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00005768-201007000-0000600005768_2010_42_1269_katayama_deoxygenation_7miscellaneous-article< 144_0_31_7 >Medicine & Science in Sports & Exercise©2010The American College of Sports MedicineVolume 42(7)July 2010pp 1269-1278Muscle Deoxygenation during Sustained and Intermittent Isometric Exercise in Hypoxia[BASIC SCIENCES: Contrasting Perspectives]KATAYAMA, KEISHO1,2; YOSHITAKE, YASUHIDE3; WATANABE, KOHEI2; AKIMA, HIROSHI1,2; ISHIDA, KOJI1,21Research Center of Health, Physical Fitness and Sports, Nagoya University, JAPAN, 2Graduate School of Education and Human Development, Nagoya University, JAPAN; and 3Department of Physiological Sciences, National Institute of Fitness and Sports, JAPANAddress for correspondence: Keisho Katayama, Ph.D., Research Center of Health, Physical Fitness and Sports, Nagoya University, Furocho, Chikusaku, Nagoya, 464-8601, Japan; E-mail: katayama@htc.nagoya-u.ac.jp.Submitted for publication June 2009.Accepted for publication November 2009.ABSTRACTPurpose: It is reported that the rate of locomotor muscle fatigue development during intermittent isometric exercise in hypoxia is accelerated compared with normoxia. In contrast, when sustained isometric contractions are used, some studies do not show any effect of hypoxia on fatigue development. Increased intramuscular pressure during sustained isometric exercise causes substantial and sustained ischemia, even in normoxia. Therefore, we hypothesized that the difference in muscle deoxygenation between normoxia and hypoxia would be small during sustained exercise compared with intermittent exercise and that this may contribute to the inconsistent findings.Methods: Subjects performed sustained and intermittent isometric, unilateral, and submaximal knee-extension exercises (60% maximal voluntary contraction to exhaustion) while breathing normoxic (inspired O2 fraction = 0.21) or hypoxic gas mixtures (inspired O2 fraction = 0.10-0.12). Muscle oxygenation (deoxyhemoglobin/myoglobin and tissue oxygenation index) using near-infrared spectroscopy and surface EMG were measured from the left vastus lateralis.Results: During intermittent isometric exercise in hypoxia, increases in deoxyhemoglobin/myoglobin and reductions of tissue oxygenation index were larger (P < 0.05) than those in normoxia. The rate of rise in integrated EMG during intermittent exercise was accelerated (P < 0.05) in hypoxia. In contrast, there were no significant differences in changes in near-infrared spectroscopy variables and integrated EMG during sustained isometric exercise between normoxia and hypoxia.Conclusions: These results suggest that muscle deoxygenation is exaggerated during intermittent isometric exercise in hypoxia compared with normoxia, whereas during sustained isometric exercise, the extent of muscle deoxygenation is the same between normoxia and hypoxia. The different extent of muscle deoxygenation during sustained and intermittent isometric exercise in normoxia and hypoxia could affect muscle fatigability, which results from the varied rate of accumulation of metabolites.It is well documented that endurance performance is reduced and the rate of limb muscle fatigue development is exacerbated during whole-body exercise in acute hypoxia. Recent studies reported that reduced arterial oxygen content (CaO2) induced a greater reduction in quadriceps muscle force output which obtained preexercise versus postexercise and a larger rate of increase in quadriceps muscle EMG during whole-body cycle exercise (3,41). However, reduction of CaO2 during whole-body exercise precipitates reduced maximal exercise capacity, that is, reduced peak workload and maximal O2 uptake (27), and this leads to a shift of a given absolute workload to higher relative exercise intensity (3,34,35). Different relative work intensities are expected to influence the rate of accumulation of muscle metabolites and thus influence the rate of locomotor muscle fatigue (33). This problem can be addressed using isolated isometric muscular contractions because maximal force output of a single rested muscle is not influenced by alterations in CaO2 (25,26,35). Accordingly, isometric contractions of an isolated muscle at a given absolute force output are carried out at the same relative exercise intensity regardless of CaO2 (2,35). Thus, isometric exercise is an appropriate model for investigating the effect of hypoxia on muscle fatigue (34).Isometric exercises of isolated muscles generally can be divided into two types: sustained and intermittent isometric contractions. Using intermittent isometric exercise, the rate of fatigue development was shown to be accelerated in hypoxia compared with normoxia (25,28,35). On the other hand, when sustained isometric contractions were used, some studies did not show any effect of hypoxia on fatigue development (7,9,23), although others demonstrated a difference in muscle fatigue between normoxia and hypoxia (11,14,21). Therefore, it is unclear whether breathing hypoxic gas mixture affects muscle fatigue development during sustained isometric exercise. Muscle O2 delivery (CaO2 × blood flow) affects muscle oxygenation during exercise (8). During isometric contractions, intramuscular pressure increases, which compresses the vessels of the microcirculation (30). This compression causes a rapid ejection of venous blood and restricts arterial inflow to the muscle (13). Consequently, increased intramuscular pressure accompanying sustained isometric exercise causes substantial and sustained ischemia, even in normoxia (>30% of maximal voluntary contraction (MVC)) (5-7). Taking these observations into consideration, it is hypothesized that muscle deoxygenation during sustained isometric exercise in normoxia may be similar in hypoxia. Thus, there would be no hypoxic effect on fatigue development during sustained isometric exercise. In contrast, because local, rapid increases in blood flow occur after muscle contraction (13), it is likely that muscle oxygenation during intermittent isometric exercise is maintained in normoxia. Accordingly, we hypothesized that muscle deoxygenation during intermittent exercise could be exaggerated in hypoxia compared with normoxia. Subudhi et al. (43-45) recently investigated muscle oxygenation during incremental cycle exercise in hypoxia, and they found greater muscle deoxygenation at given absolute and relative exercise intensities in hypoxia compared with normoxia. DeLorey et al. (15) also reported that muscle deoxygenation at a given absolute exercise intensity during knee-extension exercise using an ergometer was greater in hypoxia than that in normoxia. However, there are no available data regarding muscle deoxygenation during sustained or intermittent isometric exercise in hypoxia.In addition, it has been reported that the magnitude of muscle deoxygenation is related to surface EMG at a given submaximal work exercise as an index for muscle fatigue (4,36,50). The extent of difference in muscle deoxygenation between normoxia and hypoxia during sustained and intermittent isometric exercise may affect the rate of accumulation of metabolites, which result in increases in motor unit recruitment and muscle fatigue development (2,35).The purpose of the present study was to elucidate muscle deoxygenation and myoelectric activity during sustained and intermittent isometric exercise in hypoxia. For this, we determined muscle oxygenation using near-infrared spectroscopy (NIRS) and integrated EMG (iEMG) detected from the vastus lateralis during sustained and intermittent isometric submaximal quadriceps muscle contractions while breathing hypoxic gas. We then compared these variables during exercise in normoxia.METHODSSubjectsEight healthy untrained males participated in this study (means ± SE: age = 23.4 ± 0.9 yr, height = 171.0 ± 3.0 cm, and body mass = 63.3 ± 2.6 kg). Subjects were informed about the experimental procedures and potential risks involved, and written consent was obtained. This study was approved by the Human Research Committee of the Research Center of Health, Physical Fitness and Sports, Nagoya University.Experimental ProceduresAt the first visit, subjects were familiarized with the equipment used in the experiment. Subjects reported to the laboratory on four additional occasions, separated by at least 72 h, to perform the sustained and intermittent, isometric, unilateral, submaximal knee-extension exercise while breathing normoxic or hypoxic gas mixtures. The orders of exercise (sustained or intermittent) and gas mixture (normoxia or hypoxia) were randomly assigned and counterbalanced. Before submaximal exercise, an MVC test was performed (see next section). Subjects rested for 10 min after the MVC measurement. Next, subjects breathed a normoxic gas mixture through a facemask, and cardiorespiratory and NIRS parameters were measured for 3 min in normoxia (inspired O2 fraction (FIO2) = 0.21; rest 1). Then, inspiratory gas mixture was either maintained or switched to a hypoxic gas mixture, which was provided by a generator (Hypoxico OHG, New York, NY). FIO2 (0.10-0.12) during the hypoxic trials was individually adjusted to induce an arterial oxygen saturation (SaO2) of 75%-80%. The participants, blinded to the FIO2, were exposed to the respective gas mixtures for 10 min at rest before submaximal exercise (rest 2) and started sustained or intermittent isometric exercise while breathing normoxia or hypoxic gas mixtures. The highest MVC obtained on the first day was used to set the identical submaximal exercise target values (60% MVC) on all four occasions. During sustained exercise, subjects maintained the target force for as long as possible. Intermittent exercise consisted of 5 s of static quadriceps muscle contractions at 60% MVC force followed by 5 s of rest. An investigator timing the events verbally instructed the subjects to start and stop each submaximal contraction. The target and exerted forces were represented as horizontal lines on the oscilloscope for visual feedback during submaximal exercise. When the target force could not be maintained for 5 s, subjects were considered exhausted and were instructed to stop the exercise. Then endurance time to exhaustion was recorded.Measurements and AnalysisKnee-extension force.A detailed description of the apparatus is given elsewhere (47). Subjects performed maximal and submaximal voluntary contractions during unilateral isometric knee extension on a custom dynamometer. Knee-extension force was calculated from a calibrated dynamometer-mounted force transducer (LTZ-100KA; Kyowa Electronic Instruments, Kanagawa, Japan). The hip was fixed to the dynamometer by a strap, and the hip joint angle and the knee joint angle were flexed at 125° and 90° (180° is fully extended), respectively. The ankle joint was attached to a bar linked to the force transducer. During contraction, the subject was asked to exert force by knee-extension action and to fold his arms across his chest. The MVC test involved a gradual increase in the knee-extension force exerted by the quadriceps muscle from baseline to maximum in 3-4 s and then sustained at maximum for 2 s. Three trials of MVC were performed before submaximal exercise with 2-3 min rest between trials. The trial with the highest peak force was chosen for analysis. During the submaximal exercise, subjects were asked to contract their quadriceps muscle and to maintain knee-extension force at the target (60% MVC) as steady as possible. The target and exerted forces were represented as horizontal lines on the oscilloscope. The force signals were sampled at a frequency of 1000 Hz through an analog-to-digital convention (ADX-98H; Canopus, Kobe, Japan) and were stored in a computer (Vostro 200; Dell, Kanagawa, Japan).Muscle oxygenation.Muscle oxygenation was continuously monitored using a commercially available NIRS system (NIRO-200; Hamamatsu Photonics KK, Shizuoka, Japan). This apparatus has been used in previous studies (1,42). The representative time course of the original NIRS parameters during sustained and intermittent isometric exercises is shown in Figure 1. Data were simultaneously transmitted to a personal computer (T23; IBM, Tokyo, Japan) using an RS-232C wire, and all NIRS data were sampled at 2 Hz. Optodes were placed on the left vastus lateralis on the belly of the muscle midway between the lateral epicondyle and the greater trochanter of the femur. The optodes were housed in an optically dense plastic holder, thus ensuring that the position of the optodes, relative to each other, was fixed and invariant. The detector in the NIRS probe was separated from the light source by 40 mm. The optode assembly was secured on the skin surface with double-sided tape and then covered with an optically dense, black vinyl sheet, thus minimizing the intrusion of extraneous light and loss of NIR transmitted light from the field of interrogation. The thigh, with attached optodes and covering, was wrapped with an elastic bandage to minimize movement of the optodes. An indelible pen was used to mark the position of the optodes and covering for future visits. Measurement of skin thickness was made at the position of the optodes to account for skin and adipose thickness by ultrasonography (Logiq 5; General Electric, Tokyo, Japan). The absorption of light at different wavelengths (775, 810, 850 nm) was analyzed according to the modified Beer-Lambert's law. Changes in oxyhemoglobin/myoglobin (Oxy-Hb/Mb), deoxyhemoglobin/myoglobin (Deoxy-Hb/Mb), and total hemoglobin/myoglobin (Total-Hb/Mb) values were reported as a change from baseline (rest 1) in units of micrometer per centimeter (ΔOxy-Hb/Mb, ΔDeoxy-Hb/Mb, and ΔTotal-Hb/Mb; μM·cm−1) (10,42). Moreover, the NIRO-200 system directly provides tissue oxygenation index (TOI (%)). TOI% (Oxy-Hb/Total-Hb × 100) was calculated by the NIRS system from the light attenuation slope along the distance from the emitting point as detected by the sensors in the receiving optode (12,38). Change in TOI value was reported as a change from baseline (ΔTOI, %). The mean values of NIRS variables were obtained every 10 s during sustained isometric exercise and during the 5-s contractions during intermittent isometric exercise.FIGURE 1-Representative time course of original NIRS signals during sustained (panels A and B) and intermittent (panels C and D) isometric exercise in hypoxia. Oxy-Hb/Mb, oxyhemoglobin/myoglobin; Deoxy-Hb/Mb, deoxyhemoglobin/myoglobin; Total-Hb/Mb, total hemoglobin/myoglobin; TOI, tissue oxygenation index.Myoelectrical activity.The EMG was recorded from the left vastus lateralis, and electrodes were placed over the distal side of the NIRS probes, parallel to the longitudinal axis of the muscle. The skin surface was cleaned with alcohol and rubbed with sand particles. Surface bipolar electrodes (Ag-AgCl, 6-mm contact diameter, 1.5-cm interelectrode space) were placed on the muscle. The location of electrodes was drawn using permanent-ink marks to identify electrode locations on different experimental days. The EMG signals were connected to a differential amplifier (input impedance 5 MΩ, gain 1000-2000×, common-mode rejection ratio >60 dB), with a bandwidth of 5 Hz to 1 kHz (AB-621; Nihon Kohden, Tokyo, Japan). EMG signals were sampled at a frequency of 1000 Hz through analog-to-digital conversion and were stored in a computer, similar to the force signal recordings. The EMG was full-wave rectified and integrated (iEMG) after removal of the baseline shift. The value of iEMG was averaged every 10 s in the sustained isometric exercise and calculated for a 1-s period during each steady force phase in the intermittent isometric exercise. Data were normalized to the first 10-s contraction during sustained exercise and the first contraction during intermittent exercise (35).Cardiorespiratory parameters.Subjects breathed through a facemask attached to a hot-wire flowmeter (RF-H; Minato Ikagaku, Osaka, Japan), which connected to a one-way valve throughout the experiment. The dead space of the mask was <100 mL. Tidal volume, expiratory and inspiratory times, and respiratory frequency were measured with the breath-by-breath technique, and minute inspiratory ventilation (V˙I) was calculated. To monitor end-tidal O2 and CO2 fractions (FETO2 and FETCO2) using a gas analyzer (MG-360; Minato Ikagaku), a sampling tube, which was a thin vinyl tube (inner diameter = 1 mm), was inserted into the facemask. End-tidal partial pressures of O2 and CO2 (PETO2 and PETCO2) were calculated from FETO2 and FETCO2. SaO2 was also measured by a finger pulse oximeter (OLV-1200; Nihon Kohden). CaO2 was estimated assuming a Hb concentration of 15.0 g·dL−1 and an alveolar (estimated via PETO2-arterial O2 difference at 10 mm Hg; CaO2 (mL·dL−1) = [15.0 × 1.39 × SaO2 / 100] + [(PETO2 - 10) × 0.003]) (35). ECG was also measured using a three-lead arrangement throughout the experiment, and heart rate was calculated from every R-R interval obtained from the ECG. Signals from the flowmeter, gas analyzer, and pulse oximeter were stored in a computer, which was the same as that used for force and EMG measurements.Statistical analysis.Values are expressed as means ± SE. For all data, the assumption of normal distribution was verified using a Komogorov-Smirnov test. Comparison of parameters during sustained and intermittent isometric exercise in normoxia and hypoxia was achieved using a two-way ANOVA and a Bonferroni test. The SPSS (Version 11.5; SPSS, Tokyo, Japan) and the StatView (Version 5.0; SAS Institute, Tokyo, Japan) statistical packages were used for all analyses. The level of significance was set at P < 0.05.RESULTSBaseline Descriptive DataThe mean value of thigh skin thickness was 4.6 ± 0.3 mm. There were no differences in MVC and cardiorespiratory parameters under baseline resting conditions in normoxia (rest 1) on the four experimental days. Resting cardiorespiratory parameters in normoxia and hypoxia (rest 2) are shown in Table 1. In hypoxia, V˙I and HR were higher (P < 0.05), and PETCO2, PETO2, SaO2, and estimated CaO2 were lower (P < 0.05) compared with those in normoxia. Cardiorespiratory variables in normoxia or hypoxia (rest 2) were not different between sustained and intermittent exercise. For the NIRS parameters at rest in hypoxia (rest 2), ΔOxy-Hb/Mb and ΔTOI tended to be lower and ΔDeoxy-Hb/Mb and ΔTotal-Hb/Mb tended to be higher compared with values in normoxia, but differences were not statistically significant.TABLE 1. Cardiorespiratory parameters at rest (rest 2) in normoxia and hypoxia.Effects of Sustained Isometric Exercise in Normoxia and Hypoxia on Muscle Deoxygenation and Myoelectric ActivityEndurance time.The time to exhaustion during sustained exercise in normoxia and hypoxia is indicated in Figure 2 (left). There was no difference in endurance time between conditions.FIGURE 2-Endurance time to exhaustion during sustained (left) andintermittent (right) isometric exercise in normoxia and hypoxia. *P< 0.05 during intermittent exercise between normoxia and hypoxia.Statistical analysis of force output, muscle oxygenation, and myoelectrical activity during sustained exercise was limited to data collected in the first 40 s and at exhaustion because one subject could not achieve 50 s of exercise during one testing session.Force output.The changes in force output during sustained isometric exercise are shown in Table 2. There were no significant differences between normoxia and hypoxia in force output during sustained exercise.TABLE 2. Force output (N) during sustained isometric exercise.Muscle oxygenation.Changes in Oxy-Hb/Mb, Deoxy-Hb/Mb, Total-Hb/Mb, and TOI are shown in Figures 3A-D. During sustained exercise in each condition, muscle oxygenation decreased progressively from the start of exercise to approximately 30 s (↓ΔOxy-Hb/Mb, ↑ΔDeoxy-Hb/Mb, and ↓ΔTOI), and those variables reached plateaus from 30 s to exhaustion. ΔTotal-Hb/Mb was statistically unchanged during sustained exercise. Overall, there were no differences between normoxia and hypoxia in muscle deoxygenation during sustained exercise.FIGURE 3-Changes in near-infrared spectroscopy (NIRS) variables during sustained and intermittent isometric exercise in normoxia and hypoxia. Values are expressed as the change from baseline (rest 1). *P < 0.05, normoxia vs hypoxia. †Significantly different from intermittent isometric exercise in normoxia at exhaustion. §Significantly different from intermittent isometric exercise in hypoxia at exhaustion.Myoelectrical activity.The percent changes in iEMG during sustained exercise in normoxia and hypoxia are shown in Figure 4A. The increase in iEMG in hypoxia did not differ from that in normoxia during sustained exercise.FIGURE 4-Mean iEMG values during sustained (A) and intermittent (B) exercise in normoxia and hypoxia. Values are expressed as percent changes from the first 10-s contraction during sustained exercise and the first contraction during intermittent exercise. *Significantly different from normoxia, P < 0.05. †Significantly different from intermittent isometric exercise in normoxia at exhaustion. §Significantly different from intermittent isometric exercise in hypoxia at exhaustion.Effects of Intermittent Isometric Exercise in Normoxia and Hypoxia on Muscle Deoxygenation and Myoelectric ActivityEndurance time.Time to exhaustion during intermittent exercise in normoxia and hypoxia is shown in Figure 2 (right). Endurance time in hypoxia was significantly shorter (P < 0.05) than that in normoxia.Statistical analysis of force output, muscle oxygenation, and myoelectrical activity during intermittent exercise was limited to data collection in the first 20 contractions (200 s) of exercise and at exhaustion because one subject exhausted at the 21st contraction of exercise in hypoxia.Force output.Force output values during intermittent isometric exercise are shown in Table 3. Force output during intermittent contractions did not differ between normoxia and hypoxia.TABLE 3. Force output (N) during intermittent isometric exercise.Muscle oxygenation.Changes in Oxy-Hb/Mb, Deoxy-Hb/Mb, Total-Hb/Mb, and TOI during intermittent isometric exercise in normoxia and hypoxia are shown in Figures 3E-H. In both conditions, muscle oxygenation decreased progressively from the start of exercise to approximately the fifth contraction (↓ΔOxy-Hb/Mb, ↑ΔDeoxy-Hb/Mb, and ↓ΔTOI), and thereafter those variables reached a plateau to exhaustion. ΔOxy-Hb/Mb was significantly lower (P < 0.05) in hypoxia than that in normoxia from the 3rd to the 20th contraction and at exhaustion (Fig. 3E). ΔDeoxy-Hb/Mb was significantly higher (P < 0.05) in hypoxia than that in normoxia from the 2nd to the 20th contraction and at exhaustion (Fig. 3F). There was no significant difference between normoxia and hypoxia in ΔTotal-Hb/Mb during intermittent exercise (Fig. 3G). ΔTOI during intermittent exercise in hypoxia was significantly lower (P < 0.05) than that in normoxia from the 3rd to the 20th contractions and at exhaustion (Fig. 3H).Myoelectrical activity.The percent changes in iEMG during intermittent isometric exercise under each condition are shown in Figure 4B. A significantly greater (P < 0.05) increase in iEMG during intermittent exercise appeared at the 9th and from the 11th to the 20th contraction in hypoxia compared with normoxia.Comparison of the Variables between Sustained and Intermittent Isometric ExerciseComparison of force output between sustained and intermittent isometric exercise was performed only at exhaustion.Force output.There were no statistical differences in force output at exhaustion between sustained and intermittent isometric exercise.Muscle oxygenation.ΔOxy-Hb/Mb at exhaustion during sustained isometric exercise in normoxia and hypoxia (Fig. 3A) were significantly lower (P < 0.05) than those during intermittent isometric exercise in normoxia and hypoxia at exhaustion (Fig. 3E). ΔDeoxy-Hb/Mb during sustained exercise in normoxia and hypoxia (Fig. 3B) were significantly higher (P < 0.05) than that during intermittent isometric exercise in normoxia (Fig. 3F). On the other hand, there was no significant difference in ΔDeoxy-Hb/Mb at exhaustion between sustained exercise in normoxia or hypoxia and intermittent exercise in hypoxia (Figs. 3B and F). ΔTotal-Hb/Mb at exhaustion during sustained exercise in normoxia and hypoxia (Fig. 3C) was significantly lower (P < 0.05) than at exhaustion during intermittent isometric exercise in normoxia and hypoxia (Fig. 3G). ΔTOI at exhaustion during sustained isometric exercise in normoxia and hypoxia (Fig. 3D) was significantly lower (P < 0.05) than during intermittent isometric exercise in normoxia (Fig. 3H). In contrast, there was no significant difference in ΔTOI at exhaustion between sustained exercise in normoxia or hypoxia and intermittent exercise in hypoxia (Figs. 3D and H).Myoelectrical activity.iEMG at exhaustion during sustained isometric exercise in normoxia and hypoxia (Fig. 4A) were significantly lower (P < 0.05) than those at exhaustion during intermittent isometric exercise in normoxia and hypoxia (Fig. 4B).DISCUSSIONThe major findings of this study were as follows: 1) there was no difference between normoxia and hypoxia in NIRS variables during sustained isometric quadriceps exercise; 2) the extent of increases in ΔDeoxy-Hb/Mb and decreases in ΔTOI during intermittent isometric exercise in hypoxia was significantly larger than those in normoxia; 3) there were no differences between normoxia and hypoxia in changes in iEMG and endurance time to exhaustion during sustained isometric exercise; 4) during intermittent isometric exercise, increases in iEMG were significantly greater and endurance to exhaustion was significantly shorter in hypoxia compared with normoxia; and 5) there was no significant difference in ΔDeoxy-Hb/Mb and ΔTOI at exhaustion between sustained exercise in normoxia or hypoxia and intermittent exercise in hypoxia. These findings support our hypothesis that muscle deoxygenation during sustained isometric exercise in hypoxia may be similar in normoxia and that the extent of difference in muscle deoxygenation between normoxia and hypoxia during sustained and intermittent isometric exercise may affect the rate of rise in muscle fatigue development and motor unit recruitment. To our knowledge, this is the first study to perform simultaneous measurements and comparisons of muscle oxygenation and muscle fatigue during sustained and intermittent isometric muscle exercises in hypoxia.Muscle Oxygenation during Sustained and Intermittent Isometric ExerciseIn the present study, we adjusted FIO2 individually to induce an SaO2 of 75%-80% at rest (rest 2). If resting SaO2 and estimated CaO2 in hypoxia were different between sustained and intermittent exercise trials, NIRS variables and iEMG would have been difficult to compare. However, as shown in Table 1, there were no differences in SaO2 and estimated CaO2 between normoxia and hypoxia before each exercise trial (rest 2). Thus, it seems reasonable to compare changes in muscle deoxygenation and iEMG during sustained and intermittent exercise in hypoxia.Several studies have reported that muscle oxygenation in acute hypoxia at rest maintains its level in normoxia (15,40). Similarly, we also found no statistical differences in NIRS variables between normoxia and hypoxia at rest (rest 2), although ΔOxy-Hb/Mb tended to be slightly higher and ΔDeoxy-Hb/Mb and ΔTOI tended to be lower than those in normoxia (Fig. 3). From these results, resting muscle oxygenation is maintained in acute hypoxia. DeLorey et al. (15) also found a lack of change in muscle deoxygenation at rest in hypoxia, accompanied by an increase in leg blood flow. Thus, despite a lower CaO2 in hypoxia, it seems likely that O2 delivery to the leg is maintained in acute hypoxia, similar to normoxia (15,40).As mentioned previously, using intermittent isometric exercise, many investigators have confirmed the accelerated rate of fatigue development in hypoxia compared with normoxia (25,28,35). In contrast, when sustained isometric exercise was used, some studies reported that hypoxia had no significant influence on the rate of fatigue development (7,9,23), although others demonstrated a difference in muscle fatigue between normoxia and hypoxia (11,14,21). Muscle O2 delivery (CaO2 × blood flow) affects muscle oxygenation during exercise (8). During isometric contractions, intramuscular pressure increases, and elevated intramuscular pressure compresses the vessels of the microcirculation (30). This compression causes a rapid ejection of venous blood and restricts arterial inflow to the muscle (13). Accordingly, increased intramuscular pressure during sustained isometric exercise induces substantial and sustained ischemia, even in normoxia (>30% of MVC) (5-7). As a result, O2 delivery to muscle could be reduced during sustained isometric exercise. Taking these observations into consideration, we hypothesized that muscle deoxygenation during sustained isometric exercise in normoxia may be similar in hypoxia. Thus, there would be no hypoxic effect on fatigue development during sustained isometric exercise. In the present study, there were no significant differences in ΔOxy-Hb/Mb, ΔDeoxy-Hb/Mb, and ΔTOI during sustained exercise between normoxia and hypoxia (Figs. 3A, B, and D). In contrast, during intermittent isometric exercise, ΔOxy-Hb/Mb and ΔTOI were significantly lower, and ΔDeoxy-Hb/Mb was significantly higher in hypoxia than that in normoxia (Figs. E, F, and H). ΔTotal-Hb/Mb, which indicates changes in regional blood volume, during sustained exercise was unchanged in either normoxia or hypoxia (Fig. 3C), whereas it increased progressively during intermittent isometric exercise in each condition (Fig. 3G). From this result, it is conceivable that blood flow to muscles could be inhibited because of an increase in intramuscular pressure during sustained muscle contraction. However, because we did not measure blood flow to the working muscle, it is unclear if 60% MVC used in this study caused complete suppression of blood flow to working muscle.Regarding comparisons of muscle deoxygenation between sustained and intermittent isometric contractions, ΔDeoxy-Hb/Mb and ΔTOI at exhaustion during sustained exercise in normoxia and hypoxia did not differ from those during intermittent exercise in hypoxia (Figs. 3B and D). These results suggested that the extent of muscle deoxygenation during sustained isometric exercise, even in normoxia, could be exacerbated to the same degree as compared with that found during intermittent exercise in hypoxia. In this study, changes in ΔOxy-Hb/Mb, ΔDeoxy-Hb/Mb, and ΔTOI appeared at the first 30 s during sustained isometric exercise and at the first several contractions during intermittent isometric exercise; thereafter, those parameters reached a plateau to exhaustion. These findings are in agreement with results of previous studies, which used submaximal isometric muscle contractions (10,24). Subudhi et al. (43) also found a plateau of Deoxy-Hb/Mb during a high-intensity cycling exercise. In their study, subjects were able to continue exercising after the appearance of the plateau of Deoxy-Hb/Mb, and they supposed that the observed levels of tissue deoxygenation were not directly responsible for the termination of exercise in normoxia and hypoxia. Taken together, it seems likely that the difference in muscle deoxygenation between hypoxia and normoxia per se during exercise may not be directly responsible for muscle fatigue development.Alternatively, one must consider that the extent of muscle deoxygenation during exercise influences the accumulation of muscle metabolites (33) and that the accumulation of muscle metabolites affects locomotor muscle fatigue development. Changes in the rate of metabolic accumulation, that is, protons or phosphates, during intermittent isometric exercise are major determinant of the accelerated exercise-induced muscle fatigue in hypoxia. Compared with normoxia, an increased level of exercise-induced metabolic acidosis is likely to occur in hypoxia (33), and protons are traditionally thought to be a key determinant of locomotor muscle fatigue (37,48). However, more recent in vitro studies have questioned the deleterious role of [H+] in the development of metabolic fatigue (37), and the relative contribution of protons to muscle fatigue remains controversial (49). More recently, inorganic phosphate (Pi) has been suggested to be a major contributor to metabolic fatigue (19,48). It is supposed that cytoplasmic Pi enters the sarcoplasmic reticulum and binds to Ca2+ to form a precipitate (CaPi) and that reducing the amount of releasable Ca2+ contributes to perturbations of excitation-contraction coupling (19). It has been shown that the rate of phosphocreatine hydrolysis and concomitant inorganic Pi accumulation is faster in hypoxia than that in normoxia (32,33). Recapitulating, because oxygen delivery has been shown to influence muscle deoxygenation and Pi accumulation, different rates of Pi aggregation might be a key mechanism explaining the accelerated rate of muscle fatigue during intermittent isometric exercise in hypoxia.Myoelectrical activity.It is well known that surface EMG activity is enhanced during fatiguing exercise. Also, surface EMG provides a measure of the motor unit recruitment and their firing rate because of changes in intracellular metabolism in response to muscle fatigue development. Because the extent of muscle deoxygenation during exercise affects the rate of accumulation of metabolites, it is likely that the magnitude of muscle deoxygenation is related to surface EMG during exercise. In fact, the relationship between EMG and muscle oxygenation measure by NIRS during exercise has been reported in several studies (4,36,50). Thus, we supposed that the different extent of muscle deoxygenation during sustained and intermittent exercise between normoxia and hypoxia would affect myoelectrical activity. For this, we measured iEMG of the vastus lateralis muscle throughout each exercise. Consequently, the increased rate of rise in iEMG during sustained exercise in hypoxia was similar to that in normoxia (Fig. 4A). In contrast, the greater increase in iEMG during intermittent isometric exercise occurred in hypoxia versus normoxia (Fig. 4B). From these findings, it is assumed that additional motor units are recruited and/or the firing rate of already recruited motor units is altered during intermittent quadriceps contractions in hypoxia to compensate for progressive failure within the contractile apparatus compared with normoxia (22,46). Moreover, the greater increase in iEMG during intermittent isometric exercise in hypoxia also may reflect changes in fiber-type recruitment, although measurements of surface EMG are certainly subject to a variety of artifacts (16). During fatiguing exercise in hypoxia, a shift toward an increased type II fiber recruitment as a direct effect of hypoxia per se has been shown (17). Increased type II fibers are associated with higher spike amplitudes (29,39,46), and this may contribute to the enhanced iEMG observed during hypoxic exercise. Because type II fibers are associated with an increased rate of metabolic accumulation and fatigue development relative to type I fibers (20), the O2-dependent change in fiber-type contribution (more type II fibers in hypoxia) might account for at least a portion of the exaggerated muscle fatigue associated with reduced CaO2.iEMG at exhaustion during sustained isometric exercise was significantly lower (P < 0.05) than that during intermittent isometric exercise. From this result, it is speculated that greater motor unit recruitment and/or firing rate of motor units may occur during intermittent isometric exercise compared with sustained isometric exercise. Although we are not certain for the reasons for this finding, it is possible that a difference in blood flow may be associated with greater iEMG findings at exhaustion during intermittent contractions. In intermittent isometric exercise, blood flow removal of contraction-inhibiting metabolites is facilitated by the intervening rest period, which does not occur during sustained isometric exercise (18,31). The varied extent of metabolites accumulation could influence to the magnitude of motor unit recruitment and the firing rate of motor units. Further study is required to confirm this assumption.In conclusion, during intermittent isometric knee-extension exercise in hypoxia, reductions of ΔOxy-Hb/Mb and ΔTOI and an increase in ΔDeoxy-Hb/Mb were larger than those in normoxia. The rate of rise in iEMG during intermittent isometric exercise was accelerated in hypoxia compared with normoxia. In contrast, there were no significant differences between normoxia and hypoxia in changes in NIRS variables and iEMG during sustained isometric exercise. ΔDeoxy-Hb/Mb and ΔTOI at exhaustion during sustained exercise in normoxia and hypoxia did not differ from those during intermittent exercise in hypoxia. These results suggest that muscle deoxygenation is exaggerated during intermittent isometric exercise in hypoxia compared with normoxia, whereas during sustained isometric exercise, the extent of muscle deoxygenation is the same between normoxia and hypoxia. Our results also suggest that muscle deoxygenation during sustained isometric exercise, even in normoxia, is exacerbated.This study was supported in part by a Grant-in-Aid for Scientific Research from the Japanese Ministry of Education, Science, Sports and Culture (grant No. 20700523).The authors acknowledge Mr. Y. Takeuchi and Mr. O. Fujita for experimental implementation and Mr. H. Maeda (Hamamatsu Photonics KK) for technical assistance. The authors also thank Dr. R. Kime (Tokyo Medical University) and Dr. K. 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