David F. Pegelow

Arterial oxygenation influences central motor output and exercise performance via effects on peripheral locomotor muscle fatigue in humans.

Changing arterial oxygen content (C  aO 2 ) has a highly sensitive influence on the rate of peripheral locomotor muscle fatigue development. We examined the effects of C  aO 2 on exercise performance and its interaction with peripheral quadriceps fatigue. Eight trained males performed four 5 km cycling time trials (power output voluntarily adjustable) at four levels of C  aO 2 (17.6–24.4 ml O2 dl−1), induced by variations in inspired O2 fraction (0.15–1.0). Peripheral quadriceps fatigue was assessed via changes in force output pre‐ versus post‐exercise in response to supra‐maximal magnetic femoral nerve stimulation (ΔQtw; 1–100 Hz). Central neural drive during the time trials was estimated via quadriceps electromyogram. Increased C  aO 2 from hypoxia to hyperoxia resulted in parallel increases in central neural output (43%) and power output (30%) during cycling and improved time trial performance (12%); however, the magnitude of ΔQtw (−33 to −35%) induced by the exercise was not different among the four time trials (P > 0.2). These effects of C  aO 2 on time trial performance and ΔQtw were reproducible (coefficient of variation = 1–6%) over repeated trials at each F  IO 2 on separate days. In the same subjects, changing C  aO 2 also affected performance time to exhaustion at a fixed work rate, but similarly there was no effect of ΔC  aO 2 on peripheral fatigue. Based on these results, we hypothesize that the effect of C  aO 2 on locomotor muscle power output and exercise performance time is determined to a significant extent by the regulation of central motor output to the working muscle in order that peripheral muscle fatigue does not exceed a critical threshold.

Opioid‐mediated muscle afferents inhibit central motor drive and limit peripheral muscle fatigue development in humans

We investigated the role of somatosensory feedback from locomotor muscles on central motor drive (CMD) and the development of peripheral fatigue during high‐intensity endurance exercise. In a double‐blind, placebo‐controlled design, eight cyclists randomly performed three 5 km time trials: control, interspinous ligament injection of saline (5KPlac, L3–L4) or intrathecal fentanyl (5KFent, L3–L4) to impair cortical projection of opioid‐mediated muscle afferents. Peripheral quadriceps fatigue was assessed via changes in force output pre‐ versus postexercise in response to supramaximal magnetic femoral nerve stimulation (ΔQtw). The CMD during the time trials was estimated via quadriceps electromyogram (iEMG). Fentanyl had no effect on quadriceps strength. Impairment of neural feedback from the locomotor muscles increased iEMG during the first 2.5 km of 5KFentversus 5KPlac by 12 ± 3% (P < 0.05); during the second 2.5 km, iEMG was similar between trials. Power output was also 6 ± 2% higher during the first and 11 ± 2% lower during the second 2.5 km of 5KFentversus 5KPlac (both P < 0.05). Capillary blood lactate was higher (16.3 ± 0.5 versus 12.6 ± 1.0%) and arterial haemoglobin O2 saturation was lower (89 ± 1 versus 94 ± 1%) during 5KFentversus 5KPlac. Exercise‐induced ΔQtw was greater following 5KFentversus 5KPlac (−46 ± 2 versus−33 ± 2%, P < 0.001). Our results emphasize the critical role of somatosensory feedback from working muscles on the centrally mediated determination of CMD. Attenuated afferent feedback from exercising locomotor muscles results in an overshoot in CMD and power output normally chosen by the athlete, thereby causing a greater rate of accumulation of muscle metabolites and excessive development of peripheral muscle fatigue.

Severity of arterial hypoxaemia affects the relative contributions of peripheral muscle fatigue to exercise performance in healthy humans

We examined the effects of hypoxia severity on peripheral versus central determinants of exercise performance. Eight cyclists performed constant‐load exercise to exhaustion at various fractions of inspired O2 fraction (FIO2 0.21/0.15/0.10). At task failure (pedal frequency < 70% target) arterial hypoxaemia was surreptitiously reversed via acute O2 supplementation (FIO2= 0.30) and subjects were encouraged to continue exercising. Peripheral fatigue was assessed via changes in potentiated quadriceps twitch force (ΔQtw,pot) as measured pre‐ versus post‐exercise in response to supramaximal femoral nerve stimulation. At task failure in normoxia (haemoglobin saturation (SpO2) ∼94%, 656 ± 82 s) and moderate hypoxia (SpO2∼82%, 278 ± 16 s), hyperoxygenation had no significant effect on prolonging endurance time. However, following task failure in severe hypoxia (SpO2∼67%; 125 ± 6 s), hyperoxygenation elicited a significant prolongation of time to exhaustion (171 ± 61%). The magnitude of ΔQtw,pot at exhaustion was not different among the three trials (−35% to −36%, P= 0.8). Furthermore, quadriceps integrated EMG, blood lactate, heart rate, and effort perceptions all rose significantly throughout exercise, and to a similar extent at exhaustion following hyperoxygenation at all levels of arterial oxygenation. Since hyperoxygenation prolonged exercise time only in severe hypoxia, we repeated this trial and assessed peripheral fatigue following task failure prior to hyperoxygenation (125 ± 6 s). Although Qtw,pot was reduced from pre‐exercise baseline (−23%; P < 0.01), peripheral fatigue was substantially less (P < 0.01) than that observed at task failure in normoxia and moderate hypoxia. We conclude that across the range of normoxia to severe hypoxia, the major determinants of central motor output and exercise performance switches from a predominantly peripheral origin of fatigue to a hypoxia‐sensitive central component of fatigue, probably involving brain hypoxic effects on effort perception.

Fatiguing inspiratory muscle work causes reflex reduction in resting leg blood flow in humans

1 We recently showed that fatigue of the inspiratory muscles via voluntary efforts caused a time‐dependent increase in limb muscle sympathetic nerve activity (MSNA) ( St Croix et al. 2000 ). We now asked whether limb muscle vasoconstriction and reduction in limb blood flow also accompany inspiratory muscle fatigue. 2 In six healthy human subjects at rest, we measured leg blood flow (Q̇L) in the femoral artery with Doppler ultrasound techniques and calculated limb vascular resistance (LVR) while subjects performed two types of fatiguing inspiratory work to the point of task failure (3‐10 min). Subjects inspired primarily with their diaphragm through a resistor, generating (i) 60 % maximal inspiratory mouth pressure (PM) and a prolonged duty cycle (TI/TTOT= 0.7); and (ii) 60 % maximal PM and a TI/TTOT of 0.4. The first type of exercise caused prolonged ischaemia of the diaphragm during each inspiration. The second type fatigued the diaphragm with briefer periods of ischaemia using a shorter duty cycle and a higher frequency of contraction. End‐tidal PCO2 was maintained by increasing the inspired CO2 fraction (FI,CO2) as needed. Both trials caused a 25–40 % reduction in diaphragm force production in response to bilateral phrenic nerve stimulation. 3 Q̇ L and LVR were unchanged during the first minute of the fatigue trials in most subjects; however, Q̇L subsequently decreased (‐30 %) and LVR increased (50‐60 %) relative to control in a time‐dependent manner. This effect was present by 2 min in all subjects. During recovery, the observed changes dissipated quickly (< 30 s). Mean arterial pressure (MAP; +4‐13 mmHg) and heart rate (+16‐20 beats min−1) increased during fatiguing diaphragm contractions. 4 When central inspiratory motor output was increased for 2 min without diaphragm fatigue by increasing either inspiratory force output (95 % of maximal inspiratory pressure (MIP)) or inspiratory flow rate (5 × eupnoea), Q̇L, MAP and LVR were unchanged; although continuing the high force output trials for 3 min did cause a relatively small but significant increase in LVR and a reduction in nQ̇L. 5 When the breathing pattern of the fatiguing trials was mimicked with no added resistance, LVR was reduced and Q̇L increased significantly; these changes were attributed to the negative feedback effects on MSNA from augmented tidal volume. 6 Voluntary increases in inspiratory effort, in the absence of diaphragm fatigue, had no effect on Q̇L and LVR, whereas the two types of diaphragm‐fatiguing trials elicited decreases in Q̇L and increases in LVR. We attribute these changes to a metaboreflex originating in the diaphragm. Diaphragm and forearm muscle fatigue showed very similar time‐dependent effects on LVR and Q̇L.

Group III and IV muscle afferents contribute to ventilatory and cardiovascular response to rhythmic exercise in humans

We investigated the role of somatosensory feedback on cardioventilatory responses to rhythmic exercise in five men. In a double-blind, placebo-controlled design, subjects performed the same leg cycling exercise (50/100/150/325 ± 19 W, 3 min each) under placebo conditions (interspinous saline, L(3)-L(4)) and with lumbar intrathecal fentanyl impairing central projection of spinal opioid receptor-sensitive muscle afferents. Quadriceps strength was similar before and after fentanyl administration. To evaluate whether a cephalad migration of fentanyl affected cardioventilatory control centers in the brain stem, we compared resting ventilatory responses to hypercapnia (HCVR) and cardioventilatory responses to arm vs. leg cycling exercise after each injection. Similar HCVR and minor effects of fentanyl on cardioventilatory responses to arm exercise excluded direct medullary effects of fentanyl. Central command during leg exercise was estimated via quadriceps electromyogram. No differences between conditions were found in resting heart rate (HR), ventilation [minute ventilation (VE)], or mean arterial pressure (MAP). Quadriceps electromyogram, O(2) consumption (VO(2)), and plasma lactate were similar in both conditions at the four steady-state workloads. Compared with placebo, a substantial hypoventilation during fentanyl exercise was indicated by the 8-17% reduction in VE/CO(2) production (VCO(2)) secondary to a reduced breathing frequency, leading to average increases of 4-7 Torr in end-tidal PCO(2) (P < 0.001) and a reduced hemoglobin saturation (-3 ± 1%; P < 0.05) at the heaviest workload (∼90% maximal VO(2)) with fentanyl. HR was reduced 2-8%, MAP 8-13%, and ratings of perceived exertion by 13% during fentanyl vs. placebo exercise (P < 0.05). These findings demonstrate the essential contribution of muscle afferent feedback to the ventilatory, cardiovascular, and perceptual responses to rhythmic exercise in humans, even in the presence of unaltered contributions from other major inputs to cardioventilatory control.

Exercise-induced arterial hypoxaemia in healthy young women

1 We questioned whether exercise‐induced arterial hypoxaemia (EIAH) occurs in healthy active women, who have smaller lungs, reduced lung diffusion, and lower maximal O2 consumption rate (V̇O2,max) than age‐ and height‐matched men. 2 Twenty‐nine healthy young women with widely varying fitness levels (V̇O2,max, 57 ± 6 ml kg−1 min−1; range, 35‐70 ml kg−1 min−1; or 148 ± 5 %; range, 93‐188 % predicted) and normal resting lung function underwent an incremental treadmill test to VO2,max during the follicular phase of their menstrual cycle. Arterial blood samples were taken at rest and near the end of each workload. 3 Arterial PO2 (Pa,O2) decreased > 10 mmHg below rest in twenty‐two of twenty‐nine subjects at V̇O2,max (Pa,O2, 77.5 ± 0.9 mmHg; range, 67‐88 mmHg; arterial O2 saturation (Sa,O2), 92.3 ± 0.2 %; range, 87‐94 %). The remaining seven subjects maintained Pa,O2 within 10 mmHg of rest. Pa,O2 at VO2,max was inversely related to the alveolar to arterial O2 difference (A‐aDO2) (r= ‐0.93; 35‐52 mmHg) and to arterial PCO2 (Pa,CO2) (r= ‐0.62; 26‐39 mmHg). 4 EIAH was inversely related to V̇O2,max (r= ‐0.49); however, there were many exceptions. Almost half of the women with significant EIAH had VO2,max within 15 % of predicted normal values (VO2,max, 40‐55 ml kg−1 min−1); among subjects with very high VO2,max (55‐70 ml kg−1 min−1), the degree of excessive A‐aDO2 and EIAH varied markedly (e.g. A‐aDO2, 30‐50 mmHg; Pa,O2, 68‐91 mmHg). 5 In the women with EIAH at V̇O2,max, many began to experience an excessive widening of their A‐aDO2 during moderate intensity exercise, which when combined with a weak ventilatory response, led to a progressive hypoxaemia. Inactive, less fit subjects had no EIAH and narrower A‐aDO2 when compared with active, fitter subjects at the same VO2 (40‐50 ml kg−1 min−1). 6 These data demonstrate that many active healthy young women experience significant EIAH, and at a VO2,max that is substantially less than those in their active male contemporaries. The onset of EIAH during submaximal exercise, and/or its occurrence at a relatively low V̇O2,max, implies that lung structure/function subserving alveolar to arterial O2 transport is abnormally compromised in many of these habitually active subjects.

Effect of inspiratory muscle work on peripheral fatigue of locomotor muscles in healthy humans

The work of breathing required during maximal exercise compromises blood flow to limb locomotor muscles and reduces exercise performance. We asked if force output of the inspiratory muscles affected exercise‐induced peripheral fatigue of locomotor muscles. Eight male cyclists exercised at ≥ 90% peak O2 uptake to exhaustion (CTRL). On a separate occasion, subjects exercised for the same duration and power output as CTRL (13.2 ± 0.9 min, 292 W), but force output of the inspiratory muscles was reduced (−56%versus CTRL) using a proportional assist ventilator (PAV). Subjects also exercised to exhaustion (7.9 ± 0.6 min, 292 W) while force output of the inspiratory muscles was increased (+80%versus CTRL) via inspiratory resistive loads (IRLs), and again for the same duration and power output with breathing unimpeded (IRL‐CTRL). Quadriceps twitch force (Qtw), in response to supramaximal paired magnetic stimuli of the femoral nerve (1–100 Hz), was assessed pre‐ and at 2.5 through to 70 min postexercise. Immediately after CTRL exercise, Qtw was reduced −28 ± 5% below pre‐exercise baseline and this reduction was attenuated following PAV exercise (−20 ± 5%; P < 0.05). Conversely, increasing the force output of the inspiratory muscles (IRL) exacerbated exercise‐induced quadriceps muscle fatigue (Qtw=−12 ± 8% IRL‐CTRL versus−20 ± 7% IRL; P < 0.05). Repeat studies between days showed that the effects of exercise per se, and of superimposed inspiratory muscle loading on quadriceps fatigue were highly reproducible. In conclusion, peripheral fatigue of locomotor muscles resulting from high‐intensity sustained exercise is, in part, due to the accompanying high levels of respiratory muscle work.

Implications of group III and IV muscle afferents for high‐intensity endurance exercise performance in humans

Non‐Technical Summary  We investigated the influence of group III/IV muscle afferents on central motor drive, the development of peripheral locomotor muscle fatigue, and endurance performance time during high‐intensity constant‐load cycling exercise to exhaustion. Our findings suggest that, on the one hand, afferent feedback ensures adequate circulatory and ventilatory responses to exercise which optimizes muscle O2 transport and thereby facilitates exercise performance by preventing premature peripheral fatigue. On the other hand, afferent feedback inhibits central motor drive, which is reflected in the restriction of the neural excitation of the locomotor musculature and the reduced tolerance for peripheral muscle fatigue, and thereby limits exercise performance. Taken together, the current investigation revealed the net effects of sensory afferent feedback on time to exhaustion during high‐intensity constant‐load cycling exercise and showed that intact group III/IV muscle afferent feedback is a vital component in achieving optimal endurance performance.

Somatosensory feedback from the limbs exerts inhibitory influences on central neural drive during whole body endurance exercise

We investigated whether somatosensory feedback from contracting limb muscles exerts an inhibitory influence on the determination of central command during closed-loop cycling exercise in which the subject voluntarily determines his second-by-second central motor drive. Eight trained cyclists performed two 5-km time trials either without (5K(Ctrl)) or with lumbar epidural anesthesia (5K(Epi); 24 ml of 0.5% lidocaine, vertebral interspace L(3)-L(4)). Percent voluntary quadriceps muscle activation was determined at rest using a superimposed twitch technique. Epidural lidocaine reduced pretime trial maximal voluntary quadriceps strength (553 +/- 45 N) by 22 +/- 3%. Percent voluntary quadriceps activation was also reduced from 97 +/- 1% to 81 +/- 3% via epidural lidocaine, and this was unchanged following the 5K(Epi), indicating the presence of a sustained level of neural impairment throughout the trial. Power output was reduced by 9 +/- 2% throughout the race (P < 0.05). We found three types of significant effects of epidural lidocaine that supported a substantial role for somatosensory feedback from the exercising limbs as a determinant of central command throughout high-intensity closed-loop cycling exercise: 1) significantly increased relative integrated EMG of the vastus lateralis; 2) similar pedal forces despite the reduced number of fast-twitch muscle fibers available for activation; 3) and increased ventilation out of proportion to a reduced carbon dioxide production and heart rate and increased blood pressure out of proportion to power output and oxygen consumption. These findings demonstrate the inhibitory influence of somatosensory feedback from contracting locomotor muscles on the conscious and/or subconscious determination of the magnitude of central motor drive during high intensity closed-loop endurance exercise.

Effects of respiratory muscle training versus placebo on endurance exercise performance

We evaluated the effects of a 5 week (25 sessions); (30-35 min/day, 5 days/week), respiratory muscle training (RMT) program in nine competitive male cyclists. The experimental design included inspiratory resistance strength training (3-5 min/session) and hyperpnea endurance training (30 min/session), a placebo group which used a sham hypoxic trainer (n=8), and three exercise performance tests, including a highly reproducible 8 km time trial test. RMT intensity, measured once a week in terms of accumulated inspiratory pressure and the level of sustainable hyperpnea increased significantly after 5 weeks (+64% and +19%, respectively). The RMT group showed a significant 8% increase in maximal inspiratory pressure (P<0.05) while the placebo group showed only a 3.7% increase (P>0.10). RMT and placebo groups both showed significant increases in the fixed work-rate endurance test performance time (+26% and +16%, respectively) and in the peak work-rate achieved during the incremental maximal oxygen consumption (V(O2)max) test (+9 and +6%). The 8 km time trial performance increased 1.8+/-1.2% (or 15+/-10 sec; P<0.01) in the RMT group with 8 of 9 subjects increasing; the placebo group showed a variable non-significant change in 5 of 8 subjects (-0.3+/-2.7%, P=0.07). The changes observed in these three performance tests were not, however, significantly different between the RMT and placebo groups. Heart rate, ventilation, or venous blood lactate, at equal work-rates during the incremental exercise test or at equal times during the fixed work-rate endurance test were not changed significantly across these exercise trials in either group. We propose that the effect of RMT on exercise performance in highly trained cyclists does not exceed that in a placebo group. Significant placebo and test familiarization effects must be accounted for in experimental designs utilizing performance tests which are critically dependent on volitional effort.