Written and conducted by Stephen J. Bailey, Lee M. Romer, James Kelly, Daryl P. Wilkerson, Fred J. Dimenna, and Andrew M. Jones
Fatigue of the respiratory muscles during intense exercise might compromise leg blood flow, thereby constraining oxygen uptake (V̇o2) and limiting exercise tolerance. We tested the hypothesis that inspiratory muscle training (IMT) would reduce inspiratory muscle fatigue, speed V̇o2 kinetics and enhance exercise tolerance. Sixteen recreationally active subjects (mean ± SD, age 22 ± 4 yr) were randomly assigned to receive 4 wk of either pressure threshold IMT [30 breaths twice daily at ∼50% of maximum inspiratory pressure (MIP)] or sham treatment (60 breaths once daily at ∼15% of MIP). The subjects completed moderate-, severe- and maximal-intensity “step” exercise transitions on a cycle ergometer before (Pre) and after (Post) the 4-wk intervention period for determination of V̇o2 kinetics and exercise tolerance. There were no significant changes in the physiological variables of interest after Sham. After IMT, baseline MIP was significantly increased (Pre vs. Post: 155 ± 22 vs. 181 ± 21 cmH2O; P < 0.001), and the degree of inspiratory muscle fatigue was reduced after severe- and maximal-intensity exercise. During severe exercise, the V̇o2 slow component was reduced (Pre vs. Post: 0.60 ± 0.20 vs. 0.53 ± 0.24 l/min; P < 0.05) and exercise tolerance was enhanced (Pre vs. Post: 765 ± 249 vs. 1,061 ± 304 s; P < 0.01). Similarly, during maximal exercise, the V̇o2 slow component was reduced (Pre vs. Post: 0.28 ± 0.14 vs. 0.18 ± 0.07 l/min; P < 0.05) and exercise tolerance was enhanced (Pre vs. Post: 177 ± 24 vs. 208 ± 37 s; P < 0.01). Four weeks of IMT, which reduced inspiratory muscle fatigue, resulted in a reduced V̇o2 slow-component amplitude and an improved exercise tolerance during severe- and maximal-intensity exercise. The results indicate that the enhanced exercise tolerance observed after IMT might be related, at least in part, to improved V̇o2 dynamics, presumably as a consequence of increased blood flow to the exercising limbs.
the increased activation of the muscle contractile machinery at the onset of exercise results in an immediate increase in the rate of ATP turnover. However, oxygen uptake (V̇o2) rises exponentially following the start of exercise, with the energy equivalent of the “O2 deficit” compensated through an increased energy yield from phosphocreatine (PCr) degradation and “anaerobic” glycolysis (36, 45). After the onset of moderate-intensity exercise below the gas-exchange threshold (GET), pulmonary V̇o2 reaches a “steady state” within 2–3 min (68, 69). In contrast, during supra-GET exercise, the development of the so-called V̇o2 slow component delays the attainment of steady state during heavy-intensity exercise (below the critical power) or results in a continued increase in V̇o2 until the maximal O2 uptake (V̇o2max) is reached during severe-intensity exercise (above the critical power) (47, 69, 71). The V̇o2 slow component reflects an increased muscle energy turnover as constant-work-rate exercise proceeds (8, 57) and is associated with a concomitant depletion of the finite PCr stores (57) and greater glycogen utilization (38). Therefore, interventions that speed the overall V̇o2 kinetics, reduce the V̇o2 slow-component amplitude, and/or increase the V̇o2max would be expected to enhance exercise tolerance by reducing the utilization of the finite anaerobic reserves and the accumulation of metabolites associated with the fatigue process (4, 5, 14, 30).
Classically, the respiratory system has been considered to be overbuilt relative to the other components of the O2 delivery system and was therefore not deemed as rate limiting to limb O2 delivery or utilization (18, 58, 66). During high-intensity exercise, however, the respiratory muscles consume ∼10–15% of the total V̇o2 (1), require up to 14–16% of the cardiac output (25), and are susceptible to fatigue (3, 28). These data suggest that the respiratory system has the potential to limit leg O2 delivery and thus V̇o2. Fatigue of the inspiratory muscles results in a sympathetically mediated metaboreflex that increases sympathetic efferent discharge (63), thereby reducing limb blood flow both at rest (60, 61) and during exercise (24, 51). Alleviating respiratory muscle work during severe exercise via a proportional assist ventilator prevents diaphragmatic fatigue (2) and increases leg blood flow and the proportional contribution of leg V̇o2 to pulmonary V̇o2 (24). Moreover, reducing the work of breathing with HeO2 results in a reduction of the V̇o2 slow-component amplitude during severe exercise (17). Conversely, increasing the work of breathing reduces leg blood flow and the proportional contribution of leg V̇o2 to pulmonary V̇o2 (24) and also increases the amplitude of the V̇o2 slow component (16). Importantly, unloading the respiratory muscles increases the tolerance to severe exercise (26, 27, 48), consequent to reductions in peripheral limb muscle fatigue (53) and the sensations of limb discomfort and dyspnea (26, 53). In contrast, loading the respiratory muscles reduces severe exercise tolerance (26, 53), exacerbates limb muscle fatigue (53), and heightens the sensations of limb discomfort and dyspnea (26, 53). Collectively, these data suggest that fatigue of the inspiratory muscles, which is consistently observed in response to high-intensity exercise, compromises leg blood flow, V̇o2, and exercise tolerance, whereas interventions that reduce inspiratory muscle fatigue have the opposite effects.
One practical intervention that may reduce exercise-induced inspiratory muscle fatigue is inspiratory muscle training (IMT) (44, 54, 65). IMT has been hypothesized to increase leg blood flow and O2 delivery (43, 56, 74) and has often been associated with improved exercise performance (e.g., 23, 40, 44, 54, 65). A period of IMT has also been shown to reduce peripheral limb muscle fatigue after prior inspiratory muscle fatigue (43), blood lactate accumulation (11, 12, 40, 62), dyspnea (23, 54, 65), limb discomfort (54), and occasionally minute ventilation (V̇e) (11, 40). Reducing V̇e at a given work rate post-IMT would be expected to reduce the blood flow requirements of the respiratory muscles to such that a greater proportion of cardiac output would be available to distribute to the exercising limbs. Moreover, IMT has the potential to reduce lactate accumulation in the contracting inspiratory muscles (12), which might reduce the stimulation of diaphragm metaboreceptors (51, 61) and vasoconstrictor outflow (63) and thereby increase limb blood flow and O2 delivery.
It is known that interventions that might increase muscle O2 delivery, including the performance of priming exercise (4, 13, 32) and the inspiration of a hyperoxic gas mixture (41, 49, 52, 70), result in a reduced V̇o2 slow-component amplitude, faster “overall” V̇o2 kinetics, and an increased tolerance of high-intensity exercise (4, 70). It is therefore possible that IMT might reduce the metabolic requirements of the inspiratory muscles during intense exercise, delaying inspiratory muscle fatigue, facilitating increased limb O2 availability, and resulting in a reduced V̇o2 slow-component amplitude and improved exercise tolerance. The purpose of the present study was therefore to assess the influence of a 4-wk period of either IMT or a placebo intervention (Sham) on pulmonary V̇o2 kinetics, V̇e, blood lactate accumulation, and exercise tolerance during moderate-, severe-, and maximal-intensity exercise. We hypothesized that IMT, but not Sham, would be expected to reduce the V̇o2 slow-component amplitude and improve exercise tolerance during severe- and maximal-intensity exercise. We also hypothesized that these adaptations in the IMT group would be accompanied by reductions in blood lactate accumulation, V̇e, and the sensations of limb and respiratory discomfort at the same absolute work rates posttraining.
Sixteen healthy subjects (12 men, mean ± SD age = 22 ± 4 yr, stature = 1.79 ± 0.06 m, body mass = 77 ± 8 kg; and 4 women, age = 20 ± 1 yr, stature = 1.63 ± 0.05 m, body mass = 65 ± 6 kg) volunteered to participate in this study. All subjects were nonsmokers, free from asthma and other respiratory impairments, and had normal pulmonary function (forced vital capacity = 5.21 ± 0.99 liters; forced expiratory volume in 1 s = 4.44 ± 0.86 liters; forced expiratory volume in 1 s/forced vital capacity = 85 ± 7%). The subjects participated in exercise at a recreational level but were not highly trained and were familiar with laboratory exercise testing procedures, having previously participated in studies employing cycle ergometry in our laboratory. The procedures employed in this study were approved by the University of Exeter Research Ethics Committee, and all subjects were required to give their written informed consent before the commencement of the study after the experimental procedures, associated risks, and potential benefits of participation had been explained. Subjects were instructed to arrive at the laboratory in a rested and fully hydrated state, at least 3 h postprandial, and to avoid strenuous exercise in the 24 h preceding each testing session. Each subject was also asked to refrain from caffeine and alcohol 6 and 24 h before each test, respectively. All tests were performed at the same time of day (±2 h).
The subjects were required to report to the laboratory on five occasions over a 2-wk period prior to the intervention period, with all tests separated by at least 24 h. During these five laboratory visits, subjects underwent a number of preliminary tests for the determination of maximum inspiratory pressure (MIP), V̇o2max and GET, V̇o2 kinetics, and exercise tolerance. After completion of the preliminary tests, subjects were randomly assigned to either the IMT or Sham group. After completion of the training protocols, subjects returned to the laboratory on five occasions and repeated all the baseline tests at the same absolute work rates to determine the effect of the respective training interventions on the physiological and performance parameters.
Both before and after the intervention period, the subjects completed a ramp incremental exercise test for determination of the V̇o2max and GET (67). All exercise tests were performed on an electrically braked cycle ergometer (Lode Excalibur Sport, Groningen, The Netherlands). Initially, subjects performed 3 min of baseline cycling at 0 W, after which the work rate was increased by 30 W/min for male subjects and by 25 W/min for female subjects until the limit of tolerance. The subjects cycled at a self-selected pedal rate (70–90 rpm), and this pedal rate, along with saddle and handle bar height and configuration, was recorded and reproduced in subsequent tests. Breath-by-breath pulmonary gas-exchange data were collected continuously during the incremental tests and averaged over consecutive 10-s periods. The V̇o2max was taken as the highest 30 s average value attained before the subject's volitional exhaustion in the test. The GET was determined from a cluster of measurements including 1) the first disproportionate increase in CO2 production (V̇co2) from visual inspection of individual plots of V̇co2 vs. V̇o2, 2) an increase in expired ventilation (V̇e)/V̇o2 with no increase in V̇e/V̇co2, and 3) an increase in end-tidal O2 tension with no fall in end-tidal CO2 tension. The data collected during the incremental test were used to calculate the work rates that were employed during the subsequent step tests. Specifically, the work rates that would require 80% of the GET (termed “moderate” exercise), 60% of the difference between the work rate at the GET and V̇o2max (60%Δ; termed “severe” exercise), and 100% V̇o2max (termed “maximal” exercise) were subsequently calculated, with account taken of the mean response time for V̇o2 during ramp exercise (i.e., two-thirds of the ramp rate was deducted from the work rate at GET and peak) (67).
Both before and after the intervention period, the subjects completed two step tests on four occasions for the determination of pulmonary V̇o2 kinetics. The protocol comprised one moderate-intensity followed by either one severe-intensity or one maximal-intensity cycle transition. Therefore, all subjects performed a total of four bouts of moderate-intensity exercise, two bouts of severe-intensity exercise, and two bouts of maximal-intensity exercise both before and after the intervention period. The order of the administered step test combinations was randomly assigned and counterbalanced, and each subject completed the same order of step tests following the intervention period. Each transition began with 3 min of baseline cycling at 20 W before an abrupt transition to the target work rate. A passive recovery of 15 min separated the transitions. The four moderate-intensity steps were each of 6-min duration both before and after the intervention period. Of the two severe-intensity transitions performed before and after the intervention period, one was of 6-min duration, whereas the other was continued to the limit of tolerance. The two maximal-intensity transitions performed before the intervention period were both continued to the limit of tolerance. After the intervention period, one of the maximal transitions was continued to the limit of tolerance, whereas the remaining transition was terminated at the preintervention task failure iso-time (defined as the mean limit of tolerance recorded in the two maximal transitions completed before the intervention period). The time to task failure was used as a measure of exercise tolerance and was recorded when the pedal rate fell more than 10 rpm below the required pedal rate.
After the initial stage of experimental testing, the male and female subjects were ranked separately by baseline MIP and then assigned to either the IMT group (age 20 ± 2 yr, stature 1.75 ± 0.10 m, body mass 74 ± 10 kg) or the Sham group (age 22 ± 4 yr, stature 1.75 ± 0.09 m, body mass 74 ± 9 kg). Both groups contained six male and two female subjects. Each subject performed a total of 1,680 inspiratory maneuvers over a 4-wk period. The IMT group completed 30 dynamic inspiratory efforts twice daily for a 4-wk period against a pressure-threshold load equivalent to ∼50% of the MIP, as employed previously (e.g., Refs. 64, 65). The Sham group completed 60 slow protracted breaths once daily for 4 wk at ∼15% of the MIP, a protocol known to elicit negligible changes in inspiratory muscle function (54, 65). Subjects were instructed to initiate each breath from residual volume and to continue the inspiratory effort until the maximal lung volume was attained. A nose clip was worn during all breaths, and, to avoid hyperventilation, subjects were instructed to maintain a low breathing frequency. The initial training loads were set by the investigators, and all of the inspiratory efforts were performed using a pressure-threshold device (Powerbreathe, HaB International, Southam, UK). The subjects in the IMT group were instructed to periodically increase the resistive load, such that the completion of 30 breaths approximated the limit of inspiratory muscle tolerance, whereas the subjects in the placebo group were instructed to retain the resistive load set by the investigators for the duration of the training intervention. To ensure that subjects adhered to the specific training requirements of the respective training interventions, subjects reported to the laboratory on a twice weekly basis to ensure that the pressure-threshold load was increasing as expected for the IMT group and was unchanged for the Sham group and to observe that the correct breathing technique was upheld. To ensure that the subjects were naive to the purpose and hypotheses of the investigation, the IMT group was told they were undertaking an inspiratory strength training intervention, and the Sham group was informed that they were undertaking an inspiratory endurance training intervention. All subjects ceased training 48 h before the posttraining exercise tests.
During all exercise tests, pulmonary gas exchange and ventilation were measured continuously using a portable metabolic cart (MetaMax 3B, Cortex Biophysik, Leipzig, Germany), as described previously (4–6). A DVT turbine digital transducer measured inspired and expired airflow, and an electrochemical cell O2 analyzer and infrared CO2 analyzer simultaneously measured expired gases. Subjects wore nose clips and breathed through a low-dead-space, low-resistance mouthpiece that was securely attached to the volume transducer. The inspired and expired gas volume and gas concentration signals were continuously sampled via a capillary line connected to the mouthpiece. The gas analyzers were calibrated before each test with gases of known concentration, and the turbine volume transducer was calibrated using a 3-liter syringe (Hans Rudolph, Kansas City, MO). Pulmonary gas exchange and ventilation were calculated and displayed breath-by-breath. Heart rate (HR) was measured during all tests using short-range radiotelemetry (Polar S610, Polar Electro Oy, Kempele, Finland).
During one of the transitions to moderate-, severe-, and maximal-intensity exercise, pre- and posttraining, a blood sample was collected from a fingertip into a capillary tube over the 20 s preceding the step transition in work rate and within the last 20 s of exercise. A capillary blood sample was also collected at the limit of tolerance for the severe- and maximal-intensity bouts. These whole blood samples were subsequently analyzed to determine blood lactate concentration (YSI 1500, Yellow Springs Instruments, Yellow Springs, OH) within 30 s of collection. Blood lactate accumulation was calculated as the difference between blood lactate concentration at the end of exercise and blood lactate concentration at baseline. Ratings of perceived exertion (RPE; respiratory and leg discomfort) were also obtained every 2 min using Borg's 6–20 scale.
MIP was assessed in a standing position using a handheld mouth pressure meter (Micro Medical, Kent, UK) as described previously (22). Each MIP was initiated at residual volume, and subjects wore nose clips during the inspiratory maneuvers. A minimum of five well-executed MIP measurements were conducted, and the highest of three measurements within 5 cmH2O difference was defined as the maximum (22). MIP was assessed pre- and postintervention in the IMT and Sham groups at baseline and at 2 and 10 min following the completion of all exercise bouts. In addition, MIP was assessed after the preintervention task failure iso-time during maximal exercise following the intervention period, where appropriate. The baseline MIP was taken as the mean of the five measurements made at baseline on the testing day in question.
Data analysis procedures.
The breath-by-breath V̇o2 data from each test were initially examined to exclude errant breaths caused by coughing, swallowing, sighing, and so forth, and those values that were more than four standard deviations from the local mean were removed. The breath-by-breath data were subsequently linearly interpolated to provide second-by-second values, and, for each individual, like transitions were time aligned to the start of exercise and ensemble averaged to enhance the signal-to-noise ratio and improve confidence in the parameters derived from the model fits (39). The first 20 s of data after the onset of exercise (i.e., the phase I response) were deleted (68), and a nonlinear least-squares algorithm was used to fit the data thereafter. A single-exponential model was used to characterize the V̇o2 responses to moderate exercise, and a biexponential model was used for severe exercise as described in Eqs. 1 and 2, respectively.
An iterative process was used to minimize the sum of the squared errors between the fitted function and the observed values. V̇o2baseline was defined as the mean V̇o2 measured over the final 90 s of baseline pedaling. The end-exercise V̇o2 was defined as the mean V̇o2 measured over the final 30 s of exercise. Because the asymptotic value (As) of the exponential term describing the V̇o2 slow component may represent a higher value than is actually reached at the end of the exercise, the amplitude of the V̇o2 slow component at the end of exercise was defined as The parameter was compared at the same iso-time (360 s) pre- and posttraining for severe exercise. During maximal exercise, was compared according to fits 1–3 as described above. The amplitude of the V̇o2 slow component was also described relative to the entire V̇o2 response.
We also modeled the HR response to exercise in each condition. For this analysis, HR data were linearly interpolated to provide second-by-second values, and, for each individual, identical repetitions from like transitions were time aligned to the start of exercise and ensemble averaged. A nonlinear least-square monoexponential model without time delay was used to fit the data to moderate-, severe-, and maximal-intensity exercise, with the fitting window commencing at t = 0 s. The derived HR mean response time provides an insight into the overall rate of adjustment of HR dynamics. To determine whether V̇e was influenced by the IMT or Sham intervention, we compared V̇e at baseline (90 s preceding step transition) and at 120 s, at 360 s, and at exhaustion (average response over the final 30 s) during moderate-, severe-, and maximal-intensity exercise before and after the intervention period, as appropriate.
A two-way (time-by-group) ANOVA with repeated measures for time was employed to determine the effects on the relevant physiological variables elicited by the different interventions. Where the analysis revealed a significant main or interaction effect, simple follow-up contrasts were employed to determine the origin of such effects. The relationship between changes in MIP and changes in V̇o2 kinetics and exercise tolerance were assessed with Pearson product moment correlation coefficients. All data are presented as means ± SD unless otherwise indicated. Statistical significance was accepted at P < 0.05.
All subjects were recreationally active on recruitment to the study, and the physiological parameters of interest (i.e., MIP, V̇o2max, V̇o2 at GET, V̇o2 phase II τp, V̇o2 slow-component amplitude) were not significantly different between the IMT and Sham groups before the commencement of the study (Tables 1–3). Each subject self reported 100% compliance to the prescribed training and also self-reported that they did not alter their physical activity for the duration of the study.
The V̇o2max preintervention was 47 ± 5 ml·kg−1·min−1 in the IMT group and 48 ± 8 ml·kg−1·min−1 in the Sham group, with the GET occurring at ∼50% V̇o2max in both groups. There were no significant changes in the V̇o2, V̇e, or work rate attained at the GET or at peak exercise during the incremental test following either the IMT or Sham interventions.
Maximum inspiratory pressure.
The MIP at baseline and after moderate-, severe-, and maximal-intensity exercise for the IMT and Sham groups, pre- (Pre) and postintervention (Post), are presented in Table 1. There was a significant interaction effect between the IMT and Sham groups (P < 0.01) such that baseline MIP was significantly increased (17%) after IMT (155 ± 22 Pre vs. 181 ± 21 cmH2O Post; P < 0.01) but not changed with Sham (153 ± 34 Pre vs. 159 ± 30 cmH2O Post).
Compared to baseline, the MIP was not significantly reduced at 2 or 10 min after the completion of moderate exercise either before or after the intervention in either group (Table 1). However, a significant interaction effect was observed for the absolute MIP at both time points after moderate exercise (P < 0.05), with MIP being significantly increased in the IMT group (P < 0.05) but not in the Sham group (P > 0.05). After 6 min of severe exercise and severe exercise to exhaustion, MIP was reduced compared with baseline in the IMT and Sham groups both before and after the intervention period (Table 1). However, after the intervention period, the absolute MIP after severe exercise manifested a significant interaction effect (P < 0.01), with the MIP increased in the IMT group (P < 0.05) but not in the Sham group (P > 0.05; Table 1). Ten minutes after the completion of 6 min of severe exercise, MIP was not significantly different from the baseline value in the IMT group but remained significantly below the baseline value at all time points after Sham (Table 1). Similar to results with severe exercise, MIP was significantly reduced below the baseline following maximal exercise in both the IMT and Sham groups prior to the intervention period (Table 1). After the intervention period, there was a significant interaction effect between the IMT and Sham groups for the MIP after maximal exercise (P < 0.05), with the absolute MIP being significantly increased at the preintervention exhaustion time (iso-time) and also after maximal exercise to exhaustion in the IMT (P < 0.05) group but not in the Sham group (P > 0.05). Moreover, the MIP was not significantly different from the baseline after exhaustive maximal exercise post-IMT, whereas it remained significantly below baseline following Sham (Table 1).
The V̇e results at baseline and during moderate-, severe-, and maximal-intensity exercise in the IMT and Sham groups for Pre and Post are presented in Table 2. There was no significant difference in the absolute V̇e during moderate and severe exercise after either the IMT or Sham interventions. During maximal exercise, however, there was a significant main effect for time for the V̇e at 120 s (P < 0.05). Follow-up analyses revealed that the V̇e at 120-s was significantly reduced after IMT (P < 0.05) but was not significantly different after Sham (P > 0.05; Table 2).
The parameters of V̇o2 dynamics before and after the IMT and Sham interventions during moderate-, severe-, and maximal-intensity exercise are presented in Table 3 and illustrated in Figs. 1, 2, and 3, respectively. The dynamics of V̇o2 during moderate exercise were unaffected by the IMT and Sham interventions (Table 3, Fig. 1).
There was a significant interaction effect between the IMT and Sham groups for the overall V̇o2 kinetics during severe exercise (P < 0.01; as assessed with a monoexponential function), with follow-up analyses revealing that the overall V̇o2 kinetics was 21% faster after IMT (99 ± 18 s Pre vs. 78 ± 13 s Post; P < 0.01) but was not different after Sham. The phase II V̇o2 time constant was not significantly altered by IMT or Sham. However, there was a significant main effect for time for the fundamental and slow-component V̇o2 amplitudes (P < 0.05). Subsequent analyses revealed that the fundamental component V̇o2 amplitude was significantly increased (1.77 ± 0.41 l/min Pre vs. 1.92 ± 0.49 l/min Post; P < 0.05) and the V̇o2 slow-component amplitude was significantly reduced (0.60 ± 0.20 l/min Pre vs. 0.53 ± 0.24 l/min Post; P < 0.05) during severe exercise after IMT, whereas these parameters were not significantly different after Sham (Table 3, Fig. 2). The V̇o2 at exhaustion was not significantly different from the V̇o2max measured in the initial incremental test either before or after the interventions.
During maximal exercise, there was a significant interaction effect between the IMT and Sham groups for the V̇o2 at 120 s (P < 0.05), with a significantly greater V̇o2 at 120 s after IMT (3.31 ± 0.63 l/min Pre vs. 3.41 ± 0.64 l/min Post; P < 0.01) but not after Sham. During maximal exercise, the V̇o2 phase II time constant and the mean response time were unaffected after the IMT and Sham interventions regardless of the fitting procedure employed (Table 3). However, using fit 1, the V̇o2 fundamental component amplitude was significantly increased (2.07 ± 0.45 l/min Pre vs. 2.23 ± 0.52 l/min Post; P < 0.05), and the V̇o2 slow-component amplitude was significantly reduced after IMT (0.28 ± 0.14 l/min Pre vs. 0.18 ± 0.07 l/min Post; P < 0.05), whereas these parameters were not significantly different after Sham (Fig. 3). There was a significant main effect for time (P < 0.05) with no interaction effect (P > 0.05) for the peak value of V̇o2 attained during maximal exercise. The follow-up t-test revealed that V̇o2 at exhaustion was significantly greater after IMT than before IMT (P < 0.01). The V̇o2 at exhaustion was significantly lower (P < 0.05) than the V̇o2max measured in the initial incremental test before, but not after, the IMT intervention.
HR dynamics and blood lactate concentration.
HR was not significantly different during moderate-, severe-, and maximal-intensity exercise after the IMT and Sham intervention periods (Table 4). Blood lactate accumulation was unaffected after the IMT and Sham interventions during moderate exercise. However, there was a significant interaction effect for the blood lactate accumulation over the first 360 s of severe exercise (P < 0.05), whereby blood lactate accumulation was significantly reduced after IMT (6.0 ± 1.2 mM Pre vs. 5.0 ± 1.0 mM Post; P < 0.01) but was not significantly altered after Sham (Table 4). During maximal exercise, the blood lactate concentration at exhaustion was significantly greater after IMT (7.2 ± 1.8 mM Pre vs. 9.0 ± 1.2 mM Post; P < 0.01) but was not significantly different after Sham.
Ratings of dyspnea and limb discomfort.
Ratings of dyspnea and limb discomfort were not significantly different during moderate exercise following either the IMT or Sham interventions (Table 5). During severe exercise, however, ratings of dyspnea (P < 0.01) and limb discomfort (P < 0.05) were significantly reduced at 2, 4, and 6 min of exercise following IMT, whereas only limb RPE at 2 min was reduced after the sham intervention (P < 0.05). During maximal exercise, dyspnea, but not limb discomfort, was significantly reduced at 2 min of exercise after IMT, but neither dyspnea nor limb discomfort was affected by the Sham intervention.
A significant main effect for time (P < 0.01) was observed for severe-intensity exercise tolerance. Four weeks of IMT resulted in a 39% improvement in severe-intensity exercise tolerance (765 ± 249 s Pre vs. 1,061 ± 304 s Post; P < 0.01), whereas the 8% increase after Sham was not significant (992 ± 188 s Pre vs. 1,068 ± 374 s Post; Fig. 4). A significant interaction effect between groups was observed for maximal-intensity exercise tolerance (P < 0.01), with maximal exercise tolerance being significantly enhanced (by 18%) after IMT (177 ± 24 s Pre vs. 208 ± 37 s Post; P < 0.01) but not significantly different (5%) after Sham (167 ± 28 s Pre vs. 176 ± 32 s Post; Fig. 4).
Relationships between changes in MIP and changes in V̇o2 kinetics and exercise tolerance.
Although IMT resulted in improvements in baseline MIP and in V̇o2 kinetics and exercise tolerance during severe- and maximal-intensity exercise, the changes in these variables were not significantly correlated. For example, changes in baseline MIP were not significantly correlated with changes in overall V̇o2 kinetics (severe: r = 0.20, P = 0.63; maximal: r = −0.62, P = 0.10) or the V̇o2 slow-component amplitude (severe: r = 0.20, P = 0.63; maximal: r = −0.62, P = 0.10). Changes in baseline MIP were also not significantly correlated with changes in exercise tolerance during severe-intensity (r = 0.60, P = 0.12) or maximal-intensity (r = 0.29, P = 0.48) exercise.
This is the first investigation to comprehensively assess the influence of IMT on V̇o2 kinetics and exercise tolerance across a range of exercise intensities. The principal original finding was that, compared with Sham training, 4 wk of pressure threshold IMT resulted in significant changes in several features of the dynamic V̇o2 response to severe- and maximal-intensity (but not moderate-intensity) exercise in young healthy adults. For severe exercise, the faster overall V̇o2 dynamics was accompanied by reductions in blood lactate accumulation and the perceptions of dyspnea and limb discomfort at the same absolute work rate posttraining and improved exercise tolerance. Similarly, during maximal exercise, the V̇o2 slow-component amplitude was reduced, and end-exercise V̇o2 and exercise tolerance were increased after IMT. These results demonstrate that IMT, presumably through reducing the extent of fatigue and therefore the metabolic requirements of the inspiratory muscles during high-intensity exercise, enhanced V̇o2 dynamics and exercise tolerance. The improvements in exercise tolerance after IMT that have been reported previously (e.g., 23, 40, 44, 54, 65) might therefore be linked, at least in part, to changes in V̇o2 kinetics.
MIP and pulmonary ventilation.
We observed a 17% increase in baseline MIP following IMT, indicating that the maximum force-generating capacity of the inspiratory muscles was substantially increased post-IMT, consistent with earlier studies (44). Moderate exercise did not cause significant changes in MIP. However, after severe exercise before the intervention period, the MIP was significantly reduced (by ∼23%) below the baseline value, suggestive of the development of inspiratory muscle fatigue. After IMT, the extent of this fatigue was reduced, with the MIP being within 9% of the baseline, consistent with previous studies (54, 65). Furthermore, 10 min after 6 min of severe-intensity exercise, the MIP was not significantly different from the baseline value, indicating that the inspiratory muscles recovered more rapidly after IMT than after Sham. Short-duration maximal-intensity exercise also resulted in a significant reduction (by ∼18%) of MIP below the baseline value. The extent of this reduction was reduced after IMT (MIP was 8% lower than baseline).
The absolute V̇e during moderate- and severe-intensity exercise was not different after IMT or Sham. However, V̇e was slightly but significantly reduced at 2 min during maximal-intensity exercise after IMT. Some previous studies have also reported reductions in V̇e after IMT (10, 11, 40), although others have found no change (62, 64, 73). This reduction in V̇e during maximal-intensity exercise might have contributed to the reduced degree of inspiratory muscle fatigue that was measured and the reduced perception of dyspnea. A reduction in V̇e for the same work rate after IMT might also reduce the metabolic requirements of, and thus blood flow commandeered by, the respiratory muscles.
Fatigue of the inspiratory muscles stimulates diaphragm innervating metaboreceptors (7), invoking sympathetically mediated vasoconstrictor outflow (63) and a reduction in limb blood flow (60). It is known that the metaboreflex is activated once a threshold of fatiguing inspiratory work has been exceeded (61) and in response to the accumulation of fatigue-related metabolites, including lactic acid (51). We observed a reduced blood lactate accumulation during the first 6 min of severe exercise after IMT, which may be, in part, due to the reduced inspiratory muscle fatigue (12). Therefore, the reduced blood lactate accumulation and inspiratory muscle fatigue might have reduced the magnitude of the metaboreflex (74) and, subsequently, increased blood flow to the exercising limbs. The reduced V̇e during maximal-intensity exercise would also reduce the V̇o2 requirements of the respiratory muscles (1) such that leg blood flow might be greater. Although empirical evidence that IMT increases leg blood flow during whole-body exercise is currently lacking, it is clear that reducing the work of breathing via proportional assist ventilator prevents diaphragm fatigue (2) and increases leg blood flow (24), whereas increasing the work of breathing reduces leg blood flow (24).
The phase II V̇o2 time constant, which reflects the rate at which V̇o2 in the contracting muscles increases toward the required metabolic rate (21, 37), was not altered by IMT during moderate-, severe-, or maximal-intensity exercise. This is consistent with previous reports that indicate that the phase II V̇o2 time constant is insensitive to interventions which might enhance muscle O2 delivery, at least in young healthy subjects performing large muscle group exercise (4, 13, 41, 45, 70, 72). The results for moderate-intensity exercise are also consistent with a previous report that IMT did not alter V̇o2 kinetics (20). However, the amplitudes of the fundamental and slow components of V̇o2 were increased and decreased, respectively, during both severe- and maximal-intensity exercise. It has been suggested that the fundamental and slow-component V̇o2 response amplitudes might be sensitive to muscle O2 availability (32, 35). Interventions that likely result in an acute increase in muscle O2 delivery during exercise, such as the performance of prior exercise and the inspiration of hyperoxic gas, result in an increased V̇o2 fundamental component amplitude and/or a reduced V̇o2 slow-component amplitude (4, 13, 41, 70), whereas interventions that might compromise muscle O2 delivery have the opposite effects (34, 35). That IMT altered V̇o2 dynamics during severe- and maximal-intensity exercise in which inspiratory muscle fatigue was reduced, but not during moderate-intensity exercise, which did not fatigue the inspiratory muscles, suggests that a redistribution of blood flow from the respiratory muscles to the exercising limbs might have facilitated the altered V̇o2 response. However, it is noteworthy that the effects of IMT on V̇o2 kinetics during severe exercise (i.e., ∼12% reduction in the V̇o2 slow-component amplitude and ∼21% speeding of the overall V̇o2 dynamics) are somewhat less impressive than the effects of interventions such as training and prior exercise, both of which can result in 40–50% reductions in the V̇o2 slow-component amplitude and V̇o2 mean response time. This is likely because, in addition to enhancing muscle O2 delivery, these other interventions also alter factors such as motor unit recruitment patterns and muscle oxidative enzyme activity (and thus O2 utilization) (4, 5, 31, 32).
Measurements of pulmonary V̇o2 predominantly reflect leg muscle V̇o2 over both the fundamental (21, 37) and slow phases (37, 46) of the V̇o2 response to exercise. It has been reported that loading the inspiratory muscles during intense cycle exercise reduces leg blood flow and leg V̇o2 as a percentage of pulmonary V̇o2, whereas unloading the inspiratory muscles increases leg blood flow and leg V̇o2 as a percentage of pulmonary V̇o2 (24). In the present study, IMT increased the V̇o2 fundamental component amplitude during severe- and maximal-intensity exercise, presumably by enabling a greater leg blood flow. This suggests that muscle O2 delivery might play an important role in setting the V̇o2 fundamental component amplitude during high-intensity exercise and that IMT, through reducing inspiratory muscle fatigue and thus the onset of the metaboreflex, increased muscle O2 delivery and thus V̇o2 in the early minutes of such exercise.
The increased V̇e during high-intensity exercise has been estimated to account for up to 24% of the V̇o2 slow-component amplitude (15). In keeping with this, loading the inspiratory muscles increases the V̇o2 slow-component amplitude (16), whereas changing lung mechanics by breathing HeO2 reduces the V̇o2 slow-component amplitude (17). A reduction in absolute V̇e (as was observed at 2 min into maximal-intensity exercise) or in the V̇o2 requirement for a given V̇e (i.e., improved efficiency) might therefore contribute to the reduced V̇o2 slow component that we observed after IMT. Specific training of the respiratory muscles has been reported to increase the proportion of type I fibers in the external intercostal muscles (50), which would be expected to result in improved contractile efficiency (9). Another explanation for the reduced V̇o2 slow component after IMT is that an enhanced leg blood flow across the initial exercise transient reduced the rate of limb muscle fatigue development (24, 53) and thus the requirement to recruit lower-efficiency type II muscle fibers to support power production as exercise continued. This delayed-onset recruitment of type II muscle fibers has been proposed to be a key determinant of the V̇o2 slow component (9, 38, 46, 57).
The V̇o2 at exhaustion during maximal-intensity exercise was significantly greater after IMT. This observation is somewhat surprising given that previous studies have shown no effect of IMT on V̇o2max, at least during incremental exercise (e.g., 42, 44, 59, 64). It is possible that high-intensity exercise is terminated when the energy available from substrate-level phosphorylation has been exhausted and/or fatigue-related muscle metabolites have accumulated to intolerable levels (33, 47). During maximal-intensity (or “extreme”) exercise (71), the duration of exercise might be so short (≤3 min) that the limit of tolerance is reached before the V̇o2max is attained. Consistent with this, the V̇o2 attained at the termination of maximal-intensity exercise in the present study was slightly but significantly lower than the V̇o2max measured in the initial incremental test before, but not after, the IMT intervention. It is possible that the higher V̇o2 (and thus oxidative contribution to energy turnover) over the first 2 min of maximal-intensity exercise after IMT spared the energetic contribution from substrate-level phosphorylation, thereby extending the duration of exercise and permitting the V̇o2max to be attained.
After 4 wk of IMT, which significantly increased MIP and reduced the extent of inspiratory muscle fatigue, exercise tolerance was improved by a mean of 39% and 18% during severe- and maximal-intensity exercise, respectively. Improved exercise performance has also been observed previously during constant work-rate tests to exhaustion (10, 11, 20, 42), as well as during time trials (29, 54, 65) and fixed duration exercise (23) after training of the respiratory muscles. Increasing the work of breathing exacerbates peripheral leg fatigue (53), heightens dyspnea and sensations of leg discomfort, and compromises leg blood flow and whole body exercise tolerance (26, 53). However, when the work of breathing is reduced, the extent of peripheral limb muscle fatigue (53), diaphragm fatigue (2), dyspnea, and leg discomfort (53) are reduced, and leg blood flow (24) and exercise tolerance (26, 27, 48) are improved. Collectively, these findings indicate that the increased inspiratory muscle fatigue resistance that we observed post-IMT might have reduced the fraction of total cardiac output required by the respiratory muscles during exercise and blunted the accumulation of fatigue-related metabolites. In this way, any potential reflex vasoconstrictive effects on the locomotor muscle vasculature would be attenuated (61, 74). Leading to an increased limb blood flow (24) and enhanced exercise tolerance (26).
Given that certain aspects of V̇o2 dynamics are sensitive to changes in muscle O2 availability (41, 45, 70) and IMT has the potential to increase leg O2 supply, the improved exercise performance often observed after IMT might be ascribed, in part, to an enhanced dynamic V̇o2 response to exercise. A faster adjustment of oxidative phosphorylation in response to the same absolute work rate after IMT would reduce the magnitude of the O2 deficit and thus the energy contribution from substrate-level phosphorylation (14, 45). Likewise, a reduction in the V̇o2 slow-component amplitude would reduce PCr breakdown (57) and glycogen depletion (38). Interventions that elicit such alterations in the V̇o2 response would therefore spare the finite anaerobic reserves, reduce the accumulation of fatiguing metabolites, and improve exercise tolerance (4–6, 14, 30). Consistent with earlier studies, blood lactate accumulation (10, 11, 40, 62) and the perceptions of dyspnea and limb discomfort (23, 54, 65) were reduced after IMT during severe exercise. The improved V̇o2 dynamics after IMT would be expected to reduce blood lactate accumulation (4, 5), which, through reduced group III and IV afferent discharge, may reduce the sensations of respiratory and limb muscle discomfort and improve exercise tolerance (56). It should be noted, however, that despite the concomitant changes in V̇o2 dynamics and exercise tolerance after IMT, the changes in MIP were not significantly correlated with changes in V̇o2 kinetics or the time to task failure. It is possible that this lack of significant relationship was a function of the relatively low sample size (n = 8) and interindividual variability in the physiological responses to IMT.
Specific training of the inspiratory muscles increased baseline MIP, reduced inspiratory muscle fatigue and enhanced V̇o2 dynamics and exercise tolerance during severe- and maximal-intensity exercise. We propose that a reduction of inspiratory muscle fatigue after IMT spared the O2 and blood-flow requirements of ventilation and offset the metaboreflex (61, 74), thereby increasing limb O2 delivery (24). Increased muscle O2 availability, in turn, resulted in a speeding of the overall V̇o2 dynamics (perhaps by reducing the rate of fatigue development and delaying the recruitment of low-efficiency fibers) (9, 38) and enhancement of exercise tolerance (4, 14, 70).
Pressure-threshold IMT appears to present a practical and efficacious means for modulating the V̇o2 response to high-intensity exercise in healthy young people. These changes are likely to be, at least in part, responsible for the enhanced exercise tolerance after IMT that has been reported herein and in previous investigations. IMT therefore appears to have considerable potential as an adjunct to physical training for the enhancement of exercise performance. Further research is required to establish whether similar (or greater) effects on V̇o2 kinetics and exercise tolerance are possible in the elderly or in populations with ventilatory or cardiovascular impairments.
No conflicts of interest, financial or otherwise, are declared by the authors.
1. Aaron EA, Seow KC, Johnson BD, Dempsey JA. Oxygen cost of exercise hyperpnea: implications for performance. J Appl Physiol 72: 1818 –1825, 1992.
2. Babcock MA, Pegelow DF, Harms CA, Dempsey JA. Effects of respiratory muscle unloading on exercise-induced diaphragm fatigue. J Appl Physiol 93: 201–206, 2002.
3. Babcock MA, Pegelow DF, Taha BH, Dempsey JA. High frequency diaphragmatic fatigue detected with paired stimuli in humans. Med Sci Sports Exerc 30: 506 –511, 1998.
4. Bailey SJ, Vanhatalo A, Wilkerson DP, DiMenna FJ, Jones AM. Optimizing the “priming” effect: influence of prior exercise and recovery duration on O2 uptake kinetics and severe-intensity exercise tolerance. J Appl Physiol 107: 1743–1756, 2009.
5. Bailey SJ, Wilkerson DP, DiMenna FJ, Jones AM. Influence of repeated sprint training on pulmonary O2 uptake and muscle deoxygenation kinetics in humans. J Appl Physiol 106: 1875–1887, 2009.
6. Bailey SJ, Winyard P, Vanhatalo A, Blackwell JR, Dimenna FJ, Wilkerson DP, Tarr J, Benjamin N, Jones AM. Dietary nitrate supplementation reduces the O2 cost of low-intensity exercise and enhances tolerance to high-intensity exercise in humans. J Appl Physiol 107: 1144 –1155, 2009.
7. Balzamo E, Lagier-Tessonnier F, Jammes Y. Fatigue-induced changes in diaphragmatic afferent and cortical activity in the cat. Respir Physiol 90: 213–226, 1992.
8. Bangsbo J, Krustrup P, González-Alonso J, Saltin B. ATP production and efficiency of human skeletal muscle during intense exercise: effect of previous exercise. Am J Physiol Endocrinol Metab 280: E956 –E964, 2001.
9. Barstow TJ, Jones AM, Nguyen PH, Casaburi R. Influence of muscle fiber type and pedal frequency on oxygen uptake kinetics of heavy exercise. J Appl Physiol 81: 1642–1650, 1996.
10. Boutellier U, Buchel R, Kundert A, Spengler C. The respiratory system as an exercise limiting factor in normal trained subjects. Eur J Appl Physiol 65: 347–353, 1992.
11. Boutellier U, Piwko P. The respiratory system as an exercise limiting factor in normal sedentary subjects. Eur J Appl Physiol 64: 145–152, 1992.
12. Brown PI, Sharpe GR, Johnson MA. Inspiratory muscle training reduces blood lactate concentration during volitional hyperpnoea. Eur J Appl Physiol 104: 111–1117, 2008.
13. Burnley M, Doust JH, Carter H, Jones AM. Effects of prior exercise and recovery duration on oxygen uptake kinetics during heavy exercise in humans. Exp Physiol 86: 417–425, 2001.
14. Burnley M, Jones AM. Oxygen uptake kinetics as a determinant of sports performance. Eur J Sports Sci 7: 63–79, 2007.
15. Candau R, Belli A, Millet GY, Georges D, Barbier B, Rouillon JD. Energy cost and running mechanics during a treadmill run to voluntary exhaustion in humans. Eur J Appl Physiol Occup Physiol 77: 479 –485, 1998.
16. Carra J, Candau R, Keslacy S, Giolbas F, Borrani F, Millet GP, Varray A, Ramonatxo M. Addition of inspiratory resistance increases the amplitude of the slow component of O2 uptake kinetics. J Appl Physiol 94: 2448 –2455, 2003.
17. Cross TJ, Sabapathy S, Schneider DA, Haseler LJ. Breathing HeO2 attenuates the slow component of O2 uptake kinetics during exercise performed above the respiratory compensation threshold. Exp Physiol 95: 172–183, 2010. 18. Dempsey JA. JB Wolffe Memorial Lecture. Is the lung built for exercise? Med Sci Sports Exerc 18: 143–155, 1986.
19. Derchak PA, Sheel AW, Morgan BJ, Dempsey JA. Effects of expiratory muscle work on muscle sympathetic nerve activity. J Appl Physiol 92: 1539 –1552, 2002.
20. Edwards AM, Cooke CB. Oxygen uptake kinetics and maximal aerobic power are unaffected by inspiratory muscle training in healthy subjects where time to exhaustion is extended. Eur J Appl Physiol 93: 139 –144, 2004.
21. Grassi B, Poole DC, Richardson RS, Knight DR, Erickson BK, Wagner PD. Muscle O2 uptake kinetics in humans: implications for metabolic control. J Appl Physiol 80: 988 –998, 1996.
22. Green M, Road J, Sieck GC, Similowski T. ATS/ERS Statement on Respiratory Muscle Testing Tests of Respiratory Muscle Strength. Am J Respir Crit Care Med 166: 528 –542, 2002.
23. Griffiths LA, McConnell AK. The influence of inspiratory and expiratory muscle training upon rowing performance. Eur J Appl Physiol 99: 457– 466, 2007.
24. Harms CA, Babcock MA, McClaran SR, Pegelow DF, Nickele GA, Nelson WB, Dempsey JA. Respiratory muscle work compromises leg blood flow during maximal exercise. J Appl Physiol 82: 1573–1583, 1997.
25. Harms CA, Wetter TJ, McClaran SR, Pegelow DF, Nickele GA, Nelson WB, Hanson P, Dempsey JA. Effects of respiratory muscle work on cardiac output and its distribution during maximal exercise. J Appl Physiol 85: 609 –618, 1998.
26. Harms CA, Wetter TJ, St. Croix CM, Pegelow DF, Dempsey JA. Effects of respiratory muscle work on exercise performance. J Appl Physiol 89: 131–138, 2000.
27. Johnson BD, Aaron EA, Babcock MA, Dempsey JA. Respiratory muscle fatigue during exercise: implications for performance. Med Sci Sports Exerc 28: 1129 –1137, 1996.
28. Johnson BD, Babcock MA, Suman OE, Dempsey JA. Exercise-induced diaphragmatic fatigue in healthy humans. J Physiol 460: 385–405, 1993.
29. Johnson MA, Sharpe GR, Brown PI. Inspiratory muscle training improves cycling time-trial performance and anaerobic work capacity but not critical power. Eur J Appl Physiol 101: 761–770, 2007.
30. Jones AM, Burnley M. Oxygen uptake kinetics: an under-appreciated determinant of exercise performance. Int J Sports Physiol Perform 4: 524 –532, 2009.
31. Jones AM, Carter H. The effect of endurance training on parameters of aerobic fitness. Sports Med 29: 373–386, 2000.
32. Jones AM, Koppo K, Burnley M. Effects of prior exercise on metabolic and gas exchange responses to exercise. Sports Med 33: 949 –971, 2003.
33. Jones AM, Wilkerson DP, DiMenna F, Fulford J, Poole DC. Muscle metabolic responses to exercise above and below the “critical power” assessed using 31P-MRS. Am J Physiol Regul Integr Comp Physiol 294: R585–R593, 2008.
34. Jones AM, Wilkerson DP, Wilmshurst S, Campbell IT. Influence of L-NAME on pulmonary O2 uptake kinetics during heavy-intensity cycle exercise. J Appl Physiol 96:1033–1038, 2004.
35. Koga S, Shiojiri T, Shibasaki M, Kondo N, Fukuba Y, Barstow TJ. Kinetics of oxygen uptake during supine and upright heavy exercise. J Appl Physiol 87: 253–260, 1999.
36. Krogh A, Lindhard J. The changes in respiration at the transition from work to rest. J Physiol 53: 431–439, 1920.
37. Krustrup P, Jones AM, Wilkerson DP, Calbet JA, Bangsbo J. Muscular and pulmonary O2 uptake kinetics during moderate- and highintensity sub-maximal knee-extensor exercise in humans. J Physiol 587: 1843–1856, 2009.
38. Krustrup P, Soderlund K, Mohr M, Bangsbo J. The slow component of oxygen uptake during intense, sub-maximal exercise in man is associated with additional fibre recruitment. Pflügers Arch 447: 855–866, 2004.
39. Lamarra N, Whipp BJ, Ward SA, Wasserman K. Effect of interbreath fluctuations on characterising exercise gas exchange kinetics. J Appl Physiol 62: 2003–2012, 1987.
40. Leddy JJ, Limprasertkul A, Patel S, Modlich F, Buyea C, Pendergast DR, Lundgren CEG. Isocapnic hyperpnea training improves performance in competitive male runners. Eur J Appl Physiol 99: 665–676, 2007.
41. MacDonald M, Pedersen PK, Hughson RL. Acceleration of V˙ O2 kinetics in heavy submaximal exercise by hyperoxia and prior high-intensity exercise. J Appl Physiol 83: 1318 –1325, 1997.
42. Markov G, Spengler CM, Knöpfli-Lenzin C, Stuessi C, Boutellier U. Respiratory muscle training increases cycling endurance without affecting cardiovascular responses to exercise. Eur J Appl Physiol 85: 233–239, 2001.
43. McConnell AK, Lomax M. The influence of inspiratory muscle work history and specific inspiratory muscle training upon human limb muscle fatigue. J Physiol 577: 445–457, 2006.
44. McConnell AK, Romer LM. Respiratory muscle training in healthy humans: resolving the controversy. Int J Sports Med 25: 284 –293, 2004.
45. Poole DC, Barstow TJ, McDonough P, Jones AM. Control of oxygen uptake during exercise. Med Sci Sports Exerc 40: 462–474, 2008.
46. Poole DC, Schaffartzik W, Knight DR, Derion T, Kennedy B, Guy HJ, Prediletto R, Wagner PD. Contribution of exercising legs to the slow component of oxygen uptake kinetics in humans. J Appl Physiol 71: 1245–1260, 1991.
47. Poole DC, Ward SA, Gardner GW, Whipp BJ. Metabolic and respiratory profile of the upper limit for prolonged exercise in man. Ergonomics 31: 1265–1279, 1988.
48. Powers SK, Jacques M, Richard R, Beadle RE. Effects of breathing a normoxic He-O2 gas mixture on exercise tolerance and V˙ O2max. Int J Sports Med 7: 217–221, 1986.
49. Powers SK, Lawler J, Dempsey JA, Dodd S, Landry G. Effects of incomplete pulmonary gas exchange on V˙ O2max. J Appl Physiol 66: 2491–2495, 1989.
50. Ramirez-Sarmiento A, Orozco-Levi M, Guell R, Barreiro E, Hernandez N, Mota S, Sangenis M, Broquetas JM, Casan P, Gea J. Inspiratory muscle training in patients with chronic obstructive pulmonary disease: structural adaptation and physiologic outcomes. Am J Respir Crit Care Med 166: 1491–1497, 2002.
51. Rodman JR, Henderson KS, Smith CA, Dempsey JA. Cardiovascular effects of the respiratory muscle metaboreflexes in dogs: rest and exercise. J Appl Physiol 95: 1159 –1169, 2003.
52. Romer LM, Haverkamp HC, Lovering AT, Pegelow DF, Dempsey JA. Effect of exercise-induced arterial hypoxemia on quadriceps muscle fatigue in healthy humans. Am J Physiol Regul Integr Comp Physiol 290: R365–R375, 2006.
53. Romer LM, Lovering AT, Haverkamp HC, Pegelow DF, Dempsey JA. Effect of inspiratory muscle work on peripheral fatigue of locomotor muscles in healthy humans. J Physiol 571: 425–439, 2006.
54. Romer LM, McConnell AK, Jones DA. Inspiratory muscle fatigue in trained cyclists: effects of inspiratory muscle training. Med Sci Sports Exerc 34: 785–792, 2002.
55. Romer LM, Miller JD, Haverkamp HC, Pegelow DF, Dempsey JA. Inspiratory muscles do not limit maximal incremental exercise performance in healthy subjects. Respir Physiol Neurobiol 156: 353–361, 2007.
56. Romer LM, Polkey MI. Exercise-induced respiratory muscle fatigue: implications for performance. J Appl Physiol 104: 879 –888, 2008.
57. Rossiter HB, Ward SA, Howe FA, Kowalchuk JM, Griffiths JR, Whipp BJ. Dynamics of intramuscular 31P-MRS Pi peak-splitting and the slow components of PCr and O2 uptake during exercise. J Appl Physiol 93: 2059 –2069, 2002.
58. Saltin B, Strange S. Maximal oxygen uptake: “old” and “new” arguments for a cardiovascular limitation. Med Sci Sports Exerc 24: 30 –37, 1992.
59. Sheel AW. Respiratory muscle training in healthy individuals: physiological rationale and implications for exercise performance. Sports Med 32: 567–581, 2002.
60. Sheel AW, Derchak PA, Morgan BJ, Pegelow DF, Jacques AJ, Dempsey JA. Fatiguing inspiratory muscle work causes reflex reduction in resting leg blood flow in humans. J Physiol 537: 277–289, 2001.
61. Sheel AW, Derchak PA, Pegelow DF, Dempsey JA. Threshold effects of respiratory muscle work on limb vascular resistance. Am J Physiol Heart Circ Physiol 282: H1732–H1738, 2002.
62. Spengler CM, Roos M, Laube SM, Boutellier U. Decreased exercise blood lactate concentrations after respiratory endurance training in humans. Eur J Appl Physiol 79: 299 –305, 1999.
63. St Croix CM, Morgan BJ, Wetter TJ, Dempsey JA. Fatiguing inspiratory muscle work causes reflex sympathetic activation in humans. J Physiol 529: 493–504, 2000.
64. Stuessi C, Spengler CM, Knopfli-Lenzin C, Markov G, Boutellier U. Respiratory muscle endurance training in humans increases cycling endurance without affecting blood gas concentrations. Eur J Appl Physiol 84: 582–586, 2001. 65. Volianitis S, McConnell AK, Koutedakis Y, McNaughton L, Backx K, Jones DA. Inspiratory muscle training improves rowing performance. Med Sci Sports Exerc 33: 803–809, 2001.
66. Wagner PD. New ideas on limitations to V˙ O2max. Exerc Sport Sci Rev 28: 10 –14, 2000.
67. Whipp BJ, Davis JA, Torres F, Wasserman K. A test to determine parameters of aerobic function during exercise. J Appl Physiol 50: 217– 221, 1981.
68. Whipp BJ, Ward SA, Lamarra N, Davis JA, Wasserman K. Parameters of ventilatory and gas exchange dynamics during exercise. J Appl Physiol 52: 1506 –1513, 1982.
69. Whipp BJ, Wasserman K. Oxygen uptake kinetics for various intensities of constant-load work. J Appl Physiol 33: 351–356, 1972.
70. Wilkerson DP, Berger NJ, Jones AM. Influence of hyperoxia on pulmonary O2 uptake kinetics following the onset of exercise in humans. Respir Physiol Neurobiol 153: 92–106, 2006.
71. Wilkerson DP, Koppo K, Barstow TJ, Jones AM. Effect of work rate on the functional “gain” of phase II pulmonary O2 uptake response to exercise. Respir Physiol Neurobiol 142: 211–23, 2004.
72. Wilkerson DP, Rittweger J, Berger NJ, Naish PF, Jones AM. Influence of recombinant human erythropoietin treatment on pulmonary O2 uptake kinetics during exercise in humans. J Physiol 568: 639 –652, 2005.
73. Williams JS, Wongsathikun J, Boon SM, Acevedo EO. Inspiratory muscle training fails to improve endurance capacity in athletes. Med Sci Sports Exerc 34: 1194 –1198, 2002.
74. Witt JD, Guenette JA, Rupert JL, McKenzie DC, Sheel AW. Inspiratory muscle training attenuates the human respiratory muscle metaboreflex. J Physiol 584: 1019 –1028, 2007.