l lstituto di Biologia, Facolt~t di Medicina, Universit,~ di Udine, Udine, Italy and 2D~partement de Physiologie, Centre M~dical Universitaire, Geneva, Switzerland
(Accepted 22 March 1990) Abstract. The factors limiting~'o2maxin humans are analyzed according to a multifactorial model derived from the 02 conductance equation. In this context, alveolar ventilation (~rA)and lung 02 transfer (GL) are not considered to be limiting,at least at sea level, because changes in VA and/or in GL are not accompanied by changes in Vo2maxdue to the shape of the 02 dissociation curve. Thus, the limits to Vo2max are shared between blood 02 transport (FQ') and a peripheral factor. This last includes tissue 02 transfer (Ft') and mitochondrial 02 utilization (Fm'). In untrained subjects at sea level, blood 02 transport is found to be responsible for ~ 70~o of the overall limits to ~'o2max (FQ' = 0.7), the rest depending on the peripheral factors. FQ', as well as the sum of Ft' and Fm', are unchanged after training or upon return to sea level followingexposure to chronic hypoxia (altitude higher than 5000 m). In the latter condition, however, since tissue 02 transfer, which sets Ft', is facilitated, and mitochondrial 02 utilization, which sets Fm', is impaired, Ft' is reduced and Fm' increased as compared to control condition and/or after training.
Alveolar ventilation; Animal, man; Diffusing capacity, pulmonary; Gas exchange; Hemoglobin; Cardiac output, maximal; 02 consumption, maximal; Muscle morphometry; Blood, 02 dissociation curve
Several physiological variables have been called u p o n as possible determinants of the maximal 0 2 c o n s u m p t i o n ('V'o2max). A m o n g others, ventilation, 0 2 diffusion at the lung level, 0 2 transport by the circulation, peripheral perfusion a n d diffusion, a n d mitochondrial function have been considered. The role played by the above factors in limiting Vo2max has long since been debated. At least for non-athletic subjects at sea level, Vo2max is generally believed to be limited by 0 2 transport by the circulation. However, the mitochondrial function, as well as the 0 2 diffusion at the lung or tissue level, the latter particularly at extreme altitude a n d / o r in athletes, have also been considered as major limiting factors (Dempsey et al., 1984; Kaijser, 1970; West, 1983). Correspondence to: P.E. di Prampero, Istituto di Biologia, Facolt~tdi Medicina, Universitgtdi Udine, Via Gervasutta 48, 33100 Udine, Italy. * Dedicated to Dr. Johannes Piiper on the occasion of his 65th birthday anniversary. ** Presented at the symposium "Factors determining ~'o2maxin Humans", 73rd Annual Meeting of the Federation of American Societies for Experimental Biology,New Orleans LA, March 19-23, 1989.
0034-5687/90/$03.50 © 1990 Elsevier Science Publishers B.V. (Biomedical Division)
114
P.E. DI PRAMPERO AND G. FERRETTI
The present article is devoted to a discussion of the factors limiting 'V'o~max in man during exercise involving large muscle groups. It is divided into two sections. In the first one a general model, allowing a quantitative analysis of the relative weight of (some of) the above factors, will be proposed and discussed. In the second section, the model will be applied to calculate the role played by: (i) the 02 transport by the circulation, (ii) the 02 perfusion and diffusion at the muscle level and (iii)the mitochondrial function in limiting Vo:max after long term endurance training and upon return to sea level after high altitude acclimatization (acute normoxia). The p a t h w a y for o x y g e n
The 02 path from the environment to the mitochondria can be considered equivalent to a cascade of resistances in series, each resistance being overcome by a specific pressure gradient. If this is so, the overall resistance to 02 flow, RT, is the sum of the specific resistances R i, and the maximal 02 flow through the system is set by: ,~o~max = -APT -, RT
(1)
where APT is the overall pressure gradient. Since at steady state the flow through each R i is the same, then: APT RT
AP i
Ri
(2)
where APi is the pressure gradient across the ith resistance R i. This means that the following equalities must also apply at Vo~max: "V'o:max = (PI - PA)/Rv = (PA - Pa)/RL = (Pa - PV)/RQ = (pro _ Pt)/Rt = (Pt - Pm)/Rm = (PI - Pm)/RT,
(3)
where PI, PA, Pa, PV, Pt and Pm indicate the average partial pressures o f O 2 in inspired and alveolar air, arterial and mixed venous blood, the muscle tissue and the mitochondria, respectively. Correspondingly, the overall resistance to 02 flow from environment to mitochondria (RT) has been partitioned in the following five major steps depending on: (i) alveolar ventilation (Rv), (ii)lung perfusion and diffusion (RL), (iii)blood 02 transport (RQ), (iv) peripheral perfusion and diffusion (Rt), and (v) mitochondrial 02 utilization (Rm). Equation (3) can also be written in the equivalent form of the so-called 02 conductance equation (Shephard, 1969): Vo~max = (PI - PA) X G v = (PA - Pa) x GL = ( P a - PV) x GQ = ( P V - Pt) x Gt = ( P t - Pm) x Gm = (P! - Pm) × GT,
(4)
LIMITS OF MAXIMAL 02 CONSUMPTION
115
whereby the following applies: R = 1/G. In all cases G has the dimensions of amount of 02 per unit of time and unit of O z partial pressure, measurable in ml 02 • min - 1. T o r r - 1. Equations (3) and (4) allow to identify the physiological variables that constitute some of the above conductances or resistances: G v = 1/Rv = ~'A" fig GQ = 1/RQ = (~-/~o,
(5a) (5b)
where ~/Ais the alveolar ventilation, fig the transport coefficient in the gas phase at 37 ° C (1.16 ml 02" L - 1 . T o r r - 1 ) , 0 the cardiac output,/To the transport coefficient in the blood, equal to the average slope of the blood 02 dissociation curve. Whereas the conductance terms of eqs. 5a and b are appropriate physiological variables that can actually be measured, GL, G t and G m are not. Indeed, they depend in a complex way on diffusion and perfusion at the lung (GL) and muscle tissue (Gt) level, and on the overall capacity of the mitochondria to utilize 02 (Gin). Equations (3) and (4) show that the fraction of the overall resistance due to any given physiological step (defined as F with the appropriate suffix) is equal to the ratio of the corresponding pressure drop divided by the overall pressure gradient: (PI (PA (Pa (P~ (Pt -
PA)/(PI Pa)/(PI PV)/(PI Pt)/(PI Pm)/(PI -
Pm) = G T / G v = R v / R T = F v Pm) = GT/GL = RL/RT = FL Pm) = GT/GQ = RQ/RT = FQ Pm) = G T / G t = Rt/RT = Ft Pm) = G T / G m = R m / R T - F m
(6a) (6b) (6c) (6d) (6e)
A direct consequence of eq. (6) is that, if the system behaves linearly, the fractions of the total resistance due to the above identified factors can be calculated on the basis of the 02 partial pressures assumed to hold at the different levels of the 02 cascade. These, together with the corresponding F's, are reported in table 1 for maximal aerobic exercise at sea level and at extreme altitude on the top of Mount Everest (8848 m). In table 1, due to the difficulty of establishing reasonable Pt values, Rt and Rm have been considered as a single peripheral resistance (Rp--- Rt + Rm), so that Fp = Ft + F m = (PV - Pm)/(PI - Pm). Table 1 shows that, at sea level ~40~o of RT is located at the lungs, ~ , 4 5 - 5 0 ~ is due to the 02 transport by the circulation, and the remaining fraction represents the sum of peripheral perfusion and diffusion and mitochondrial capacity. The resistance at the lung level is about equally partitioned between ventilatory conductance and 02 transfer from alveoli to capillaries. The ventilatory factor, can be subdivided further into an external ventilation plus a dead space component. This last is equal to the ratio (PE - PA)/(PI - PA), where PE is the 02 partial pressure in mixed expired air. At maximal exercise, it corresponds to ,~ 5 ~ of Rv. The resistance to 02 transfer from alveoli to capillaries plays a progressively greater role at higher work
116
P.E. DI PRAMPERO AND G. FERRETTI TABLE 1
Factors limiting "¢o2maxon the assumption that the 0 2 conductance equation has a linear solution Sea levela
Vo2max L/min PI Torr PA Torr Pa Torr PV Torr Pm Torr Fv=(PI-PA)/(PI-Pm) FL = (PA-Pa)/(PI-Pm) FQ (Pa-Prc)/PI-Pm) FP = (P~-Pm)/(PI-Pm) =
Everest (8848 m)b
Sedentary
Athlete
3.60 150 120 95 20 0 0.20 } 0.17 0.37 0.50 0.13
4.90 150 116 83 18 0 0.23 } 0.22 0.45 0.43 0.12
1.05 43 36 28 15 0 0.16 } 0.19 0.35 0.30 0.35
a From Cerretelli and di Prampero (1987). b From West (1983). intensities, as shown by the widening of the (PA - Pa) pressure gradient. As a consequence, RE turns out greater in athletes than in sedentary subjects (table 1). At extreme altitude the total resistance to 02 transport is about equally partitioned among pulmonary factors, circulatory O z transport, and peripheral 0 2 transfer and utilization (see table 1). This is the result of the fact that at high altitude: (i) An extreme increase in alveolar ventilation leads to a reduction in Rv; (ii)The arterial 0 2 partial pressure is on the steep part of the 0 2 dissociation curve, of which the average slope (fib) is therefore increased, thus leading to a smaller RQ; This is necessarily followed by (iii) a correspondingly larger fraction of the resistance due to the peripheral factors (see table 1). Because of the further drop of the Oz partial pressure in arterial blood upon work onset, during maximal exercise in chronic hypoxia RE plays an even larger role. The advantage of the above described model of the pathway for O2 is its simplicity which somewhat restricts its applicability. Indeed, not all the described resistances to 02 flow correspond to well defined physiological processes. This is particularly evident at the lung level, where the resistance RE takes into account the complex interactions between diffusive and perfusive factors (Piiper and Scheid, 1981), the effects of "~'A/0 inhomogeneities, and the role played by functional and structural shunts in pulmonary circulation. The same applies to the term Rt, which takes into account the passive and facilitated (by myoglobin) diffusion of 02, and muscle perfusion, which is known to be inhomogeneously distributed (Piiper, 1990). In addition, during maximal exercise, not only the muscles, but also other tissues and organs are active, a fact not considered by the simple resistive model described above. Finally, it should be noted that GL and Gt and the corresponding resistances are obtained from alveolar to arterial and from mixed venous to tissue 02 partial pressure differences, respectively. As such, they are larger than the lung and tissue 02 diffusing
LIMITS OF MAXIMAL02 CONSUMPTION
117
capacities which should be obtained on the basis of the average partial pressures of O z in the lung (PEL) and systemic (PEs) capillaries. Indeed, the present analysis is based on the assumption that the O a flow through each resistance in series is the same. Thus, the Oa flow through the circulation ((~/319. (Pa - P~)) must be equal to the immediately upstream (GL. (PA - Pa)) and downstream (Gt- (P~ - Pt)) ones (see eq. 4). If the O 2 pressure differences at the lung and tissue levels in eq. (4) were replaced by PA - PcL and PEs - Pt, respectively, and GL and Gt by the corresponding 02 diffusing capacities, the circulatory conductance (Qflb) would tend to infinity since the corresponding pressure difference (PEL - P~s) would become vanishingly small, an obviously nonsensical conclusion. On Rv and RL as limiting steps Apart from the above limitations, the model shows that Vo2max is not limited by a single factor, but by a series of physiological variables whose limiting role can be quantitatively assessed on the basis of the model itself. In addition, if the system behaves linearly, and if the overall pressure gradient from environment to mitochondria is constant, any given change of the ith resistance will lead to a change in Vo2max proportional to the relative magnitude of the resistance in question (Fi in eq. 6). However, an increase in alveolar ventilation brings about an increase in PA and Pa without sizeables changes in '~/o2max. In fact, the reduction in Rv ensuing from the higher VA is offset by an approximately equal increase in RQ. This is brought about by a concomitant decrease in/5"0, for the increase in Pao2 occurs on the fiat part of the O z dissociation curve and is not associated with sizeable changes in Pvo~. On the contrary, when Pao2 is situated on the steep part of the Oz dissociation curve, as is the case in deep hypoxia, an increase in VA is more effective in increasing Vo:max. Thus, because of the shape of the 0 2 dissociation curve of blood, at the level of the alveolar arterial step, the system is markedly non-linear. Therefore, even if pulmonary ventilation and diffusion are responsible for a large fraction of the overall 0 z pressure gradient, their role as "limiting factors" is very minor indeed: changing their values leads to negligible modifications of the overall 0 2 flow, at least in healthy non athletic subjects at sea level. Sharing the limits to ~/o2max between circulation and muscles Neglecting, therefore, pulmonary ventilation and alveolar-arterial 02 transfer, in the section that follows we will attempt a partition of the resistance to 02 transport downstream from the lung into two fractions: (i) FQ', due to 02 transport and (ii) Fp' due to both capillary 02 diffusion and mitochondria102 utilisation (Fp' = Ft' + Fm'). (Note again that, whereas FQ and Fp refer to the overall 02 cascade, FQ' and Fp' refer to the portion of the cascade downstream from the lung only). FQ' and Fp' will be estimated from data of changes in "qo2max due to measured changes in blood 02 carrying capacity, obtained by acute alteration of either Hb
Blood withdrawal
Ekblom et aL (1972)
Subsequent withdrawals at 2 days intervals of 1 unit of blood Blood withdrawal Blood infusion Induced hypervolemia Cold Heat Induced anemia 3.48 3.80 3.01
5.33 4.85 4.57 4.57 4.40 4.40 4.49 4.49 4.49 4.27 4.27 4.22 3.34 3.70 2.53
5.58 5.11 4.09 4.40 4.79 4.63 4.21 4.03 3.78 4.03 4.61 4.18 1.042 1.027 1.190
0.955 0.949 1.117 1.039 0.919 0.950 1.067 1.114 1.188 1.060 0.926 1.010 20.0 19.8
28.7 28.7 27.4
B
B/A
B
A
I~max (L/min)
X)o2max (L/min)
19.0 18.6
29.5 28.3 29.5
A
151 158 146 146 132 132 149 149 149 154 147
B
Hb (g/L)
163 167 127 132 149 150 133 126 122 138 161
A
4.08
5.92 5.65 5.37
B
t)o 2 (L/min)
3.01
5.46 6.11 5.31
A
0.050 0.061 0.262
- 0.080 - 0.057 0.130 0.096 - 0.129 - 0.136 0.107 0.154 0.221 0.078 - 0.081 -0.011
ARQ'/RQ'
Vo2max, maximal 0 2 consumption; 0 m a x , maximal cardiac output; Hb, blood hemoglobin; I)o2, convective 0 2 flow in arterial blood. For ARQ'/RQ', see the text for details. (B = before; A = after).
Mc Ardle et al. (1976) Rowell et al. (1966) Woodson et al. (1978)
Kanstrup and Ekblom (1982)
Ekblom et al. (1976)
Blood infusion
Buick et al. (1980)
Blood infusion
Conditions
Authors
Average effects on "~o2max and on the blood 0 2 transport system of manipulations that do not alter Rt and Rm, as from the quoted references.
TABLE 2
"t
rn
Z t7
©
'~
.m
oo
LIMITS OF MAXIMAL 0 2 CONSUMPTION
119
concentration (withdrawal or reinfusion of red blood cells or of blood) or 0 m a x (heat or cold exposure). These data are summarized in table 2. Under these conditions, the overall pressure gradient from arterial blood to mitochondria cannot be expected to change (APT = constant). Hence, assuming that the reduced system behaves linearly, the changes in V o m a x must be due to an equal (and opposite) change of the total resistance to O2 flow (RT'; di Prampero, 1985): 9o~max + A~'o~max = APo~/(RT + ART).
(7)
Dividing eq. (7) by eq. (1): 9o2max/(Vo~max + AVo max ) = (RT' + A R T ' ) / R T ' .
(8)
Since, under these conditions, ART = ARQ + ARp, eq. (8) becomes: Vo~max/('¢o:max + A'~'o2max ) = 1 + (ARQ' + A R p ' ) / R T ' .
(9)
Furthermore, according to the definition of F (eq. 6): Ri'/RT' = Fi' × ARi'/Ri'.
(10)
Thus, combining eqs. (9) and (10): Vo2max/('~o~max + AVo2max) = 1 + FQ' × ARQ'/RQ' + Fp' x A R p ' / R p ' .
(11) Since the experiments reported in table 2 were done acutely, the peripheral resistance (Rp') is assumed to remain essentially unchanged. Hence, ARp' = 0, so that eq. (11) reduces to: ~'o~max/('¢o2max + A'V'o~max) = 1 + FQ' x ARQ'/RQ'.
(12)
Therefore, if one plots the '¢o2max ratio (value before over value after) as a function of ARQ'/RQ', a linear relationship is obtained, with a slope equal to FQ' and an intercept equal to 1. Indeed, least squares linear regression of the data shown in table 2 yields: y = 1.01 + 0.70x,
(13)
where y = Vo2max/(~Zo2max + A~Zo2max) and x --- ARQ'/RQ' (r = 0.97; N = 15; P < 0.001), whence FQ' = 0.70 (and eonsequently Fp' = 0.30) (fig. 1). These values are similar to those that can be calculated from table 1 for sea level conditions; FQ' = 0.78; Fp' = 1 - FQ' = 0.22. In table 2, the changes in the resistance to O 2 transport (ARQ'/RQ') were calculated (in 9 out of 15 cases) from the [Hb] changes alone, thus neglecting any eventual changes
120
P.E. DI PRAMPERO A N D G. FERRETTI
~/02max '~'02max+& 1.3
/
1.2 t.I ARQ -0.2, -0.1 RQ 7 ' o ~°
o
o:,
o:2
o:3
0.9
0.8 Fig. 1. Changes in Vo2max(expressed as the ratio between the values before and after the manipulation) induced by any manipulation acutelyaffectingthe 02 transport system, as a functionof the relative changes in the resistance to 02 flowon the circulatoryside (ARQ'/RQ').Points refer to the experimental data shown in table 2. The regression equation is: y = 1.006 + 0.70 x, r = 0.97,n = 15. The slopeofthe line (0.70)is equal to the fractional limits to XTo2maximposed by circulation 02 transport (FQ', see eq. 14).
in Qmax. When measured, these were found to be rather small. If taken into account, they would tend to reduce the calculated value of ARQ'/RQ' thus leading to a larger slope of the regression equation of fig. 1, and hence to a greater value o f F Q ' . In addition, in calculating ARQ/RQ, it was also assumed that the fib changes with increasing [Hb] are proportional to the changes in [Hb] itself. However, because of the shape of the 02 dissociation curve, the changes in fib with increasing [Hb] are larger than the changes in [Hb] itself. Thus, if taken into account, the actual changes in/3b would lead to larger calculated values of ARQ'/RQ' and hence to smaller values of FQ'. It can therefore be concluded that the two approximations used in calculating ARQ'/RQ' in table 2 lead to opposite errors, which can be shown to be equivalent. Thus the above calculated value o f F Q ' ( = 0.70) can be taken to represent indeed the fraction of the total resistance to 02 flow (downstream from the lung) due to the Oz transport system. As stated above, Fp' (= 0.30) is the sum of Ft' plus F m ' . How F p ' is partitioned between Ft' and F m ' , however, is unknown, because the average O z pressure in the muscles, just outside the mitochondria, cannot be determined and is likely to undergo great local variations. For the sake of the present discussion, the arbitrary assumption is made that, in all conditions considered in table 2 and fig. 1, Ft' = F m ' --- 0.30/2 = 0.15 (see di Prampero, 1985, for a more detailed discussion of this topic).
LIMITS OF MAXIMAL02 CONSUMPTION
121
On changing Rt and Rm The above analysis was conducted on data from conditions in which Rt and Rm could be assumed to stay constant. However, conditions such as chronic environmental or exercise stresses, are accompanied by changes in body structures and functions leading to partial adaptation. For example, chronic exercise (training), besides an increased heart activity, induces a development of muscle structures that contributes to increased Vo2max. The reverse occurs in chronic hypoxia, as a consequence of reduced 0 2 availability (Hoppeler et al., 1990). If it is so, it can be assumed that the observed changes in Vo2max resulting from training or chronic hypoxia are the consequence of changes not only in RQ, but also in Rt and Rm. Therefore the fractional limits to Vomax must be estimated by a different procedure from that described in the preceding paragraphs. This problem will be approached by making a direct estimate of the RQ, Rt and Rm changes induced by any chronic environmental stress, starting from the conclusions arrived at in the previous paragraph. Two specific conditions will be treated, one in which Vo2max is increased (training), and one in which Vo:max is decreased (return to sea level after exposure to chronic hypoxia, a condition here defined as acute normoxia). In order to express Rt and Rm quantitatively, they are assumed to be related to muscle capillary density, [NA(C,f)], and to volume density of muscle mitochondria, [Vv(mt,f)], respectively: 1/Rt = Gt = Kt*NA(C,f) 1/Rm = Gm = Km.Vv(mt, f),
(14)
(15)
where Kt and Km are the proportionality constants, necessary to express G in the appropriate units. In addition, the assumption is made that, after training as well as after chronic hypoxia, the fraction of (~ which goes to the active muscles is unchanged. This assumption is supported by the conclusions arrived at by Clausen (1977) after the data obtained by Grimby et al. (1967) during maximal exercise for the post-training conditions. Concerning chronic hypoxia, the data of Cerretelli et al. (1984) showed a decrease in muscle blood flow (vastus lateralis) during submaximal exercise after chronic hypoxia, which is approximately the same as the decrease in 0 observed by Ferretti et al. (1990) in similar experimental conditions.
Training Aerobic exercise training induces an increase in maximal cardiac output (0max) (Saltin et al., 1968a) and hence in the amount of 0 2 transported per unit of time by convection
(t)o2). Training also increases muscle capillary density, muscle mitochondrial mass, and activity of oxidative enzymes (Anderson and Henriksson, 1977; Henriksson and Reitman, 1977). These changes result in an increase in Vo2max up to ~ 20 ~ . Measured values ofVo2max, t)max, capillary density, and of either mitochondrial density or SDH
122
P.E. DI PRAMPERO AND G. FERRETTI
activity (these two can be considered equivalent, Howald et aL, 1990) before and after training are summarized in table 3 from different sources in the literature. The relative changes of the same parameters after training appear in fig. 2. Unfortunately, to our knowledge, no longitudinal study of physical training, in which all the above variables have been determined at the same time on a given group of subjects all performing the same training program, exists in the literature. Therefore, fig. 2 and table 3 are a mixture of data from various subjects in different conditions. The following lines are devoted to an estimate of the fractional limits to Vo2max in trained subjects, calculated from the data appearing in table 3 and fig. 2. The total resistance to the maximal O 2 flow downstream from the lung, R T ' , is equal to the ratio of the 02 pressure gradient, APo2 to Vo2max (3.25 L/min before training), where APo~ is the pressure difference between arterial blood ( ~ 100 Torr) and the 0 2 mitochondrial sink (assumed to have Po2 = 0). Thus, before training, R T ' = 100/3.25 = 30.8 RU (resistance units, Torr.min/L). Since FQ' = 0.7 and Ft' = F m ' = 0.15, RQ' = FQ' x R T ' = 0.7 × 30.8 = 21.56 RU, and Rt' = R m ' , -- 0.15 R T ' = 4.62 RU. After training, RQ', Rt' and R m ' change in inverse proportion to the relative changes of the related parameters. Therefore, as from table 3 and fig. 2, after training, RQ' = 21.56/1.082 = 19.93 RU, Rt' = 4.62/1.212 = 3.81 RU, and R m ' = 4.62/1.353 = 3.41 RU. Thus R T ' , i.e. the sum of the three resistances, will be equal to 27.15 RU. The theoretical maximal 02 flow through the respiratory system
35
3O
/k 1%) 25
20 15
1
IO
n=49
Vo2max
n=23
(~ max
NA(c,f)
SDH or
Vv(mt,f)
Fig. 2. From left to right, relative changes in '~o2max,maximal cardiac output, muscle capillary density, and muscle SDH activity or mitochondrial density after endurance training. Bars indicate standard deviation. Data are from table 3.
8
13
5
7
6
5
Ekblom et al. (1968)
Henriksson and Reitman (1977)
Hoppeler et al. (1985)
Ingjer (1979)
Rowell (1962)
Saltin et al. (1968a)
3.25~3.78 +16.3~
3.30--, 3.81 + 15.5 Yo 3.15 ~ 3.68 + 16.8 Yo 3.27 ~ 3.88 + 18.6yo 3.50 --, 3.85 + 10.0 Yo 2.90 ~ 3.46 + 19.3 Yo 3.42 -o 3.87 + 13.2 ~o 3.30--, 3.91 + 18.5 Yo
Vozmax (L/min)
[Hb] is assumed not to change with training. Symbols as in the text.
Mean A
5
Anderson and Henriksson (1977)
N
21.9~23.7 +8.2~
22.8 -o 23.8 + 4.4Yo 20.0 ~ 22.8 + 11.4~o
22.4 --* 24.2 + 8.0Yo
0max (L/min)
354~429 +21.2~
387~450 +16.3~ 348~438 +25.9~
329~395 +20.1~
N a (c,f) ( m m - 2)
Effects of training on ~'ozmax and its determinants; N, number of subjects.
TABLE 3
+35.3%
9.5~12.5(SDH) +32.6~ 4.8~6.6(Vv) +38.2~
8.6~12.2(SDH) +41.9~
Vv (mt, f)* (Yo), or SDH (U/g)
F_,
Z
ta~
C3 0 Z
t"
©
,-.]
t"
124
P.E. DI PRAMPERO AND G. FERRETTI
amounts then to 100/27.15 = 3.68 L/min, to be compared with a measured ~'o2max after training of 3.78 L/rain, a value only 2.7~o higher than the predicted one. The fractional limits to "qo,max after training turn out to be FQ' = RQ'/RT' = 19.93/27.15 = 0.73; Ft' = R t ' / R T ' = 3.81/27.15 = 0.14; and Fm' = R m ' / R T ' = 3.41/27.15 = 0.13. It can thus be concluded that also in trained subjects, the fractional limits to "qo2max are essentially the same as in untrained individuals, the greatest role being played again by the 0 2 transport system. Most important, however, is to stress once again the multifactorial limits to V.o2max. Were "~'o2max limited by the 02 transport system only, the observed changes in Vo:max should have been equal to the changes in 02 transport by blood !Qo2). This is not the case: indeed fig. 2 shows that the measured percent increase in Vo:max was approximately twice the increase in 0max, and hence, assuming [Hb] to remain unchanged, in 0o2. This is the consequence of reduced resistances to 02 flow also beyond blood circulation, at the muscle level thus allowing greater 02 flows than one could predict on the basis of changes in t)o.- only. Acute normoxia A controversy among physiologists exists about the factor(s) limiting Vo2max after adaptation to chronic hypoxia. On the one hand, ~'o2max is claimed to be limited by reduced 0 2 transport (Saltin et al., 1968b), on the other by deteriorated muscle function consequent to chronic hypoxia (Cerretelli, 1980). In the present section the factors limiting "qo2max in acute normoxia, are discussed on the basis of the multifactorial
32
24
/k (%} 16
8
0
-8
~
m
-16
-24
~/o2max
(~o2
NA{c,f)
Vv(m1',f)
Fig. 3. Same as fig.2 (but with convective02 transport, 002, instead oft)max), after prolongedexposure to chronic hypoxia.Bars indicate standard deviation.From data obtained in acute normoxia and givenin table 4.
LIMITS OF MAXIMAL 02 CONSUMPTION
125
approach presented above. The purpose is to support the hypothesis that also in acute normoxia the limits to Vo2max are set by a combination of central and peripheral factors. To this aim, the data obtained in the course o f a longitudinal study on a group of subjects who participated in the 1986 Swiss expedition to M o u n t Everest will be used (Ferretti et al., 1990; Hoppeler et al., 1990). Vo2max, (~o2, muscle capillary density, and muscle mitochondrial density were assessed before departure and shortly after return from the expedition (altitude exposure longer than 8 weeks). The results of that study are briefly summarized in table 4 and fig. 3. Before the expedition, R T ' = APo2/Vo:max = 100/3.53 = 28.3 RU. For FQ' = 0.7 and Ft' = F m ' = 0.15, RQ' = 19.81 RU, and Rt' = R m ' = 4.25 RU. According to table 4, chronic hypoxia induced a reduction in 0 o 2 and in mitochondrial density, and an increase in capillary density, yielding sizeable inverse changes in the related resistances. Thus, upon return from altitude, RQ' = 19.81/0.87 = 22.77 RU, Rt' -- 4.25/1.15 = 3.68 RU, and R m ' = 4.25/0.66 = 6.38 R U . The total resistance, R T ' = RQ' + Rt' + R m ' amounted then to 22.77 + 3.68 + 6.38 = 32.83 R U , i.e. 16~o greater than before the expedition. Such resistance allows a maximal 0 2 flow of 100/32.83 = 3.05 L/min, to be compared with a measured Vo2max upon return of 3.28 L/min, a value 7.7 ~o higher than the estimated one. The fractional limits to Vo~max turn out to be: FQ' = R Q ' / R T ' = 22.77/32.83 = 0.69; F t ' = R t ' / R T ' = 3.68/32.83 = 0.11, and F m ' = R m ' / R T ' = 6.38/32.83 = 0.19. F r o m the present analysis it can be concluded that, also in acute normoxia, Vo2max is primarily limited by convective 0 2 transport. However, the two peripheral resistances still play a sizeable role, since they account for ~ 30~/o of the overall limits to Vo max. It is noteworthy that in this case the three considered resistances did vary in opposite directions: whereas RQ' and R m ' increased, Rt' decreased. However, the overall readjustment of the 0 2 pathway was such that the fractional limits to "~'o max were essentially the same as in normoxia. These conclusions contradict the opinion that in acute normoxia V o m a x is limited mostly by muscle deterioration. Indeed, muscles are deteriorated, since the mitochondrial mass and the activity of the oxidative enzymes are decreased, as well as the mean TABLE 4 Effects of chronic exposure to hypoxia on ~/o2max and its determinants. "V'o2max (L/min) Before expedition After expedition (A ~)
3.53 3.28 - 7.1
t)o2 (L/min)
N A (c,f) (mm - 2)
Vv (mt,f) (%)
4.19 3.65
468 599 540* + 15.4"
6.28 4.65 4.18* - 33.3*
- 12.9
The data have been obtained in acute normoxia on a homogeneous group of climbers, who participated in the 1986 Swiss Expedition to Mount Everest (Ferretti et al., 1990; Hoppeler et al., 1990). * Values corrected for the effects of reduced muscle mass following chronic exposure to hypoxia.
126
P.E. DI PRAMPERO AND G. FERRETTI
diameter of muscle fibers (Hoppeler et aL, 1990; Howald et aL, 1990). These changes, however, leading to an increased R m ' , imply also that the area of tissue supplied by each capillary is reduced, which in fact lowers Rt' and compensates for the increase in R m ' . In acute normoxia Vo2max is not increased, in spite of the remarkable increase in Hb, because 0 m a x is reduced by an even greater extent. The decrease in 0 m a x may be the result of a reduced maximal "~'o~and maximal work of the heart. The cardiac muscle also may lose contracting elements and mitochondria, as in the case of skeletal muscles. As previously pointed out, the above analysis is conducted on data obtained (Ferretti etaL, 1990) at sea level, shortly after exposure to chronic hypoxia. Its conclusions, therefore, cannot be applied as such to subjects sojourning at altitude. In fact, at altitude, (i) the 02 pressure gradient is reduced, and hence (ii) the average slope of the O z dissociation curve becomes steeper, thus reducing the resistance to 0 2 flow on the circulatory side. In addition, (iii) the resistances on the ventilatory side cannot be neglected, as in the above analysis, since a higher alveolar ventilation increasing Pao2 may cause Cao~ to increase, as discussed previously. This is even more important at extreme altitude ( > 8000 m above sea level), where a tremendous hyperventilation occurs even at rest, thus limiting the possibility to increase ventilation during exercise. Conclusions In conclusion, this paper discusses and supports the hypothesis that the limits to whole body ~'o~max are multifactorial. At least three resistances to maximal 0 2 flow of physiological relevance are proposed, that are provided by (i) convective 0 2 transport by the circulation of blood, (ii) peripheral 02 transfer from the capillaries to the mitochondria, and (iii) O2 utilisation in the mitochondria. Among these resistances, the greatest role as a limiting factor to "Co,max ( ~ 7 0 ~ ) is played by the convective O z transport in all tested conditions. The structural and functional readjustments in the respiratory system, following either endurance training or exposure to chronic hypoxia, do not alter the proportions on which the three resistances are combined in limiting ~/o2max.
References Andersen, P. and J, Henriksson (1977). Capillarysupply of the quadriceps femorismuscle of man: adaptive response to exercise.J. PhysioL (London) 270: 677-690. Buick, F.J., N. Gledhill, A. B. Froese, L. Spriet and E. C. Meyers (1980). Effect of induced erythrocythemia on aerobic work capacity. J. Appl. Physiol. 48: 636-642. Cerretelli, P. (1980). Gas exchangeat altitude. In: PulmonaryGas Exchange,edited by J. B. West. Academic Press, New York, Vol. 2, pp. 97-147. Cerretelli, P., C. Marconi, O. D6riaz and D. Giezendanner (1984). After effects of chronic hypoxia on cardiac output and muscle blood flow at rest and exercise. Eur..I. AppL Physiol. 53: 92-96. Cerretelli, P. and P.E. di Prampero (1987). Gas exchange at exercise. In: Handbook of Physiology. The Respiratory System IV, edited by L.E. Farhi and S.M. Tenney. Bethesda, MD, Am. Physiol. Soc., pp. 555-632. Clausen, J.P. (1977). Effect of physical training on cardiovascular adjustments to exercise in man. Physiol. Rev. 57" 779-815.
LIMITS OF MAXIMAL 02 CONSUMPTION
127
Dempsey, J. A., P.G. Hanson and K. S. Henderson (1984). Exercise-induced arterial hypoxaemia in healthy human subjects at sea level. J. Physiol. (London) 355: 161-175. di Prampero, P. E. (1985). Metabolic and circulatory limitations to Vo2max at the whole animal level. J. Exp. Biol. 115: 319-331. Ekblom, B., P. O. Ostrand, B. Saltin, J. Stenberg and B. Wallstr6m (1968). Effect of training on circulatory response to exercise. J. Appl. Physiol. 24: 518-528. Ekblom, B., A.N. Goldbarg and B. Gullbring (1972). Response to exercise after blood loss and reinfusion. J. Appl. Physiol. 33: 175-180. Ekblom, B., G. Wilson and P.O. Ostrand (1976). Central circulation during exercise after venesection and reinfusion of red blood cells. J. Appl. Physiol. 40: 379-383. Ferretti, G., U. Boutellier, D.R. Pendergast, C. Moia, A.E. Minetti, H. Howald and P.E. di Prampero (1990). Muscular exercise at high altitude. IV. Oxygen transport system before and after exposure to chronic hypoxia. Int. J. Sports Med. 11, Suppl. 1: S15-$20. Grimby, G., E. Haggendahl and B. Saltin (1967). Local xenon L33 clearance from the quadriceps muscle during exercise in man. J. Appl. Physiol. 22: 305-310. Henriksson, J. and J.S. Reitmann (1977). Time course of changes in human skeletal muscle succinate dehydrogenase and cytochrome oxidase activities and maximal oxygen uptake with physical activity and inactivity. Acta Physiol. Scand. 99: 91-97. Hoppeler, H., H. Howald, K. Conley, S.L. Lindstedt, H. Claassen, P. Vock and E.R. Weibel (1985). Endurance training in humans: aerobic capacity and structure of skeletal muscle. J. Appl. Physiol. 59: 320-327. Hoppeler, H., E. Kleinert, C. Schlegel, H. Claassen, H. Howald, S.R. Kayar and P. Cerretelli (1990). Muscular exercise at high altitude. II. Morphological adaptations of human skeletal muscle to chronic hypoxia. Int. J. Sports Med. 11 Suppl. 1 : $3-$9. Howald, H., D. Pette, J.A. Simoneau, A. Uber, H. Hoppeler and P. Cerretelli (1990). Muscular exercise at high altitude. III. Effects of chronic hypoxia on muscle enzyme activities. Int. J. SportsMed. 11 Suppl. 1 : S10-S14. Ingjer, F. (1979). Effect of endurance training on muscle fibre ATP-ase activity, capillary supply and mitochondrial content in man. J. Physiol. (London) 294: 419-432. Kaijser, L. (1970). Limiting factors for aerobic muscle performance. Acta Physiol. Scand. Suppl. 346: 1-96. Kanstrup, I. L. and B. Ekblom (1982). Acute hypervolemia, cardiac performance, and aerobic power during exercise. J. Appl. Physiol. 52:1186-1191. McArdle, W.D., J. R. Magel, G.R. Lesmes and G. S. Pechar (1976). Metabolic and cardiovascular adjustments to work in air and water at 18, 25 and 33 °C. J. Appl. Physiol. 40: 85-90. Piiper, J. and P. Scheid (1981). Model for capillary-alveolar equilibration with special reference to 02 uptake in hypoxia. Respir. Physiol. 46: 193-208. Piiper, J. (1990). Unequal distribution of blood flow in exercising muscle of the dog. Respir. Physiol. 80: 129-136. Rowell, L. B. (1962). Factors affecting the prediction of the maximal oxygen intake from measurements made during submaximal work. Ph.D. Thesis, University of Minnesota. Rowell, L.B., H.J. Marx, R.A. Bruce, R.D. Conn and F. Kusumi (1966). Reductions in cardiac output, central blood volume and stroke volume with thermal stress in normal man during exercise. J. Clin. Invest. 45: 1801-1816. Saltin, B., C.G. Blomqvist, R.C. Mitchell, R.L. Johnson, K. Wildenthal and C.B. Chapman (1968a). Response to exercise after bed rest and after training. Circulation 38 (Suppl. 7): 1-78. Saltin, B,, R.F. Grover, C.G. Blomqvist, L.H. Hartley and R.L. Johnson Jr. (1968b). Maximal oxygen uptake and cardiac output after 2 weeks at 4300 m. J. Appl. Physiol. 25: 400-409. Shephard, R.J. (1969). A non-linear solution of the oxygen conductance equation: applications to performance at sea level and at an altitude of 7,350 ft. Int. Z. angew. Physiol. 27: 212-225. West, J. B. (1983). Climbing Mount Everest without oxygen: an analysis of maximal exercise during extreme hypoxia. Respir. Physiol. 52: 265-279. Woodson, R. D., R. E. Wills and C. Lenfant (1978). Effect of acute and established anemia on 02 transport at rest, submaximal and maximal work. J. Appl. Physiol. 44: 36-43.
