Time to reconsider how ventilation is regulated above the respiratory compensation point during incremental exercise
2020; American Physiological Society; Volume: 128; Issue: 5 Linguagem: Inglês
10.1152/japplphysiol.00814.2019
ISSN8750-7587
AutoresAndrea Nicolò, Samuele Marcora, Massimo Sacchetti,
Tópico(s)Sports Performance and Training
ResumoViewpointTime to reconsider how ventilation is regulated above the respiratory compensation point during incremental exerciseAndrea Nicolò, Samuele M. Marcora, and Massimo SacchettiAndrea NicolòDepartment of Movement, Human and Health Sciences, University of Rome "Foro Italico", Rome, Italy, Samuele M. MarcoraDepartment of Biomedical and Neuromotor Sciences, University of Bologna, Bologna, Italy, and Massimo SacchettiDepartment of Movement, Human and Health Sciences, University of Rome "Foro Italico", Rome, ItalyPublished Online:15 May 2020https://doi.org/10.1152/japplphysiol.00814.2019This is the final version - click for previous versionMoreSectionsPDF (68 KB)Download PDF ToolsExport citationAdd to favoritesGet permissionsTrack citations ShareShare onFacebookTwitterLinkedInWeChat INTRODUCTIONExercise physiology textbooks teach us that, during incremental exercise, minute ventilation (V̇e) is tightly linked with carbon dioxide output (V̇co2) up to the respiratory compensation point (RCP), where V̇e then increases disproportionately to V̇co2 as a result of metabolic acidosis. The fact that the increase in V̇e after RCP plays a fundamental role in acid-base balance regulation is indisputable. However, evidence that metabolic acidosis is the primary driver of V̇e after RCP is limited, and this classical interpretation has been challenged by several studies (4, 7, 12–14, 19, 20, 23). Nevertheless, the difficulty in identifying experimentally alternative inputs which drive V̇e limits our current understanding of ventilatory control during incremental exercise. After briefly reviewing these challenges to the classical interpretation, this Viewpoint will show how the differential control of respiratory frequency (fR) and tidal volume (VT) (24, 26, 28, 32) can shed further light on this issue. It is well established that fR increases nonlinearly during incremental exercise and that it primarily accounts for the increase in V̇e after RCP, while VT usually plateaus out (18, 21). However, what is much less appreciated is that the responses of fR and VT contain important information for the control of V̇e.PREVIOUS CHALLENGES TO THE CLASSICAL INTERPRETATIONSubstantial evidence suggests that the disproportionate increase in V̇e during incremental exercise is not determined by metabolic acidosis. Indeed, V̇e partially dissociates from metabolic acidosis when an incremental test is preceded by high-intensity exercise (4, 7, 20), dietary-induced glycogen depletion (4, 13, 14, 23), or is performed by patients with McArdle's disease (12). Two main "nonmetabolic" inputs have been proposed as alternative drivers to the increase in V̇e: 1) the mechanical and metabolic stimuli sensed by group III/IV muscle afferents (muscle afferent feedback) and 2) the activity of motor and premotor areas of the brain relating to volitional/motor control (central command) (12, 13, 20, 31). This is interesting considering that the disproportionate increase in V̇e relative to V̇co2, which occurs above the RCP, is determined by fR rather than VT (21), and that muscle afferent feedback and central command, but not metabolic inputs, appear to be major drivers of fR during exercise (1, 24–26). However, only a few of the aforementioned studies have reported the responses of fR and VT (4), while none have proposed that their differential control (24, 26, 28, 32) could support alternative explanations to metabolic acidosis for the disproportionate increase in V̇e after RCP.fR MAY NOT BE SUBSTANTIALLY REGULATED BY METABOLIC ACIDOSISA convincing argument against the disproportionate increase in V̇e being primarily mediated by metabolic acidosis is the fact that fR may not be substantially regulated by metabolic inputs, as we have recently suggested elsewhere (24–26). Briefly, animal studies provide clear evidence that metabolic acidosis does not regulate fR directly (2, 3). Changes in pH have an indirect effect on fR, which changes partially with variations in VT (the V̇e component directly regulated by metabolic inputs) via the volume feedback phenomenon (2, 3). Likewise, fR is affected by volume feedback in humans, but the attenuation of this stimulus via airway anesthesia does not prevent fR from increasing nonlinearly during incremental exercise (35). However, airway anesthesia intervention provides us with only a partial understanding of this issue. Findings by Shea et al. (29) on patients with congenital central hypoventilation syndrome would suggest that chemoreceptors do contribute to the regulation of V̇e during high-intensity incremental exercise, but the time course of fR was not reported by the authors. On the other hand, a number of examples show a dissociation between fR and metabolic acidosis during incremental exercise (4, 6, 33). Collectively, these findings suggest that the nonlinear increase in fR may not be substantially determined by the direct, or even indirect, effect of metabolic acidosis.fR IS REGULATED BY FAST INPUTSUnlike metabolic acidosis, fast inputs appear to play a substantial role in regulating fR (24, 26), with muscle afferent feedback (1) and central command (24, 26) being major contributors. The proportional contribution of muscle afferent feedback to fR regulation might be higher during moderate-intensity exercise compared with high-intensity exercise (1), whereas central command appears to contribute more during high-intensity exercise compared with moderate-intensity exercise (24). One of the few conditions where the contribution of central command to ventilation can be isolated from that of other inputs is during imagined exercise under hypnosis, where fR, but not VT, increases (31). This provides direct evidence that central command may preferentially regulate fR rather than VT. While it is much more challenging to understand the role of central command during incremental exercise, there are, however, several lines of indirect evidence which suggest that central command contributes to the disproportionate increase in V̇e and fR after RCP. These include experimental conditions or models aimed at altering the magnitude of the inputs regulating ventilation during incremental exercise: glycogen depletion (4, 13, 14, 23), prior exercise (4, 7, 20), cold (10), hypoxia and hyperoxia (19), hypercapnia (6, 8), airway anesthesia (35), and exercise in patients with McArdle's disease (12). Indeed, the disproportionate increase in V̇e and fR (when reported) was still present, irrespective of the specific condition tested. These findings suggest that this phenomenon is not primarily mediated by peripheral or central chemoreceptors (6, 8, 12, 19), pulmonary stretch receptors (35), pH, or other metabolic inputs (4, 6–8, 12, 14, 20). Conversely, it is conceivable that in these studies, central command contributed substantially to the disproportionate increase in V̇e and fR because an anticipated increase in V̇e was consistently observed in the conditions where an increase in central command was expected (4, 10, 13, 14, 23). Central command may also contribute to the nonlinear increase in V̇e found in patients with McArdle's disease (12), but some researchers have challenged the use of this pathological model to investigate ventilatory control during high-intensity exercise (34). A nonlinear increase in central command with exercise intensity is in line with previous suggestions made by Mitchell and Babb (22) and with the increase in the amount of activation of the exercising muscles observed during incremental exercise (19, 20). Further evidence supporting the role of central command in the hyperventilation of high-intensity exercise has been reported by Forster et al. (9), including the results of experiments inducing muscle weakness via partial curarization of the exercising muscles. Nevertheless, the difficulty of measuring the magnitude of central command during "real" exercise conditions limits our current understanding of the regulation of fR during incremental exercise. To partially address this issue, further studies should 1) report the responses of fR and VT; 2) select experimental conditions where the contribution of central command to ventilation is increased compared with that of other inputs [an example is the eccentric exercise protocol used by Marcora et al. (16) to induce locomotor muscle fatigue without a concomitant accumulation of muscle metabolites]; and 3) verify whether muscle afferent feedback contributes substantially to the nonlinear increase in fR and V̇e. This issue can be addressed by specifically examining whether this response persists after the attenuation of the afferent feedback, using, for instance, lumbar intrathecal fentanyl injection (1).THE NONLINEAR INCREASE IN fR MAY NOT BE DUE TO THE OCCURRENCE OF THE VT PLATEAUThe control of fR during incremental exercise has so far been overlooked because fR is believed to increase as a consequence of the stabilization of VT. It has been proposed that the VT plateau is determined by mechanical limitations which prevent further rises in VT, hence triggering the well-described tachypneic breathing pattern (15). However, there is no compelling evidence suggesting that either the VT plateau or the tachypneic breathing pattern is caused by mechanical limitations in healthy individuals; conversely, this proposition has been challenged by several studies. When incremental exercise is performed under hypercapnia (6, 8, 18) or dead space loading (21), the VT plateau occurs at higher VT values compared with control conditions. These findings argue against the notion that fR increases nonlinearly as a result of the attainment of maximal VT values. The fact that the VT peak observed during incremental exercise is lower than the maximum attainable value is also suggested by mechanical models of breathing (11, 15, 28a). Of note is the fact that, unlike the fR peak, the VT peak increases proportionally with different levels of hypercapnia during incremental exercise (6), thus suggesting that metabolic acidosis may preferentially regulate VT rather than fR levels. Furthermore, a tachypneic breathing pattern with stabilization or a decrease in VT can be observed in a variety of exercise paradigms where VT is well below maximal values (17, 27, 30), which makes the occurrence of mechanical limitations unlikely. Therefore, further research is needed to 1) directly verify whether mechanical limitations occur when VT plateaus out during different exercise protocols (e.g., incremental exercise and constant workload exercise) and experimental conditions (e.g., under different levels of hypercapnia), and 2) investigate the mechanisms underlying the occurrence of the tachypneic breathing pattern both in the presence of mechanical limitations or not. Indeed, the notion that the occurrence of the tachypneic breathing pattern is secondary to the stabilization of VT fails to explain what the factors/inputs that drive this response of fR are.CONCLUSIONSThis Viewpoint was intended to encourage researchers to consider the differential control of fR and VT when investigating the nonlinear increase in V̇e during incremental exercise. The use of such an approach suggests that central command contributes more than metabolic acidosis to the nonlinear response of V̇e above the RCP. We hope that this Viewpoint will further stimulate the differentiation between fR and VT in any future research into the complex regulation of ventilation during exercise.DISCLOSURESNo conflicts of interest, financial or otherwise, are declared by the authors.AUTHOR CONTRIBUTIONSA.N drafted manuscript; A.N., S.M.M., and M.S. edited and revised manuscript; A.N., S.M.M., and M.S. approved final version of manuscript.REFERENCES1. Amann M, Blain GM, Proctor LT, Sebranek JJ, Pegelow DF, Dempsey JA. Group III and IV muscle afferents contribute to ventilatory and cardiovascular response to rhythmic exercise in humans. J Appl Physiol (1985) 109: 966–976, 2010. doi:10.1152/japplphysiol.00462.2010. Link | ISI | Google Scholar2. Borison HL, Gonsalves SF, Montgomery SP, McCarthy LE. Dynamics of respiratory VT response to isocapnic pHa forcing in chemodenervated cats. J Appl Physiol 45: 502–511, 1978. doi:10.1152/jappl.1978.45.4.502.Link | ISI | Google Scholar3. 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Marcora, and Massimo Sacchetti15 May 2020 | Journal of Applied Physiology, Vol. 128, No. 5Physiological Reports, Vol. 8, No. 12 More from this issue > Volume 128Issue 5May 2020Pages 1447-1449 Copyright & PermissionsCopyright © 2020 the American Physiological Societyhttps://doi.org/10.1152/japplphysiol.00814.2019PubMed32053402History Received 25 November 2019 Accepted 10 February 2020 Published online 15 May 2020 Published in print 1 May 2020 Keywordscentral commanddifferential controlmetabolic acidosisrespiratory frequencytidal volume Metrics
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