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WISE-2005: Exercise and Nutrition Countermeasures for Upright V˙O2pk during Bed Rest


Medicine & Science in Sports & Exercise: December 2009 - Volume 41 - Issue 12 - p 2165-2176
doi: 10.1249/MSS.0b013e3181aa04e5
Basic Sciences

Purpose: Exercise prescriptions for spaceflight include aerobic and resistive countermeasures, yet few studies have evaluated their combined effects on exercise responses after real or simulated microgravity. We hypothesized that upright aerobic capacity (V˙O2pk) is protected during a 60-d bed rest (BR) in which intermittent (40%-80% pre-BR V˙O2pk) aerobic exercise (supine treadmill exercise against lower body negative pressure) was performed 2-4 d·wk−1 and resistive exercise (inertial flywheel exercises) was performed 2-3 d·wk−1. Further, we hypothesized that ingestion of an amino acid supplement that was shown previously to counteract muscle atrophy, would reduce the decline in V˙O2pk in nonexercising subjects during BR.

Methods: Twenty-four healthy women (8 nonexercise controls (CON), 8 exercisers (EX), and 8 nonexercisers with nutritional supplementation (NUT)) underwent a 20-d ambulatory baseline period, 60 d of 6° head-down tilt BR, and 21 d of ambulatory recovery. V˙O2pk was measured pre-BR and on the third day of recovery from BR (R3).

Results: In the EX group, V˙O2pk (mean ± SE) was not different from pre-BR (−3.3 ± 1.2%) on R3, although it decreased significantly in the CON (−21.2 ± 2.1%) and NUT (−25.6 ± 1.6%) groups.

Conclusions: These results indicate that alternating aerobic and resistive exercise on most days during prolonged microgravity simulated by BR is sufficient to preserve or allow quick recovery of upright aerobic capacity in women but that a nutritional supplementation alone is not effective.

1University of New Mexico, Albuquerque, NM; 2Cardiovascular Laboratory, Wyle Integrated Science and Engineering Group, Houston, TX; 3University of California, San Diego, CA; and 4University of North Texas Health Science Center, Fort Worth, TX

Address for correspondence: Suzanne M. Schneider, Ph.D., Department of Health, Exercise and Sports Sciences, University of New Mexico, MSC 04 2610, Albuquerque, NM 87131-0001; E-mail:

Submitted for publication December 2008.

Accepted for publication April 2009.

During prolonged spaceflight, exercise countermeasures are used to maintain crew health and fitness and to ensure adequate physical capacity for extravehicular activity, planetary exploration, and emergency egress. Traditionally, aerobic countermeasures have been emphasized to maintain cardiorespiratory function. More recently, a resistive exercise device has been tested and flown on the International Space Station to help preserve muscle mass and function (33). The type and amount of exercise required to preserve functional capacity during prolonged spaceflight has not been defined but most likely will involve more than one exercise modality. As on Earth, high-intensity aerobic exercise may be necessary to maintain aerobic capacity (V˙O2pk) and exercise endurance while resistive exercise may be necessary to maintain muscle mass and strength.

A particular challenge after microgravity exposure is to maintain upright aerobic capacity, where the decline in V˙O2pk is much larger when exercise is performed in an upright position compared with supine (12). Recently, we have shown that exercise performed against lower body negative pressure (LBNP/ex) for 40 min, 6 d·wk−1, is an effective means to maintain upright, running V˙O2pk after 5, 15, or 30 d of BR (27,28,41). We have proposed this countermeasure for a long-duration spaceflight, but we have not determined the minimum frequency of exercise needed nor have we performed a BR study where a resistive exercise countermeasure was also performed. An inertial flywheel resistive exercise countermeasure has been evaluated in several BR studies, and it was found to maintain thigh muscle mass and strength and to counteract decrements in the calf plantarflexors (1,2). This countermeasure has not been evaluated in subjects who also performed an aerobic exercise countermeasure during BR.

Poor nutrition has been associated with decreased protein synthesis and decreased lean tissue mass (LTM) during short- (36) and long-duration spaceflights (34). This decrease of LTM may contribute to the postflight decline in V˙O2pk in several ways. First, a change in body composition with a reduction in metabolically active tissue compared with fat mass (FM) would reduce V˙O2pk (mL·kg−1·min−1). Second, decreased muscle mass and strength may directly impact the ability to perform maximal exercise. Reduced leg muscle power and endurance would result in an earlier onset of fatigue. Third, cardiac muscle atrophy has been observed after spaceflight and bed rest (BR) (32). A nutritional countermeasure may preserve cardiac mass and function (14,15) and thus reduce the decline in V˙O2pk. In ambulatory subjects, it is well established that amino acid supplements stimulate protein synthesis and increase muscle mass (8,42), and diets enriched with leucine are prescribed to prevent sarcopenia in the elderly (24,31). During BR, administration of amino acid supplements help preserve muscle protein synthesis and counteract the losses in muscle mass and strength (30,37,38). Although it is known that amino acid supplementation administered after an exercise stimulus is more effective than supplementation alone (7,25), it is important to understand the separate effect of nutritional supplementation, in the event crewmen are unable (because of health issues or equipment failure) or unwilling to perform the recommended aerobic and resistive exercise countermeasures.

The Women's International Space Simulation for Exploration (WISE-2005) was a multi-investigator project conducted to examine the effectiveness of a combined exercise countermeasure program and, separately, of nutritional supplementation. This article addresses the effectiveness of these countermeasures to preserve V˙O2pk in healthy young women during 60 d of BR. We hypothesized that V˙O2pk is protected during a 60-d BR by a moderate-intensity interval exercise protocol (supine treadmill exercise against LBNP) performed 2-4 d·wk−1 and a resistive exercise protocol (inertial flywheel exercises) performed 2-3 d·wk−1. A second purpose of this study was to examine the effectiveness of an amino acid nutritional supplement to reduce the decline in aerobic capacity. We hypothesized that nutritional supplementation, by preserving LTM and reducing the decline in leg muscle strength, partially counteracts the post-BR decrease in V˙O2pk. Other aspects of this international cooperative study will be reported elsewhere.

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Twenty-four healthy, nonsmoking, adult women volunteered to participate in this study. Before testing, subjects received written and verbal explanations of the study protocols and provided written informed consent. This aspect of the study protocol was approved by the Comité Consultatif de Protection des Personnes dans la Recherche Biomédicale, the National Aeronautics and Space Administration (NASA)-Johnson Space Center, and the University of California, San Diego institutional review boards. To be selected for this study, subjects were free from cardiovascular, pulmonary, or blood-clotting disorders, were not osteopenic (subjects were excluded if the left part of their hip or lumbar column bone mineral density T scores exceeded −1.5), had at least average aerobic fitness (as defined by American College of Sports Medicine norms), and were not orthostatically intolerant (completed a 10-min tilt test). They self-reported they were eumenorrheic and had not taken oral contraceptives for at least 2 months before the study. Medical tests performed during screening included a medical history, clinical and psychological examinations, chest x-ray, ECG, echocardiogram, Doppler examination of the lower limb veins, a head-up tilt test, a peak cycle exercise test, dual-energy x-ray absorptiometry (DXA) scans, and standard laboratory tests (hematology, blood chemistry, urine analysis).

The subjects were assigned to three groups in a balanced manner to minimize group differences in V˙O2pk (mL·kg−1·min−1; Table 1). The control group (CON, n = 8) would undergo no exercise or nutritional countermeasure during BR. The exercise group (EX, n = 8) would perform aerobic and resistive exercise countermeasures during BR. The nutrition group (NUT, n = 8) was given an amino acid nutritional supplement during BR. The three groups were similar except for the average age of the NUT group, which was 3 yr younger than the CON group.



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Overall study protocol.

Subjects were housed in the Institute for Space Physiology (MEDES) at the Hospital of Rangueil, Toulouse, France, throughout the study. The study was conducted in two "campaigns," with half the subjects from each group studied during the first campaign conducted from January to May 2005 and the remaining subjects studied during the second campaign conducted from August to December 2005.

The protocol included a 20-d ambulatory baseline period, followed by 60 d of a 6° head-down tilt BR, and 21 d of ambulatory recovery. During the BR period, subjects were monitored continuously by hospital staff using real-time video to ensure their compliance with the strict head-down tilt BR protocol. The EX group performed both aerobic (2-4 times per wk) and resistive exercises (2-3 times per week), whereas the CON and NUT groups did not exercise. The protein content in the diet of the CON and EX groups was 1 g·kg−1·d−1. In the NUT group, dietary protein content was increased to 1.45 g·kg−1·d−1 by adding 3.6 g·d−1 free leucine, 1.8 g·d−1 free isoleucine, and 1.8 g·d−1 free valine. Details of the diet and training schedule are presented in another report from this study (40).

Caloric intake and diet composition were controlled throughout the study in an effort to minimize changes in BM. Each subject received a caloric intake of 140% of their resting metabolic rate during baseline and reambulation periods and 110% of their resting metabolic rate during BR. Resting metabolic rate and FM were determined during the baseline period and every 15 d during BR by indirect calorimetry and DXA, respectively. The specific caloric intakes for CON, EX, and NUT subjects during the pre-BR, BR, and post-BR phases of this study are summarized in another report (40). Subjects refrained from alcohol and caffeine throughout the study. Sodium intake was maintained at 1.2 to 1.6 mmol·kg−1·d−1, potassium intake at 0.9 to 1.1 mmol·kg−1·d−1, calcium intake at 1 g·d−1, and phosphorus intake at 1.2 to 1.6 mmol·kg−1·d−1. The maximum liquid intake of the CON and NUT group was 60 mL·kg−1·d−1, and the maximum liquid intake for the EX group was 60 mL·kg−1·d−1 on days without training and 75 mL·kg−1·d−1 on days with exercise training. BM and caloric balance were monitored daily, and caloric intake was altered after the first 30 d of BR to adjust for any changes in BM.

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LBNP/ex training protocol.

The aerobic exercise countermeasure device used in this study was similar to that used in our previous evaluations of LBNP/ex (27-29,41). This device consisted of a large vacuum chamber in which the subjects were positioned supine to run comfortably on a vertically oriented treadmill (27,41). The subject wore a neoprene kayak waist seal that is attached to the rim of a wooden plate to seal the vacuum chamber. Interchangeable wooden plates formed different-sized apertures. The size of the opening was chosen to be approximately twice the cross-sectional area of the subject's waist. In this way, the negative pressure required to produce 1.0 body mass (BM) of footward force ranged from 48 to 55 mm Hg, where footward force was measured by a scale placed under the subject's feet during a familiarization session. Chamber pressure was reduced using a high-capacity vacuum cleaner. Controlled air leakage allowed pressure regulation and helped minimize heat accumulation in the chamber caused by the treadmill motor and the exercising subject.

EX subjects performed 40 min of exercise 2 to 4 d·wk−1 followed by 10 min of resting LBNP. Target exercise intensities for this protocol consisted of supine running/walking for 7 min at 40% of pre-BR V˙O2pk, 3 min at 60%, 2 min at 40%, 3 min at 70%, 2 min at 50%, 3 min at 80%, 2 min at 60%, 3 min at 80%, 2 min at 50%, 3 min at 70%, 2 min at 40%, 3 min at 60%, and 5 min at 40% (Fig. 1). Target speeds to achieve these exercise intensities were prescribed on the basis of data from the pre-BR V˙O2pk treadmill test performed in the upright posture. During each countermeasure session, the speed was adjusted if needed to obtain the targeted training HR. LBNP was adjusted to produce a footward force of 1.0 BM at the start of BR and was adjusted across the BR days from 0.9 to 1.1 BM according to the subject's tolerance. At the conclusion of each exercise period, LBNP was continued for 10 min while the subject rested with legs fully extended and feet pressed against the treadmill.



During the course of the 60-d BR, 29 LBNP/ex sessions were prescribed for each EX subject. However, not all sessions were completed. One subject was unable to complete her first two exercise sessions because of calf pain as a result of the pre-BR muscle biopsy required for another part of this project, but she subsequently completed all other sessions. One subject was unable to complete three exercise sessions because of recurrent back or hip pain, and two other subjects were unable to complete one exercise session because of a short-term illness (fever, upper respiratory symptoms). The exercise part of the LBNP/ex countermeasure was completed in 96% of the scheduled sessions, with no subject completing less than 90%.

Postexercise resting LBNP was performed to maintain orthostatic tolerance (20) and was terminated early (before 10 min) in three subjects because of presyncopal symptoms. Resting LBNP was terminated early in two of these subjects during two sessions each. In the third subject, LBNP was terminated early in 7 of the 29 sessions.

All EX subjects completed their exercise at an LBNP level that produced approximately 1.0 BM for the first half of the BR period. Thereafter, all but one of the eight subjects exercised at greater than 1.05 BM. For one subject prone to presyncopal symptoms, the LBNP was reduced during the majority of her later sessions to approximately 0.9 BM during both exercise and postexercise periods.

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Resistive exercise training protocol.

The EX group trained their thigh and calf muscle groups using supine leg press and calf press exercises on an inertial ergometer (1,2). A total of 19 sessions were scheduled for each subject, approximately every third day (2-3 d·wk−1) beginning on the second day of BR. The inertial ergometer was oriented in the 6° head-down tilt position, and all resistive exercises were performed in this position. Ten minutes of light supine cycling and submaximal supine leg press and calf press repetitions were completed as warm-up. The supine leg press protocol consisted of four sets of seven maximal coupled concentric/eccentric movements, and the calf press prescription consisted of four sets of 14 maximal coupled concentric/eccentric movements. There were 2 min of rest between each set. Force and flywheel rotational velocity were measured, and work and power were calculated throughout each repetition and are presented in a separate paper (40).

Owing to various medical aspects that arose during the BR period, joint and muscle discomforts (perhaps due to the volume/intensity of the combined aerobic and resistance exercise programs) and occasional mild illness, not all sessions were completed as planned. The first three sessions were prescribed at 70%, 80%, and 90% of maximal effort, with all subsequent sessions planned to be performed at maximal effort. Data compiled at the end of both BR campaigns provided a profile of the exercise sessions. For the leg press sessions, 82% were conducted as planned, 13% were performed at reduced effort, and 5% were not conducted. For the calf press sessions, 74% were conducted as planned, 20% were performed at reduced effort, and 6% were not completed. The number of submaximal and missed resistance exercise sessions varied among the volunteers and were scattered throughout the 60-d BR period.

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Pre- and post-BR treadmill testing protocol.

A graded, continuous upright maximal treadmill protocol was performed twice during the baseline period (a familiarization test and the pre-BR test) and on the third day of reambulation (R3). On BR day 60 (R0), a shortened, submaximal exercise test protocol was performed. On the morning of the pre-BR and R0 tests, before the exercise tests, blood volume (BV) was measured using the carbon monoxide rebreathing method, a tilt-LBNP orthostatic test and a balance test were performed (these data will be presented elsewhere). On R0, subjects were returned to the supine position between tilt-LBNP, balance, and exercise testing.

Before each exercise test, subjects lay supine while electrodes were adhered to their chest for EKG monitoring. A chest strap with a transmitter was donned for HR monitoring (Polar Vantage XL; Polar Electro Oy, Kempele, Finland). The subject then stood on the treadmill, was fitted with a headgear and mouthpiece, and was loosely strapped in a suspension harness. The harness was intended to support subjects should they stumble or experience orthostatic problems during or after the exercise test. It offered no support while standing and ambulating and did not interfere with normal gait. After approximately 5 min of quiet standing, resting HR and blood pressure were measured, and the exercise test commenced. The protocol started with 2 min of walking each at 2.7, 3.5, and 4.8 km·h−1 (1.7, 2.2, and 3.0 mph). During the familiarization sessions, treadmill speed was then increased for 3 min each at 6.4, 8.0, and 9.7 km·h−1 (4.0, 5.0, and 6.0 mph) and 0% grade. Treadmill speed then remained constant at the highest speed, but grade was increased each minute in 3% increments until volitional fatigue. Treadmill speed and grade were then lowered to 2.4 km·h−1 (1.5 mph) and 0% grade, respectively, for an active cool-down. For the subsequent maximal exertion treadmill tests (pre-BR and R3), the treadmill speeds for the 3-min stages (after the walking warm-up) were prescribed to correspond to approximately 65%, 75%, and 85% of each subject's pre-BR V˙O2pk on the basis of their linear relationship between treadmill speed and V˙O2 from the familiarization session. The same treadmill speeds were used for the pre-BR and R3 tests.

During the familiarization session, pre-BR and R3 tests, the test protocol was terminated when the subject could not maintain the running speed and signaled to have the treadmill slowed. For R0 testing, the European Space Agency (ESA) Advisory Committee and the medical supervisory staff of the Institute for Space Physiology decided that the potential risks of maximal exercise testing outweighed the information gathered from this test protocol. They therefore dictated that testing would be terminated after the last walking stage at 4.8 km·h−1 (3.0 mph).

During each treadmill test, measurements of oxygen consumption (V˙O2), carbon dioxide production (V˙CO2), ventilation (V˙E), and respiratory exchange ratio (RER) were obtained using a Parvo Medics True One® 2400 Metabolic Cart (Salt Lake City, UT). The pneumotach and gas analyzers were calibrated immediately before each test. Subjects reported their rating of perceived exertion (RPE; Borg's 6-20 scale) during the last 20 s of each exercise stage. HR was measured every 15 s with the Polar heart watch, and an ECG was recorded and monitored by a physician. Oxygen pulse was calculated by dividing oxygen consumption (mL·min−1) by HR (bpm).

V˙O2pk was determined as the average of the last two 30-s measurements during the final minute of exercise. At least two of the following criteria were met: RER exceeded 1.15, HR was greater than 85% of the age-predicted HR maximum, and the V˙O2/exercise intensity curve reached a plateau. The final two 30-s values of V˙O2, V˙CO2, V˙E, and RER for the three walking stages and the three submaximal exercise stages were averaged to represent each exercise stage. HR was determined as the value obtained during the final 15 s of each stage.

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Body composition0

Body composition was determined from triplicate whole-body scans performed before (BR-2) and on the last day of BR (BR-60) with a Hologic QDR 4500W DXA scanner running software version 11.2 (Hologic, Inc., Bedford, MA). From each scan, whole-body mass (BM), lean tissue mass (LTM), and body fat (BF) were determined. The same technician acquired these images before and after BR, and the analysis was performed by the NASA-Johnson Space Center Bone and Mineral Laboratory using their standard methodology (35). Using these procedures, the percent error for repeated tests (reliability) for the determination of the LTM was 0.9%.

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Blood and plasma volumes.

Red cell mass (RCM) was measured in all subjects at the same time of day and in the supine position pre-BR (BR-6) and on R0 using the carbon monoxide rebreathing method as described by Burge and Skinner (9). The methods and results are described in more detail in another publication (20). Briefly, a priming dose of carbon monoxide was introduced while subjects breathed for 10 min into a low-volume closed-circuit rebreathing system to raise blood carboxyhemoglobin (HbCO) to 2%-3%. A first blood sample was collected to determine the baseline total hemoglobin, HbCO, and hematocrit (CO-oximeter; Nova Biomedical, Waltham, MA). A test dose of carbon monoxide, on the basis of subject mass and the result of HbCO after priming, was then administered to raise HbCO saturation to approximately 8%. After 10 min of rebreathing, a second blood sample was collected for the final determination of HbCO. BV and plasma volume (PV) were then calculated using the equations of Burge and Skinner (9).

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Statistical analyses.

Subject characteristics of the three groups before BR were compared using a one-factor ANOVA, and the results are reported as means ± SD for each group.

Walking responses (HR, V˙E, V˙O2, and RER) were analyzed using a three-factor ANOVA, where BR condition (pre, R0, and R3) and exercise level (2.7, 3.5, and 4.8 km·h−1) were the repeated-measures factors and group (CON, EX, and NUT) was the non-repeated-measures factor. Because only five CON subjects were able to complete at least 1 min of the 75% exercise level and none could complete the 85% exercise level on R3, only the 65% submaximal intensity could be compared for group differences. Therefore, exercise responses (HR, V˙E, V˙O2, and RER) at 65% V˙O2pk were analyzed using a two-factor ANOVA, where BR condition (pre and R3) was the repeated-measures factor and group (CON, EX, and NUT) was the non-repeated-measures factor. V˙O2pk and peak exercise responses also were compared using a two-factor ANOVA, where BR condition (pre and R3) was the repeated-measures factor and group (CON, EX, and NUT) was the non-repeated-measures factor.

Body composition results (BM, LTM, and BF) were compared using a two-factor ANOVA design, where BR condition (BR-2 and BR-60) was the repeated-measures factor and group (CON, EX, and NUT) was the non-repeated-measures factor. Relative changes in body composition from pre-BR (BR-2) to post-BR (BR-60) were compared between groups using a one-factor repeated-measures ANOVA design. Changes (mL and mL·kg−1) in blood volume (BV), plasma volume (PV), and red cell mass (RCM) from pre-BR (BR-6) to BR-60 were also compared between groups using a one-factor repeated-measures design.

Select correlations were performed combining data from all three groups. The percent change in V˙O2pk (as mL·kg−1·min−1 and as mL·min−1) was correlated against the percent change in LTM and the percent changes in BV, PV, and RCM. Also, HR responses on R0 were correlated against the percent change in V˙O2pk on R3.

All post hoc comparisons were performed using Tukey's Honestly Significant Difference Tests. Statistical analyses were performed using STATISTICA 7.1 (StatSoft, Inc., Tulsa, OK). Data are presented as means ± SE unless specifically stated. A comparison was considered statistically significant if the P value was <0.05.

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Peak exercise results (V˙O2pk) on R3.

Before BR, V˙O2pk and all other peak exercise responses were similar among the three groups (Table 2). On R3, the total exercise time and V˙O2pk (expressed as L·min−1 or as mL·kg−1·min−1) were reduced significantly from pre-BR in CON and NUT groups but were maintained in the EX group. Further, the percent change in V˙O2pk (L·min−1) was significantly smaller in the EX group (−8.3 ± 1.1%) compared with the CON (−25.9 ± 2.1%) and NUT (−27.2 ± 1.7%) groups. Similar percent changes and group differences were found when V˙O2pk was expressed relative to BM (mL·kg−1·min−1; Fig. 2).





Peak HR, RPE, and RER were not significantly different from pre-BR in any group (Table 2). At R3, peak V˙E was significantly lower than pre-BR only in the NUT group. Peak O2 pulse was reduced significantly from pre-BR in the CON and NUT groups but was maintained in the EX group. The peak O2 pulse was significantly higher in the EX group on R3 compared with that in the CON and NUT groups.

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Resting, walking, and running responses on R3.

On R3, supine HR was similar to pre-BR for the three groups (Fig. 3). Upon standing, HR was significantly higher than pre-BR for the NUT group but not for the CON or EX groups.



During walking, HR was not different from pre-BR in the CON and EX groups, but HR was significantly higher than pre-BR in the NUT group during the second and third walking speeds. None of the other exercise measurements (V˙O2, V˙E, RER, and RPE) were different from pre-BR during R3 testing for each of the three groups.

All subjects completed the three running stages at 65%, 75%, and 85% V˙O2pk pre-BR. On R3, all subjects completed the first running stage (65% pre-BR V˙O2pk). At the second running stage (75% pre-BR V˙O2pk), only five CON subjects and two of the NUT subjects completed at least 1 min, although all eight EX subjects completed this stage. At the third running stage (85% pre-BR V˙O2pk), six of the CON subjects and none of the NUT subjects completed at least 1 min; all eight EX subjects completed this stage. At the 65% exercise stage, HR and V˙E were significantly elevated above pre-BR for CON and NUT groups but not for the EX group (Figs. 3 and 4). RPE was significantly elevated for CON but not for the EX or the NUT group (Fig. 5). V˙O2 did not differ from pre-BR for any group.





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Resting and walking responses immediately after bed rest (R0).

On R0, the supine resting HR was elevated compared with pre-BR in the CON group but not in the EX or the NUT group (Fig. 3). However, upon standing, HR was significantly higher than pre-BR in all groups. During walking, HR was elevated above pre-BR in the CON and NUT groups, but HR declined and was no longer significantly higher than pre-BR at all three walking speeds in the EX group.

On R0, V˙O2 and RER during the three walking speeds (mL·kg−1·min−1) were similar to pre-BR and were not different among groups. V˙E was significantly higher than pre-BR in the CON group during the second and third walking speeds but was not significantly elevated in the EX group during walking. In the NUT group, V˙E was elevated above pre-BR during the first two walking speeds but not during the third waking speed (Fig. 4). RPE was significantly higher than pre-BR in the CON group during the last two walking speeds and in the NUT group during all walking speeds. RPE was significantly higher than pre-BR in the EX group only during the second walking speed (Fig. 5).

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Body composition results.

BM decreased significantly during BR in each group (Table 3). The percent loss was similar for CON and EX subjects but was significantly smaller in the NUT group compared with that in CON and EX. LTM also decreased significantly in CON and NUT, and this change was less (P < 0.05) compared to the EX group. The loss of LTM was similar for the CON and NUT groups. Fat mass (FM) did not change significantly in the CON or NUT groups but decreased significantly in the EX group.



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BV results.

A detailed description of the BV results for the CON and EX groups will be published separately (20). For this article, we present only the percent changes in absolute BV during BR to assess how such changes might affect the exercise results. Owing to technical difficulties with one post-BR sample, BV could be calculated for only seven of the EX subjects. The percent changes for all other subjects were as follows: BV (mL): CON = −9 ± 2%, EX = −4 ± 3%, and NUT = −13 ± 3%; PV (mL): CON = −7 ± 3%, EX = −2 ± 4%, and NUT = −13 ± 3%; or RCM (mL): CON = −11 ± 2%, EX = −6 ± 5%, and NUT = −14 ± 4% during BR. Combining the data from all three groups, BV, PV, and RCM each significantly decreased during BR (P < 0.01, ANOVA BR effect). However, the percent changes in BV, PV, or RCM during BR were not significantly different among the three groups.

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Correlations of the HR responses on R0 and the changes in BV.

After combining the data for all three groups, correlations were performed between the percent changes in BV or PV during BR and the HR responses on R0. The supine HR on R0 did not correlate significantly with the BR-induced changes in BV or PV. However, standing HR correlated significantly with both the percent change in PV (r = −0.42) and the percent change in BV (r = −0.43). HR during each of the three walking stages did not correlate significantly with the percent changes in PV or BV.

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Correlation of V˙O2pk changes on R3 and changes in BV and LTM during bed rest.

Again combining the data for all subjects, correlations were performed to examine the relationship between the percent changes in V˙O2pk (mL·min−1 or mL·kg−1·min−1) measured on R3 and the percent changes in RCM or LTM during BR. Here, we must assume that changes in RCM or LTM between R0 and R3 are small. The correlations in each case were not significant: RCM versus V˙O2pk as milliliters per minute (r = 0.39) or as milliliters per kilogram per minute (r = 0.37) and LTM versus V˙O2pk as milliliters per minute (r = 0.36) or as milliliters per kilogram per minute (r = 0.30).

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Correlation of HR responses on R0 and the change in V˙O2pk on R3.

The data from all subjects were combined to examine the relationship between HR responses on R0 and the decline in V˙O2pk (mL·min−1 or mL·kg−1·min−1) measured on R3. The supine and standing HR on R0 did not correlate significantly with changes in aerobic capacity measured on R3. However, HR during each of the three walking stages correlated significantly with the percent change in V˙O2pk on R3, and the correlation increased with increasing walking speed. For V˙O2pk (mL·kg−1·min−1), the significant correlations were −0.50 (at 2.7 km·h−1), −0.54 (at 3.5 km·h−1), and −0.58 (at 4.8 km·h−1). Similar significant correlations were found between walking HR and percent changes in absolute V˙O2pk (mL·min−1).

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Main results and importance of findings.

This article reports the effectiveness of a combined aerobic plus LBNP and resistive exercise program to preserve upright aerobic capacity in women during 60 d of strict BR. In previous BR studies, the LBNP/ex countermeasure maintained aerobic capacity (28,41), whereas the inertial flywheel resistive exercise countermeasure maintained muscle mass and strength but not aerobic capacity (1,2). Our results indicate that in microgravity simulated by BR, the exercise countermeasures used in the present investigation are compatible and able to maintain aerobic capacity when subjects exercise only 40 min·d−1. Thus, our findings support a feasible approach to maintain functional capacity of astronauts during long-duration spaceflight.

We also hypothesized that an amino acid nutrition supplement would attenuate the decline in aerobic capacity by providing protection against the loss of LTM and leg strength during BR. However, this was not the case because we found a similar decline in LTM and V˙O2pk in the NUT group as in the CON group, and Trappe et al. (40) found that subjects in the NUT group had similar decreases in leg isometric and dynamic strength. Thus, during BR without an exercise stimulus, this nutrition countermeasure is not effective in maintaining aerobic capacity.

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Effect of LBNP/ex to maintain aerobic capacity during bed rest.

Greenleaf et al. (18) reported that 60 min·d−1 of intermittent supine cycle exercise (40%-90% V˙O2pk) maintained supine aerobic capacity after 30 d of BR. We adapted their intermittent exercise approach, but instead used treadmill exercise against LBNP, to simulate gravity loading during exercise in microgravity simulated by BR to protect upright aerobic capacity. During a 5-d BR study (27), male subjects ran supine on this vertical treadmill within LBNP for 30 min·d−1 and maintained their upright exercise responses. Next, we reduced the highest exercise intensity in the intermittent profile from 90% to 80% V˙O2pk to make the countermeasure more acceptable for implementation during spaceflight, but we extended the total exercise duration from 30 to 40 min. This modified LBNP/ex protocol maintained upright V˙O2pk (41) after 15 d of BR in seven highly fit men. Recently, we measured upright V˙O2pk after 30 d of BR in eight pairs of male and seven pairs of female identical twins, where one member of each pair was assigned to a nonexercise control group and the other twin was assigned to the LBNP/ex group. The LBNP/ex countermeasure was equally effective in male and female twins in preventing a decline in V˙O2pk (29). In the present paper, the LBNP/ex countermeasure was performed only three or four times each week, yet upright V˙O2pk was either maintained or quickly recovered after 60 d of BR. We believe that the majority of the effectiveness of our LBNP/ex countermeasure is due to the cardiovascular and musculoskeletal loading during the exercise and that little benefit is derived from LBNP alone. LBNP alone maintains BV (16,23) and improves orthostatic tolerance during BR (19), but such effects are transient (23) and most likely gone by R3 when our post-BR V˙O2pk tests were performed.

Russian investigators combine LBNP with concurrent deep knee bends and fluid loading solutions near the end of long-duration missions to improve orthostatic tolerance (11). Hughson et al. (22) reported that the reduction in V˙O2max was less when male subjects performed strenuous leg exercise 6 d·wk−1 and LBNP (40 mm Hg for 15 min) at separate times on several days near the end of a 4-wk BR.

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Effect of resistive exercise to maintain aerobic capacity during bed rest.

Few investigators have examined the ability of resistive exercise to maintain aerobic capacity during BR. Resistive exercise usually is prescribed to prevent changes in bone and muscle and neuromotor coordination, and it is not specified to maintain aerobic capacity. However, by maintaining skeletal muscle mass, oxidative capacity, and power, a resistance exercise countermeasure may reduce changes in aerobic capacity during BR. Greenleaf et al. (18) compared the separate effects of aerobic exercise and leg resistive exercise (supine isokinetic leg extensions) to maintain aerobic capacity during a 30-d BR. The post-BR change in supine cycle V˙O2pk was −18% in the nonexercise group, −9% in the resistive exercise group, and +3% in the supine cycle exercise group. Thus, after 30 d of BR, resistive exercise offered partial benefit in attenuating the decline in supine cycle aerobic capacity.

An inertial flywheel ergometer has been developed and used in several BR studies. For example, in a 29-d BR study (1), nine subjects performed no exercise, whereas eight subjects performed supine leg press and calf press exercises on the flywheel every third day. The exercise group maintained quadriceps muscle volume and had an attenuated loss of calf muscle volume compared with the controls. In a 90-d BR study (2), 17 healthy men (8 exercisers and 9 controls) were compared using the same flywheel exercise program used in the present study. Flywheel exercise prevented muscle atrophy of knee extensors (−18% in controls) and attenuated atrophy of plantar flexors in the controls (−15% vs −29%). The control group had a 32% decrease in V˙O2pk after BR (10), but the change in the flywheel group was not reported. Indeed, we can find no publication describing the effectiveness of a resistive exercise-only countermeasure on maintaining upright aerobic capacity.

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Efficacy of combining aerobic and resistive exercise to maintain aerobic capacity.

Interference has been observed between physiological adaptations when high-intensity aerobic and resistive training is done using the same muscle groups in ambulatory subjects (5,6,26). Hickson (21) first observed in 1980 that athletes training for strength had a reduced training effect when they began concurrent aerobic endurance training. Also, a converse interference training effect has been suggested; that is, endurance athletes may have a reduced training effect if they add concurrent intense resistive training (5,26). Recently, possible molecular pathways responsible for such training interferences have been described (5). Whether muscle unloading in microgravity alters susceptibility for training interference is not known.

Therefore, to avoid the potential for interference, discomfort, or injury, we reduced the frequency of our LBNP/ex countermeasure from what we tested before and avoided having the subjects perform both exercise modalities on the same day; this only occurred once because of scheduling conflicts. In a recent report from this same WISE study, Trappe et al. (40) report no obvious "interference" in the protection of muscle mass and strength in these female subjects by combining aerobic and resistive countermeasures. Similarly, our results of the LBNP/ex group support a lack of "interference" in protecting aerobic capacity. The lack of training interferences, however, must be indirectly implied because our experimental protocol does not allow a direct comparison of training programs.

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Efficacy of a nutritional countermeasure to maintain aerobic capacity during bed rest.

If a nutritional supplement maintains LTM and leg strength, it may also reduce the decline in aerobic capacity during BR. Stuart et al. (38) found that increasing dietary protein to more than 1 g·kg−1·d−1 during BR maintains nitrogen balance but does not prevent a net decrease in skeletal muscle mass. Other authors (37) have suggested that an increase in branched-chain amino acids may produce a nitrogen-sparing effect during BR. Paddon-Jones et al. (30) found that leg lean mass was maintained and the decline in leg strength was reduced by 50% when male subjects consumed a diet containing high levels of branched-chain amino acids (16.5 g of essential amino acids) and 30 g of carbohydrate during 28 d of BR compared with subjects who received a normal mixed diet. However, in the present study, amino acid supplementation did not maintain whole-body LTM, thigh and calf muscle volumes as measured by magnetic resonance imaging, or leg isometric and dynamic strength (40). Thus, the decline in V˙O2pk was not attenuated in the NUT group.

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Factors that contributed to lower upright aerobic capacity in the WISE women during bed rest.

By examining the results from previous publications from this same study, we may obtain insight into possible mechanisms for the decline in aerobic capacity in the CON group. V˙O2pk in this study was preserved only in the EX group on R3 (and submaximal exercise responses on R0). Yet, the effect of BR on BV was not different among the three groups (there was a nonsignificant group effect and group × BR interaction effect). Therefore, a decrease in BV did not have a major role in the post-BR decline in aerobic capacity. As further support, changes in BV and PV did not correlate with the walking HR response on R0 (this HR response was consistent with declines in V˙O2pk on R3) and changes in RCM did not correlate with changes in V˙O2pk on R3.

LTM decreased significantly in the CON and NUT groups during BR, and this change was significantly less than in the EX group. However, the lack of significant correlation between changes in LTM and the decline in V˙O2pk on R3 suggests that whole-body LTM per se was not a primary determinant of V˙O2pk in these subjects. Another group of investigators in this WISE study (40) reported that thigh muscle volume was maintained, the loss of calf muscle volume was attenuated (CON = −29 ± 1%, NUT = −28 ± 1, and EX = −8 ± 2%), and leg strength was maintained only in the EX group after BR. Trappe et al. (39) also reported that slow and fast myofiber size and contractile function of the vastus lateralis muscle were preserved only in the EX group after BR. Thus, preservation of leg muscle mass and metabolic properties may have contributed to the smaller decline in aerobic capacity in the EX group.

Diminished cardiac function has been implicated in the deterioration of exercise capacity during BR. Perhonen et al. (32) reported impaired ventricular filling after only 2 wk of BR, which they hypothesized is the result of cardiac remodeling. As coinvestigators in the present study, Dorfman et al. (14) measured the changes in ventricular volume and cardiac mass in these WISE-2005 women before and after BR. The CON group had significant reductions in right and left ventricular mass and volume, the NUT group had no change in mass but decrease in cardiac volumes, whereas the EX group had increases in ventricular mass and wall thickness and no change in cardiac volumes. The maintained ventricular volume only in the EX group may indicate a more central distribution of BV, owing to changes in cardiac function, i.e., a greater ventricular distensibility or a greater diastolic suction in the EX group (15). On the other hand, the preserved central BV in the EX group may be due to the prevention of peripheral vascular deconditioning during BR. For example, Arbeille et al. reported a greater increase in cross-sectional area of the tibial and gastrocnemius veins (4) and less reduction in femoral artery and portal flow (3) during mild LBNP in the CON and NUT groups after BR but not in the EX group. Thus, both venous and arterial constrictions may be impaired after BR without exercise countermeasures. Demiot et al. (13) evaluated endothelial function in leg blood vessels of these women after BR. They measured leg blood flow after iontophoresis of acetylcholine or nitroprusside to assess changes in endothelial-dependent and endothelial-independent vasodilation, respectively. Impaired endothelial-dependent vasodilation was evident in the CON and NUT groups after BR but not in the EX group. Thus, impaired microcirculatory vasodilation in the exercising muscles, impaired arterial vasoconstriction in inactive regions, and greater sequestration of blood in peripheral or splanchnic regions could reduce cardiac filling and contribute to the reduced V˙O2pk in the CON and NUT groups after BR.

The increased cardiac mass and wall thickness in the EX group after BR was likely produced by a training effect (17) because most of these women were not regular exercisers before entering this study. The increases in cardiac mass and ventricular volume may help to maintain exercise stroke volume (supported by the maintained oxygen pulse in the EX group) and to preserve HR responses on R0 and R3 and V˙O2pk on R3. However, the results from the NUT group argue against an importance of this effect. Although the additional protein intake prevented cardiac atrophy, it did not attenuate the reduction V˙O2pk in the NUT group after BR. Thus, to maintain maximal cardiac output and V˙O2pk during BR, it is critical to maintain central BV and to allow adequate mobilization of blood to the exercising muscles.

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The compromises in the study design that affected the V˙O2pk results included the following: the last LBNP/ex countermeasure session was performed on BR day 58 and the last resistive exercise session was performed on BR day 56 to allow other investigators to perform tests near the end of BR without short-term effects from exercise training. Also, a V˙O2pk test was not allowed until R3. Therefore, 5 d intervened between the last aerobic countermeasure session and post-BR V˙O2pk testing. These unique aspects of our study make it difficult to compare our findings directly to other BR studies or to our previous LBNP/ex studies. However, between-group comparisons to assess the effectiveness of each countermeasure are valid because each group underwent the same timeline and other environmental factors.

No attempt was made to control for menstrual cycle effects in this study, and it is likely that some responses, such as the BV changes, were influenced by the hormonal fluctuations. It is interesting that during this study, two CON subjects, one EX subject and five NUT subjects had prolonged menstrual cycles, defined as an increase in a subject's normal menstrual cycle length by more than 10 d (Charles Wade, personal communication). Menstrual cycle effects in these women may have influenced their body fluid and submaximal exercise responses.

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This study reports the effectiveness of combining two exercise countermeasures, each independently known to be effective in maintaining muscular strength or aerobic endurance, to preserve aerobic capacity in women during a prolonged BR. Less than 1 h of exercise per day, alternating between endurance and resistive exercise modalities, prevented a decline in upright treadmill V˙O2pk. These results suggest a feasible exercise approach to maintain women's health and functional capacity during long-duration spaceflight. A nutritional supplement alone did not maintain aerobic capacity.

The WISE-2005 study was sponsored by the ESA, the NASA, the Canadian Space Agency, and the French "Centre National d'Etudes Spatiales" (CNES), which has been the "Promoteur" of the study according to French law. Our part of WISE-2005 was funded by a grant from NASA (NNJ04HF71G). The study was performed at MEDES, the Institute for Space Physiology and Medicine, Toulouse, France. The authors thank the multitude of people who worked on this study; the subjects who endured the discomforts and lack of privacy involved in testing, the MEDES hospital staff, Dr. Scott Trappe and Dr. Todd Trappe and Bjorn Alkner who performed the flywheel testing, Dr. Per Tesch for use of his flywheel device, Dr. Gianni Biolo who developed and implemented the nutritional countermeasure, the Wyle Laboratories trainers who performed the LBNP/ex training, and the many students who helped with testing and training. We also thank Drs. Marie-Pierre Bareille, Arnaud Beck, and Peter Jost for coordinating and monitoring this complex WISE-2005 international BR study. There were no conflicts of interest in this study. The results do not constitute endorsement by ACSM.

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