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.

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 O 2 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. AbstractWe investigated the influence of group III/IV muscle afferents on peripheral fatigue, central motor drive (CMD) and endurance capacity during high-intensity leg-cycling. In a double-blind, placebo-controlled design, seven males performed constant-load cycling exercise (318 ± 9 W; 80% of peak power output (W peak )) to exhaustion under placebo conditions and with lumbar intrathecal fentanyl impairing spinal μ-opioid receptor-sensitive group III/IV muscle afferents. Peripheral fatigue was assessed via changes in pre-vs. post-exercise quadriceps force in response to supramaximal magnetic femoral nerve stimulation ( Q tw,pot ). CMD was estimated via quadriceps electromyogram. To rule out a direct central effect of fentanyl, we documented unchanged resting cardioventilatory responses. Compared to placebo, significant hypoventilation during the fentanyl trial was indicated by the 9% lowerV E /V CO 2 , causing a 5 mmHg increase in end-tidal P CO 2 and a 3% lower haemoglobin saturation. Arterial pressure and heart rate averaged 8 and 10% lower, respectively, during the fentanyl trial and these differences progressively diminished towards end-exercise. Although initially similar, the percent change in CMD was 9 ± 3% higher at end-exercise with fentanyl vs. placebo (P < 0.05). Time to exhaustion was shorter (6.8 ± 0.3 min vs. 8.7 ± 0.3 min) and end-exercise Q tw,pot was about one-third greater (-44 ± 2% vs. -34 ± 2%) following fentanyl vs. placebo. The rate of peripheral fatigue development was 67 ± 10% greater during the fentanyl trial (P < 0.01). Our findings suggest that feedback from group III/IV muscle afferents limits CMD but also minimizes locomotor muscle fatigue development by stimulating adequate ventilatory and circulatory responses to exercise. compromised and locomotor muscle fatigability is exacerbated with a combined net effect of a reduced endurance performance.

Key pointsr The purpose of this study was to determine the role of group III/IV muscle afferents in limiting the endurance exercise-induced metabolic perturbation assayed in muscle biopsy samples taken from locomotor muscle.r Lumbar intrathecal fentanyl was used to attenuate the central projection of μ-opioid receptor-sensitive locomotor muscle afferents during a 5 km cycling time trial.r The findings suggest that the central projection of group III/IV muscle afferent feedback constrains voluntary neural 'drive' to working locomotor muscle and limits the exercise-induced intramuscular metabolic perturbation.r Therefore, the CNS might regulate the degree of metabolic perturbation within locomotor muscle and thereby limit peripheral fatigue. It appears that the group III/IV muscle afferents are an important neural link in this regulatory mechanism, which probably serves to protect locomotor muscle from the potentially severe functional impairment as a consequence of severe intramuscular metabolic disturbance.Abstract To investigate the role of metabo-and mechanosensitive group III/IV muscle afferents in limiting the intramuscular metabolic perturbation during whole body endurance exercise, eight subjects performed 5 km cycling time trials under control conditions (CTRL) and with lumbar intrathecal fentanyl impairing lower limb muscle afferent feedback (FENT). Vastus lateralis muscle biopsies were obtained before and immediately after exercise. Motoneuronal output was estimated through vastus lateralis surface electromyography (EMG). Exercise-induced changes in intramuscular metabolites were determined using liquid and gas chromatography-mass spectrometry. Quadriceps fatigue was quantified by pre-to post-exercise changes in potentiated quadriceps twitch torque ( QT single ) evoked by electrical femoral nerve stimulation. Although motoneuronal output was 21 ± 12% higher during FENT compared to CTRL (P < 0.05), time to complete the time trial was similar (ß8.8 min). Compared to CTRL, power output during FENT was 10 ± 4% higher in the first half of the time trial, but 11 ± 5% lower in the second half (both P < 0.01). The exercise-induced increase in intramuscular inorganic phosphate, H + , adenosine diphosphate, lactate and phosphocreatine depletion was 55 ± 30, 62 ± 18, 129 ± 63, 47 ± 14 (P < 0.001) and 27 ± 14% (P < 0.01) greater in FENT than CTRL. QT single was greater following FENT than CTRL (−52 ± 2 vs −31 ± 1%, P < 0.001) and this difference was positively correlated with the difference in inorganic phosphate (r 2 = 0.79; P < 0.01) and H + (r 2 = 0.92; P < 0.01). In conclusion, during whole body exercise, group III/IV muscle afferents provide feedback to the CNS which, in turn, constrains motoneuronal output to the active skeletal muscle. This regulatory mechanism limits the exercise-induced intramuscular metabolic perturbation, preventing an abnormal homeostatic challenge and excessive peripheral fatigue.

We assessed the contribution of carotid body chemoreceptors to the ventilatory response to specific CNS hypercapnia in eight unanaesthetized, awake dogs. We denervated one carotid body (CB) and used extracorporeal blood perfusion of the reversibly isolated remaining CB to maintain normal CB blood gases (normoxic, normocapnic perfusate), to inhibit (hyperoxic, hypocapnic perfusate) or to stimulate (hypoxic, normocapnic perfusate) the CB chemoreflex, while the systemic circulation, and therefore the CNS and central chemoreceptors, were exposed consecutively to four progressive levels of systemic arterial hypercapnia via increased fractional inspired CO 2 for 7 min at each level. Neither unilateral CB denervation nor CB perfusion, per se, affected breathing. Relative to CB control conditions (normoxic, normocapnic perfusion), we found that CB chemoreflex inhibition decreased the slope of the ventilatory response to CNS hypercapnia in all dogs to an average of 19% of control values (range 0-38%; n = 6), whereas CB chemoreflex stimulation increased the slope of the ventilatory response to CNS hypercapnia in all dogs to an average of 223% of control values (range 204-235%; n = 4). We conclude that the gain of the CNS CO 2 /H + chemoreceptors in dogs is critically dependent on CB afferent activity and that CNS-CB interaction results in hyperadditive ventilatory responses to central hypercapnia.

Blain, Grégory, Olivier Meste, and Stéphane Bermon. Influences of breathing patterns on respiratory sinus arrhythmia in humans during exercise. Am J Physiol Heart Circ Physiol 288: H887-H895, 2005. First published September 23, 2004 doi:10.1152/ajpheart. 00767.2004.-Persistence of respiratory sinus arrhythmia (RSA) has been described in humans during intense exercise and attributed to an increase in ventilation. However, the direct influence of ventilation on RSA has never been assessed. The dynamic evolution of RSA and its links to ventilation were investigated during exercise in 14 healthy men using an original modeling approach. An evolutive model was estimated from the detrended and high-pass-filtered heart period series. The instantaneous RSA frequency (FRSA, in Hz) and amplitude (ARSA, in ms) were then extracted from all recordings. ARSA was calculated with short-time Fourier transform. First, measurements of FRSA and ARSA were performed from data obtained during a graded and maximal exercise test. Influences of different ventilation regimens [changes in tidal volume (VT) and respiratory frequency (FR)] on ARSA were then tested during submaximal [70% peak O2 consumption (V O2 peak)] rectangular exercise bouts. Under graded and maximal exercise conditions, ARSA decreased from the beginning of exercise to 61.9 Ϯ 3.8% V O2 peak and then increased up to peak exercise. During the paced breathing protocol, normoventilation (69.4 Ϯ 8.8 l/min), hyperventilation (81.8 Ϯ 8.3 l/min), and hypoventilation (56.4 Ϯ 6.2 l/min) led to significantly (P Ͻ 0.01) different ARSA values (3.8 Ϯ 0.5, 4.6 Ϯ 0.8, and 2.9 Ϯ 0.5 ms, respectively). In addition, no statistical difference was found in ARSA when ventilation was kept constant, whatever the FR-VT combinations. Those results indicate that RSA persists for all exercise intensities and increases during the highest intensities. Its persistence and increase are strongly linked to both the frequency and degree of lung inflation, suggesting a mechanical influence of breathing on RSA. cardiorespiratory coupling; heart period variability; paced breathing; time-varying model

In this review we discuss the implications for ventilatory control of newer evidence suggesting that central and peripheral chemoreceptors are not functionally separate but rather that they are dependent upon one another such that the sensitivity of the medullary chemoreceptors is critically determined by input from the carotid body chemoreceptors and vice versa i.e., they are interdependent. We examine potential interactions of the interdependent central and carotid body (CB) chemoreceptors with other ventilatory-related inputs such as central hypoxia, lung stretch, and exercise. The limitations of current approaches addressing this question are discussed and future studies are suggested.

We hypothesized that exercise performance is adjusted during repeated sprints in order not to surpass a critical threshold of peripheral fatigue. Twelve men randomly performed three experimental sessions on different days, i.e. one single 10 s all-out sprint and two trials of 10 × 10 s all-out sprints with 30 s of passive recovery in between. One trial was performed in the unfatigued state (CTRL) and one following electrically induced quadriceps muscle fatigue (FTNMES). Peripheral fatigue was quantified by comparing pre- with postexercise changes in potentiated quadriceps twitch force (ΔQtw-pot) evoked by supramaximal magnetic stimulation of the femoral nerve. Central fatigue was estimated by comparing pre- with postexercise voluntary activation of quadriceps motor units. The root mean square (RMS) of the vastus lateralis and vastus medialis EMG normalized to maximal M-wave amplitude (RMS.Mmax (-1)) was also calculated during sprints. Compared with CTRL condition, pre-existing quadriceps muscle fatigue in FTNMES (ΔQtw-pot = -29 ± 4%) resulted in a significant (P < 0.05) reduction in power output (-4.0 ± 0.9%) associated with a reduction in RMS.Mmax (-1). However, ΔQtw-pot postsprints decreased by 51% in both conditions, indicating that the level of peripheral fatigue was identical and independent of the degree of pre-existing fatigue. Our findings show that power output and cycling EMG are adjusted during exercise in order to limit the development of peripheral fatigue beyond a constant threshold. We hypothesize that the contribution of peripheral fatigue to exercise limitation involves a reduction in central motor drive in addition to the impairment in muscular function.

Key Pointsr The influence of specific carotid body (CB) normoxic hypocapnia, hypercapnia and normocapnia on the ventilatory sensitivity of central chemoreceptors to systemic hypercapnia was assessed in seven awake dogs with extracorporeal perfusion of the vascularly isolated CB.r Chemosensitivity in this preparation was similar to that in the intact animal. r Separation of CB circulation from that of the brain was confirmed. r When the isolated CB was hypercapnic vs. hypocapnic and when the isolated CB was normocapnic vs. hypocapnic, the group mean central CO 2 response slopes of minute ventilation (V I ) (P ࣘ 0.01) and mean inspiratory flow rate (V T /T I ) (P ࣘ 0.05) increased significantly. Tidal volume (V T ), breathing frequency (f b )and rate of rise of diaphragm EMG were increased in 6 of 7 dogs but did not achieve statistical significance.r We propose that hyperaddition is the dominant form of chemoreceptor interaction under conditions of quiet wakefulness in intact animals and over a wide range of CB P CO 2 and P O 2 .Abstract We asked if the type of carotid body (CB) chemoreceptor stimulus influenced the ventilatory gain of the central chemoreceptors to CO 2 . The effect of CB normoxic hypocapnia, normocapnia and hypercapnia (carotid body P CO 2 22, 41 and 68 mmHg, respectively) on the ventilatory CO 2 sensitivity of central chemoreceptors was studied in seven awake dogs with vascularly-isolated and extracorporeally-perfused CBs. Chemosensitivity with one CB was similar to that in intact dogs. In four CB-denervated dogs, absence of hyper-/hypoventilatory responses to CB perfusion with P CO 2 of 19-75 mmHg confirmed separation of the perfused CB circulation from the brain. The group mean central CO 2 response slopes were increased 303% for minute ventilation (V I )(P ࣘ 0.01) and 251% for mean inspiratory flow rate (V T /T I ) (P ࣘ 0.05) when the CB was hypercapnic vs. hypocapnic; central CO 2 response slopes for tidal volume (V T ), breathing frequency (f b ) and rate of rise of the diaphragm EMG increased in 6 of 7 animals but the group mean changes did not reach statistical significance. Group mean central CO 2 response slopes were also increased 237% forV I (P ࣘ 0.01) and 249% for V T /T I (P ࣘ 0.05) when the CB was normocapnic vs. hypocapnic, but no significant differences in any of the central ventilatory response indices were found between CB normocapnia and hypercapnia. These hyperadditive effects of CB hyper-/hypocapnia agree with previous findings using CB hyper-/hypoxia.We propose that hyperaddition is the dominant form of chemoreceptor interaction in quiet wakefulness when the chemosensory control system is intact, response gains physiological, and carotid body chemoreceptors are driven by a wide range of O 2 and/or CO 2 .