We have previously predicted that the decrease in maximal oxygen uptake (V̇o2max) that accompanies time in microgravity reflects decrements in both convective and diffusive O2 transport to the mitochondria of the contracting myocytes. The aim of this investigation was therefore to quantify the relative changes in convective O2 transport (Q̇o2) and O2 diffusing capacity (Do2) following long-duration spaceflight. In nine astronauts, resting hemoglobin concentration ([Hb]), V̇o2max, maximal cardiac output (Q̇Tmax), and differences in arterial and venous O2 contents (-) were obtained retrospectively for International Space Station Increments 19–33 (April 2009–November 2012). Q̇o2 and Do2 were calculated from these variables via integration of Fick’s Principle of Mass Conservation and Fick’s Law of Diffusion. V̇o2max significantly decreased from pre- to postflight (−53.9 ± 45.5%, P = 0.008). The significant decrease in Q̇Tmax (−7.8 ± 9.1%, P = 0.05), despite an unchanged [Hb], resulted in a significantly decreased Q̇o2 (−11.4 ± 10.5%, P = 0.02). Do2 significantly decreased from pre- to postflight by −27.5 ± 24.5% (P = 0.04), as did the peak - (−9.2 ± 7.5%, P = 0.007). With the use of linear regression analysis, changes in V̇o2max were significantly correlated with changes in Do2 (R2 = 0.47; P = 0.04). These data suggest that spaceflight decreases both convective and diffusive O2 transport. These results have practical implications for future long-duration space missions and highlight the need to resolve the specific mechanisms underlying these spaceflight-induced changes along the O2 transport pathway.
NEW & NOTEWORTHY Long-duration spaceflight elicited a significant decrease in maximal oxygen uptake. Given the adverse physiological adaptations to microgravity along the O2 transport pathway that have been reported, an integrative approach to the determinants of postflight maximal oxygen uptake is needed. We demonstrate that both convective and diffusive oxygen transport are decreased following ~6 mo International Space Station missions.
- maximal oxygen uptake
The physiological adaptations to spaceflight have been well documented since the early Gemini and Apollo missions (42). Of these, exercise capacity, specifically maximal oxygen uptake (V̇o2max), a measurement of integrative cardiorespiratory function, has been shown to be decreased immediately upon return to Earth (34, 41, 61). Additionally, the rate at which V̇o2max decreases and the physiological mechanisms mediating its decline may be dependent on the duration of microgravity exposure (2, 26).
Traditionally, decreases in V̇o2max following a period of microgravity exposure have been attributed primarily to “central” limitations associated with decreases in cardiac output (9, 13, 33, 34) and blood volume (30). As such, a significant relationship exists between the decrease in V̇o2max and the decrease in plasma volume following bed rest durations of <30 days (15). This, coupled with the reported minor changes in maximal difference between arterial and venous O2 contents (-), supported the assumption that “peripheral” factors do not significantly contribute to the decrease in postflight V̇o2max (33, 34). However, we and others have proposed that the decrease in V̇o2max postflight is a consequence of both central and peripheral limitations to O2 transport (2, 26). Specifically, we predicted through retrospective analysis of long-duration bed rest studies that, along with decreases in convective O2 transport (Q̇o2), a large decrease in O2 diffusing capacity (Do2) also contributes to decreases in V̇o2max (2). This hypothesis is further supported in part by the observed decreases in maximal muscle microvascular deoxygenation following 35 days bed rest (49, 56), and best rest induced structural changes within skeletal muscle microcirculation (25).
However, the studies reporting both significant decreases in V̇o2max and altered central and peripheral cardiovascular function during exercise have only involved microgravity or bed rest durations <90 days. The mission durations for the International Space Station have ranged between 60 and 199 days since the year 2000; therefore, our understanding of the determinants of V̇o2max for current and future long-duration spaceflight missions is limited.
Whereas V̇o2max provides an index of integrated cardiovascular function, it is also strongly associated with simulated extravehicular activity performance (3, 4). Given the adverse physiological adaptations to microgravity along the O2 transport pathway that have been reported, an integrative approach to the determinants of postflight V̇o2max is needed. This type of information will aid in the continued development of effective countermeasures aimed at both astronaut cardiovascular health and mission success. The primary aim of the present investigation was to expand our previous work (2) and evaluate the relative changes in the two components of O2 transport (Q̇o2 and Do2) and in V̇o2max after prolonged spaceflight aboard the International Space Station. We hypothesized that long-duration spaceflight would decrease Q̇o2, Do2, and V̇o2max.
Pre- and postflight data for 14 astronauts were retrospectively obtained for International Space Station Increments 19–33 (April 2009–November 2012) from the National Aeronautics and Space Administration (NASA) Lifetime Surveillance of Astronaut Health and Life Sciences Data Archive (41). Of the initial 14, individual data from 9 astronauts (4 women, 5 men; age, 49.5 ± 5.1 yr) contained the required variables and met the V̇o2max criteria for inclusion in the present study analysis (see Experimental procedures). Before flight, each astronaut was judged healthy and physically fit for spaceflight following a medical exam completed by qualified NASA personnel. Each astronaut provided written informed consent before participation in the study, which was approved by the Institutional Review Board at the NASA Johnson Space Center (NASA JSC, Houston, TX). In flight, each astronaut was prescribed an aerobic and resistance training regimen by NASA Astronaut Strength, Conditioning, and Rehabilitation specialists and personnel of the NASA Exercise Physiology Laboratory. Moderate- and high-intensity aerobic exercise (cycle + treadmill) was prescribed for 4–6 days/wk while upper and lower-body resistance training was prescribed 6 days/wk.
All experimental tests were performed in a temperature-controlled laboratory maintained between 20 and 23°C. Each astronaut performed an initial familiarization exercise test ~9 mo before flight on a cycle ergometer using a 3-min incremental protocol at 50, 75, and 100 W or 50, 100, and 150 W, depending on the astronaut’s body weight and self-reported level of physical activity, followed by 25-W increments every 1 min to exhaustion. This initial test was used to determine the individualized submaximal power levels to be used for subsequent exercise tests. Ninety days before launch (L-90) participants performed an experiment-specific incremental exercise test consisting of a 2-min rest period, three continuous 5-min submaximal power levels prescribed to elicit 25, 50, and 75% of the previously measured V̇o2max, followed by 1-min increments of 25 W until exhaustion. All tests were performed during upright cycle ergometry on an electronically braked ergometer (Lode Excalibur Sport, Groningen, The Netherlands). This incremental exercise test protocol facilitated the measurement of steady-state cardiorespiratory variables at various submaximal power levels and at peak exercise. A similar exercise protocol has previously been used in this population following NASA shuttle missions (34, 41) and the NASA Skylab missions (39). In all instances, the L-90 test was performed at the Exercise Physiology Laboratory at NASA JSC. The same incremental exercise test was performed 2 days after returning to Earth (R+2). Because of the variations in the locations of crew return, the R+2 tests were conducted in laboratory facilities located at either NASA JSC, The Gagarin Cosmonaut Training Center in Star City, Russia, or at the Kennedy Space Center in Titusville, FL.
Metabolic and ventilatory (V̇o2, V̇co2, and V̇e) data were continuously measured using a portable pulmonary function system (PPFS; Danish Aerospace, Odense, Denmark) and averaged over the last 60 s of each workload. The 60-s mean average for V̇o2 preceding exhaustion was considered V̇o2max if there was a lack of heart rate (HR) increase between the last two successive power levels (ΕHR <10 beats/min), the respiratory exchange ratio was >1.05, and the postflight maximal HR (HRmax) was within 95% of the preflight HRmax.
Cardiac output (Q̇T) was determined from pulmonary blood flow at rest and workloads corresponding to 25 and 50% V̇o2max via a noninvasive rebreathing technique [PPFS; Danish Aerospace (7)]. Briefly, during the last minute of seated rest and during the last minute of each of the first two exercise stages, the subjects rebreathed in a bag containing 2.0–4.0 liters (depending on power level and tidal volume) of a gas comprised of 1.0% freon-22, 1.0% SF6, 40% O2, and 58% N2. The rebreathing period lasted ~20–25 s during rest and 15–25 s during exercise (5–6 breaths). The disappearance rate of freon-22 was measured by an infrared photoacoustic gas analyzer and used to determine pulmonary blood flow. This system was used, since it is identical to the PPFS used aboard the International Space Station and has previously been used to measure Q̇T in astronauts during and following long-duration spaceflight (43, 44). This rebreathing technique using foreign gases with an infrared photoacoustic gas analyzer has previously been validated against the direct Fick and thermodiluation techniques (28). In addition, breathing frequency and rebreathing volume have been shown not to significantly alter the measurement (21). Similar rebreathing protocols to measure Q̇T have been used following long-duration bed rest (13, 25). The Q̇T-V̇o2 relationship was determined for each participant for each test via linear regression and extrapolated to V̇o2max to calculate the Q̇T at exhaustion (Q̇Tmax) (1). The regression equation was used rather than a single measurement of Q̇T at maximal exercise. This was because of technical issues such as correct timing of the procedure at maximal exercise and the hypercapnic stimulus induced during rebreathing potentially eliciting early test termination. Hemoglobin concentration ([Hb]) and hematocrit values were measured from venous blood samples and analyzed at L-90 and R+2.
The differences in arterial and venous O2 contents were calculated via Fick’s Principle of Mass Conservation, V̇o2 = Q̇T × ( – ), where, and represent arterial and venous O2 contents, respectively. Currently, arterial blood gases or O2 saturation are not part of NASA’s postspaceflight exercise protocol. Ferretti et al. (25) and Capelli et al. (13) have demonstrated that an arterial saturation () at V̇o2max before and following 42 and 90 days of bed rest can vary between 96 and 98% but does not change following bed rest. Therefore, with the use of data from these previous investigations, of 96% was used as a reference value. Because this assumption may introduce error, the effect of other values for SaO2 (94, 96, and 98%) on the below calculations was also explored. These values seem justified in light of work that demonstrates both increases and decreases in pulmonary carbon monoxide-diffusing capacity following spaceflight (50, 51, 62) coupled with no change in at V̇o2max following bed rest (13, 25). was calculated using the direct measurement of [Hb], an of 96%, and an O2 carrying capacity of 1.34 ml O2·g·Hb−1. Mixed venous Po2 () was calculated by rearranging Fick’s Principle of Mass Conservation and a modification of Hill’s equation based on the human blood O2 dissociation curve as previously described (2, 57, 63) assuming a pH of 7.2 and a venous blood temperature of 39°C. This is based on data from Ferretti et al. (25) who report an arterialized blood pH of ~7.2 that is unchanged following 42 days bed rest. However, because any variation in the decrease in pH and increased temperature of the mixed venous blood during maximal exercise would alter the rightward shift in the O2 dissociation curve, the effect of other values for pH (7.3, 7.2, and 7.1) and temperature (38–40) was also used to calculate . To further determine the sensitivity of estimating , pH, and temperature on the calculation of , a sensitivity index was calculated for each estimated parameter as previously described (31). A sensitivity index of 1.0 suggests that the calculated was completely sensitive to changes in the values of the parameter, whereas an index of <0.01 indicates that was relatively insensitive to parameter changes.
In healthy and diseased populations, Wagner and colleagues (24, 47, 53, 63) have advanced the concept that V̇o2max is not determined by one independent variable but rather the integration of steps along the O2 transport pathway. Q̇o2was calculated as:
Do2 can be mathematically described with Fick’s Law of Diffusion, V̇o2 = Do2 × ( − ), where and represent mean capillary and mitochondria Po2, respectively. Because at maximal exercise is proportional to (54) and is ~1–3 Torr (29, 52) and therefore can be assumed to be zero and omitted, a simplification of Fick’s Law of Diffusion can be derived, where V̇o2 = Do2 × k × (63, 64). From this derivation, Do2 can be calculated as the ratio of V̇o2max to (24, 63). While traditionally the calculation of Do2 has required exercise in normoxia and hypoxia (54), several recent investigations have calculated Do2 from during a single exercise test with ambient air in a similar manner as the present study (23, 37, 59). The calculations of Do2 in the present study are consistent with these previous investigations.
All statistical analyses were performed using a commercially available software package (SigmaPlot and SigmaStat; Systat Software, Point Richmond, CA). Preflight and postflight comparisons for V̇o2max, Q̇Tmax, [Hb], Q̇o2, -, and Do2 were made using Student’s paired t-tests. Linear regression analyses were used to assess the relationships among V̇o2max and Do2, Q̇o2, and -. All data are expressed as means ± SD, unless otherwise noted. Statistical significance was declared at P < 0.05.
The physical characteristics of the nine astronauts are summarized in Table 1. The mean flight duration was 168.6 ± 19.2 days. V̇o2max and peak power output, obtained by graded maximal cycle exercise, were 16 and 15% lower postflight compared with preflight, respectively (Table 1 and Fig. 1). There were no significant differences in HRmax, VEmax, or RERmax between preflight and postflight. Postflight [Hb] was not significantly different compared with preflight. Postflight Q̇Tmax was significantly decreased 7% compared with preflight. The significantly decreased Q̇Tmax, but unchanged [Hb], resulted in a significantly decreased Q̇o2 (Table 1). The dependence of Q̇o2 on estimates of is demonstrated in Table 2 and had a sensitivity index of 0.45. Across the range of reported in the literature following spaceflight and long-duration bedrest, a significant decrease in the estimated Q̇o2 consistently occurred postflight. Postflight, Do2 was significantly decreased compared with preflight. Because the calculation of and subsequent Do2 was dependent on estimates of venous blood pH and temperature, which would alter the O2 dissociation curve, a sensitivity analysis was performed (Table 2). Venous blood pH and temperature had sensitivity indexes of 0.09 and 0.05, respectively. Although the absolute values of Do2 were altered, a significant decrease in Do2 postflight remained in all conditions. -, a variable that is altered by changes in both convective and diffusive O2 transport, was significantly lower postflight than preflight. Figure 2 shows that the change in V̇o2max following long-duration spaceflight was positively and strongly associated with the change in Do2 (R2 = 0.47; P = 0.04). There were no significant associations observed between the change in V̇o2max and the change in Q̇o2 or - (P > 0.05).
The purpose of this investigation was to evaluate the relative changes in the convective (Q̇o2) and diffusive (Do2) components of O2 transport at V̇o2max following long-duration spaceflight. This study has several important findings. First, V̇o2max, Q̇o2, and Do2 all decreased following ~6 mo International Space Station missions. Second, the decreased V̇o2max postflight was associated with the decrease in Do2. These findings support our hypothesis that spaceflight decreases both convective and diffusive oxygen transport pathways, which interact to decrease postflight V̇o2max.
Changes in V̇o2max.
The decrease in V̇o2max after spaceflight was similar to previous studies investigating the effects of spaceflight exposure. Moore et al. (41) observed a similar decrease in V̇o2max in a study that used many of the same subjects as those in the current report. Likewise, Trappe et al. (61) reported a 10.4% decrease in V̇o2max following a 17-day shuttle mission, whereas Levine et al. (34) reported an ~22% decrease following 9- and 14-day Spacelab Life Science flights. The similar magnitude of decrease in V̇o2max between these studies and the present investigation despite different flight durations highlights that these changes in aerobic exercise capacity reflect living and working in space (i.e., countermeasure activity, diet, and mission objectives) in addition to the duration of weightlessness. Therefore, while the present study supports the previously reported decrease in V̇o2max following spaceflight, direct comparisons between missions should be done with caution.
The 15% decrease in V̇o2max in the present study suggests that V̇o2max does not decrease linearly at a rate of 1%/day as is the case in the 1st mo of bed rest (16). This is congruent with the hypothesis that the relationship between V̇o2max and microgravity duration is nonlinear, with the decrease in V̇o2max reaching an asymptote within a period of several weeks (2, 26). Simulated microgravity studies using the −6 head-down tilt bed rest model without exercise countermeasures report decreases in V̇o2max of between 4 and 15% within 10 days (14, 17, 18, 20, 33), resulting in an ~1% decrease in V̇o2max per day in microgravity (16). However, when the duration is extended, the rate at which V̇o2max decreases is slowed. Capelli et al. (13) reported that the rate of decrease in V̇o2max is 0.99%/day following 14 days bed rest but 0.35%/day following 90 days bed rest. In the present investigation, the average rate at which V̇o2max decreased was ~0.1%/day and suggests that our duration of microgravity coupled with exercise countermeasures altered the rate at which V̇o2max decreases compared with previous bed rest investigations. Additionally, the rate of decline may not be constant across the flight duration. Moore et al. (41) suggest that the majority of the decline in V̇o2max occurs in the 1st mo of flight, and then a slow recovery may occur in orbit, all of which may be dependent on the interaction between countermeasure effectiveness and the rate of change, as well as preflight aerobic capacity.
Contribution of diffusive O2 transport in limiting postflight V̇o2max.
The interaction between convective and diffusive O2 transport in determining the changes in V̇o2max postfight is shown in Fig. 3. The curved line represents the convective component of O2 movement described with Fick’s Principle of Mass Conservation (V̇o2 = Q̇T × [ – ]), and the straight line represents the diffusive component described with Fick’s Law of Diffusion (V̇o2 = Do2 × ), with the point of intersection representing the common V̇o2max. If the postflight V̇o2max decreased only because of decreases in convective O2 transport (reduced Q̇o2), V̇o2max would have decreased from A to B. However, the present study revealed a significantly decreased diffusive O2 transport (decreased Do2) in addition to the decreased convective O2 transport. This combined action resulted in a greater decrease in V̇o2max (from A to C). This decrease in Do2 combined with the decreased - provides important insight in the limits imposed by O2 transport in the postflight astronaut. Changes in - are a consequence of alterations in both convective and diffusive O2 transport, such that O2 extraction = 1 – where β is the linear approximation to the slope of the O2 dissociation curve (47, 53, 64). Thus, changes in - rely on changes in the ratio of Do2 to Q̇T such that a similar decrease in Q̇T and Do2 will result in a relatively unchanged O2 extraction, similar to that reported in several studies after short-duration microgravity exposure. However, in the present study, O2 extraction decreased, suggesting a greater relative decrease in Do2 compared with Q̇o2 for a given decrease in V̇o2max. This may be due in part to the immediate postflight countermeasures and the rapid postflight return of circulating plasma volume (R+2), which serve to increase Q̇T (see below).
Changes in Q̇o2.
Decreases in central cardiovascular function have consistently been reported following spaceflight and bed rest. Gemini and Apollo missions revealed that cardiac function is altered by microgravity, and the early 28–84 Skylab mission supported these findings by reporting decreases in postflight stroke volume (11, 42). Similarly Levine et al. (34) reported a 24% decrease in maximal stroke volume, but no change in maximal heart rate, resulting in a significant decrease in maximal cardiac output following short-duration spaceflight. However, unlike the subjects of the present investigation, which experienced an ~5% decrease in Q̇Tmax following long-duration spaceflight, the astronauts tested by Levine et al. (34) performed no regular inflight exercise training, which may have contributed to the different degree of Q̇T decrease between studies.
The mechanisms that underlie reductions in Q̇T following prolonged spaceflight represent the combination of several factors that include reductions in cardiac filling via decreases in circulating blood volume and decreases in left ventricular volume and mass. Changes in blood volume can have a profound impact on resting and exercising stroke volume and cardiac output (45). Evidence of this relationship can be observed following periods of microgravity exposure in which blood volume is decreased. Shibata et al. (58) observed a significant decrease in resting stroke volume and cardiac output following 18 days bed rest that was increased back to baseline values following a restored plasma volume and ventricular filling pressure via intravenous dextran infusions. Similarly, others have shown that, during upright exercise following 35 days bed rest, Q̇Tmax was lower than before bed rest, but unchanged during supine exercise, presumably when ventricular filling pressure was maintained (9).
In addition, the rate at which blood volume is restored in the days following microgravity exposure could play an important role in determining Q̇T postflight. Following 60 days bed rest, Westby et al. (66) demonstrated within 3 days following the bed rest period plasma volume and resting stroke volume were not different compared with baseline. However, left ventricular mass remained significantly lower. These findings highlight that the standard rehydration strategies and recovery of blood volume can impact the changes in Q̇Tmax observed in the initial few days postflight (12). Because the astronauts of the present study were measured 2 days postflight, it is likely that decreases in cardiac mass, not blood volume, played the primary role in mediating the ~5% decreased Q̇Tmax. Therefore, postflight rehydration strategies and the small sample size may have also contributed to our inability to detect a significant correlation between the change in V̇o2max and Q̇o2. Had the measurements been performed within hours of landing, the changes in Q̇Tmax and subsequent V̇o2max may have been greater in magnitude.
In addition to Q̇Tmax, and [Hb] determine Q̇o2. Changes, or lack thereof, in have been consistently reported following microgravity exposure. Following 14-, 42-, and 90-day bed rest periods, at V̇o2max remained above 97% (13). This is due in part to the minor changes in lung function following microgravity exposure (40, 50). Unlike , the potential for [Hb] to be changed postflight is greater. Microgravity results in a decreased red cell mass and decreased plasma volume that interact to set [Hb] (5, 19). Following bed rest, [Hb] has been shown to both significantly increase or decrease (9, 13, 27). However, in the present study, no difference in [Hb] was observed postflight, highlighting the conclusion that decreases in postflight Q̇o2 were primarily mediated by changes in Q̇Tmax, not [Hb].
Changes in Do2.
Previous conclusions that the decrease in V̇o2max following microgravity is due entirely to decreases in Q̇o2 have been supported by an unchanged - postflight (33, 34). However, this may only be the case following short-duration flight. We and others have proposed that the peripheral limitations to O2 movement and utilization may have a greater impact on V̇o2max as the spaceflight duration increases (2, 13, 15, 25, 26). This point is reinforced by the 9 and 36% decrease in the - and Do2 observed in the present study. Similarly, - calculated from the reported mean V̇o2max and Q̇Tmax by Capelli et al. (13) suggests an ~13% decrease following 90 days bed rest. These authors also revealed that the fractional limitation resulting from peripheral (muscular) factors, which reflects the resistance imposed by O2 diffusion limitations and mitochondrial respiration (i.e., 1/Do2), contributed to ~41% of the limitation to V̇o2max following bed rest. Recently, Wager (65) performed a reanalysis of a short-duration bed rest study to determine the relative contributions of convective and diffusive O2 transport on the decrease in V̇o2max. Reanalysis revealed that 20 days bed rest resulted in a significant 22% decrease in Do2. These findings, coupled with the findings of the present study, further reinforce the hypothesis that O2 diffusing capacity is reduced following long-duration spaceflight.
The potential mechanisms driving changes in Do2 following prolonged spaceflight have previously been reviewed by our group (2). Briefly, examination of Fick’s first Law of Diffusion reveals that diffusion of a gas, like oxygen, across a membrane is determined by 1) surface area, 2) membrane thickness (i.e., diffusion distance), 3) the partial pressure gradient across the membrane, and 4) the physical properties of the gas. Because intramyocyte Po2 is uniformly very low (<3 Torr) during muscular contraction (32), the available evidence suggests that the red blood cell-to-capillary surface area, which is dependent on capillary hematocrit and capillary density/volume, is the primary determinant of muscle Do2 [for review see Poole et al. (46, 48)]. As such, following aerobic exercise training, capillary-to-muscle surface area and capillary hematocrit significantly contribute to increases in Do2 (8), thus suggesting that a similar mechanism might explain the decreased Do2 observed in the present study following spaceflight. Interestingly, several studies report an unchanged skeletal muscle capillary density and capillary-to-fiber ratio following microgravity exposure, which would suggest an unaltered surface area and subsequent Do2. However, although the number of capillaries per fiber sets the upper limit for diffusion, it is most likely the number (i.e., capillary hematocrit) and velocity of red blood cells within the capillary that ultimately set diffusion surface area (46, 48) and contribute to Do2 in the postflight astronaut. When generalized to the long-duration astronaut, it seems likely that alterations in microcirculatory dynamics occur during exercise, which ultimately leads to a decrease in Do2 postflight relative to preflight. Unfortunately, no study to date has investigated the microvascular red blood cell dynamics following bed rest or spaceflight. Future work is needed to confirm the underlying mechanism that determines the Do2 in the long-duration astronaut.
Supporting the decreased Do2 reported in the present study are measurements of muscle deoxygenated hemoglobin + myoglobin ([HHb]) during exercise via noninvasive near-infrared spectroscopy. The [HHb] signal is determined by the dynamic balance between O2 delivery-to-O2 utilization, Do2, and intracellular oxidative metabolism, which in total provides insight in microvascular and tissue O2 movement. Following 35 days of head-down tilt bed rest, Porcelli et al. (49) and Salvadego et al. (56) report a significantly decreased peak deoxygenated [hemoglobin + myoglobin] measured via near-infrared spectroscopy in the vastus lateralis during incremental cycling and knee extension exercise, respectively. These findings of altered microvascular tissue deoxygenation during exercise support the decreased Do2 reported in the present study and the increased fractional limitation to O2 movement imposed by peripheral (muscular) factors reported by others (13).
Additional possible mechanisms, independent of changes in Do2, could have also altered postflight. As with previous investigations evaluating Do2 during exercise (59), in the present analysis it was assumed that no perfusion/metabolism inhomogeneity existed postflight, that the majority of the available Q̇T was distributed to the metabolically active muscle, and that postflight distribution of Q̇T was similar to preflight. Currently, no investigations have evaluated the distribution of Q̇T during exercise following a period of microgravity exposure in humans. However, McDonald et al. have done extensive work in the rat using a hindlimb unloading (HU) protocol (35, 36). They demonstrated that post-15 days HU, bulk exercise hindlimb blood flow was not significantly different compared with premeasurements (35, 36). However, the distribution of the available Q̇T was altered such that exercise blood flow to the splanchnic region and kidneys was increased compared with pre-HU. These alterations in the distribution of Q̇T during exercise may be because of changes in autonomic reflexes and vasoconstrictor responsiveness. For example, following 14 days of bed rest, human forearm vasoconstrictor responses to a cold pressor test are decreased. Additionally, arterioles from rat type IIb skeletal muscle exposed to 2 wk HU have a significantly decreased vasoconstrictor responsiveness to KCl. These previous investigations in total highlight the possibility that an impaired redistribution of Q̇Tmax could have impacted both convective O2 delivery to the muscle and . Therefore, the decreased Do2 reported in the present investigation should be interpreted with caution, since it is currently unclear how much impact variations in microvascular O2 diffusion vs. Q̇Tmax distribution have on postflight measurements of . Unfortunately, no study to our knowledge has been conducted evaluating the complex interaction between decreases in cardiac mass, changes in Do2, and the potential influences that Q̇Tmax distribution, via altered vasomotor responsiveness and autonomic reflexes, have on O2 movement during exercise and their role in determining V̇o2max.
Several methodological considerations are relevant to the interpretation of the present investigation. First, we used a noninvasive rebreathing technique to measure Q̇T in each astronaut during submaximal exercise and used linear regression to obtain an estimate of Q̇Tmax. We chose not to directly measure Q̇Tmax using the rebreathing procedure at exhaustion to minimize any effect the rebreathing may have on the subject’s normal breathing pattern and test termination. This strategy has previously been used to obtain measurements of Q̇Tmax (1). Additionally, several reports to date have validated this noninvasive rebreathing technique (28). In the present study, the relationship between Q̇T and pulmonary V̇o2 was linear and followed the established relationship [Q̇T ≈ 5–6 + 5–6 × V̇o2 (6)] both preflight (Q̇T = 5.1 + 5.0 × V̇o2) and postflight (Q̇T = 5.9 + 3.8 × V̇o2). Therefore, our calculation of Q̇Tmax is supported by previous validation studies (28) and is consistent with known physiological relationships (6). Second, the calculations of Do2 are based on whole body measurements of V̇o2, Q̇T, and calculated from the Fick principle. The use of Q̇Tmax and not muscle blood flow, which is lower than Q̇Tmax, suggests that our calculation of Do2 may have been overestimated. Whereas an approximation of muscle blood flow could have been applied, we used an established approach similar to Simonson et al. (59) and report the more transparent whole body estimate of Do2. In addition, the simplification of Fick’s Law of Diffusion used in the present analysis, like that in previous studies (23, 59), assumes linear proportionality between and [which has previously been demonstrated experimentally (54)]. This assumption may have introduced variability given that is systematically higher than (54), which would alter the accuracy of the absolute calculations of Do2. Currently, there is a great paucity of actual information in the literature with which to consider or model the arteriolar-capillary-venular system even at rest (so as to determine this relationship), with almost no information regarding changes with exercise or increased blood flow (22). We recognize that this assumption is vital for being able to simultaneously equate the two Fick equations through a common Po2, but given that the same calculations and simplifications were used pre- and postflight the relative changes should be robust even if the absolute values contain systematic errors.
In the present study’s analysis to estimate Do2, simplifying assumptions at various steps used in the convection-diffusion partition may have resulted in systematic errors. These assumptions therefore may have led to either the underestimation or overestimation of Do2. The fractional error for the estimated , pH, and temperature was between 0.05 and 2.0% (60). The fractional error for the extrapolated Q̇Tmax, using the 95% confidence intervals, was 9.9 and 11% pre- and postflight, respectively. This resulted in an absolute cumulative error in the estimation of Do2 of ±16.5 ml·min−1·mmHg−1 preflight and ±10.6 ml·min−1·mmHg−1 postflight (60), which are substantially less than the difference in the mean pre- and postflight Do2. To further validate the assumptions used in the present study’s analysis of Do2, the V̇o2max, submaximal Q̇T, and hemoglobin from the original Saltin et al. (38, 55) Dallas bed rest study were used to estimated Do2 and then compared with the Do2 calculated by Wagner (65) who used the measured Q̇Tmax and blood O2 transport values obtained via direct arterial blood gas analysis. With the use of the same assumptions as the present study, the estimated Do2 was ~18% of that obtained via Wagner’s (65) analysis. If 18% is the estimated error introduced by our assumptions, it remains substantially less than the 70% difference we observed between pre- and postflight Do2. This suggests that, while the simplifying assumptions used in the present study introduced error in the estimated Do2, the cumulative error was small and did not impact the primary conclusion that postflight Do2 is decreased compared with preflight.
Perspectives and Significance
Following long-duration spaceflight, astronauts exhibit a decreased aerobic exercise capacity, cardiac output, and O2 diffusional conductance. These results have key important practical implications for future long-duration space missions. First, they highlight the continued need to resolve the specific factors underlying spaceflight-induced central and peripheral alterations along the O2 transport pathway. This information is crucial for maintaining astronaut health in flight most effectively, given that the current in-flight countermeasures may not adequately prevent the decrease in either Q̇T or Do2. Second, these findings suggest that other parameters of exercise capacity that are determined by convective and diffusive O2 transport may also be severely compromised (10). This is essential given that the submaximal parameters of critical speed and power are associated with simulated extravehicular activity performance (3, 4). In conclusion, the relative changes in Q̇T, Q̇o2, and Do2 provide insight in the adaptations along the O2 transport pathway and how they may contribute to changes in V̇o2max in the long-duration postflight astronaut.
This study was supported by the National Aeronautics and Space Administration (NASA) research grant NNX10AK60G and NNX16AF66A awarded to C.J. Ade and T.J. Barstow.
No conflicts of interest, financial or otherwise, are declared by the authors.
C.J.A., R.M.B., A.M., and T.J.B. conception and design of research; C.J.A. analyzed data; C.J.A. interpreted results of experiments; C.J.A. prepared figures; C.J.A. drafted manuscript; C.J.A. and T.J.B. edited and revised manuscript; C.J.A., R.M.B., A.M., and T.J.B. approved final version of manuscript; A.M. performed experiments.
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