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Open Access 26-02-2022 | Invited Review

A century of exercise physiology: key concepts on coupling respiratory oxygen flow to muscle energy demand during exercise

Authors: Guido Ferretti, Nazzareno Fagoni, Anna Taboni, Giovanni Vinetti, Pietro Enrico di Prampero

Published in: European Journal of Applied Physiology | Issue 6/2022

Abstract

After a short historical account, and a discussion of Hill and Meyerhof’s theory of the energetics of muscular exercise, we analyse steady-state rest and exercise as the condition wherein coupling of respiration to metabolism is most perfect. The quantitative relationships show that the homeostatic equilibrium, centred around arterial pH of 7.4 and arterial carbon dioxide partial pressure of 40 mmHg, is attained when the ratio of alveolar ventilation to carbon dioxide flow (\({\dot{V}}_{A}/{\dot{V}}_{R}{CO}_{2}\)) is − 21.6. Several combinations, exploited during exercise, of pertinent respiratory variables are compatible with this equilibrium, allowing adjustment of oxygen flow to oxygen demand without its alteration. During exercise transients, the balance is broken, but the coupling of respiration to metabolism is preserved when, as during moderate exercise, the respiratory system responds faster than the metabolic pathways. At higher exercise intensities, early blood lactate accumulation suggests that the coupling of respiration to metabolism is transiently broken, to be re-established when, at steady state, blood lactate stabilizes at higher levels than resting. In the severe exercise domain, coupling cannot be re-established, so that anaerobic lactic metabolism also contributes to sustain energy demand, lactate concentration goes up and arterial pH falls continuously. The \({\dot{V}}_{A}/{\dot{V}}_{R}{CO}_{2}\) decreases below − 21.6, because of ensuing hyperventilation, while lactate keeps being accumulated, so that exercise is rapidly interrupted. The most extreme rupture of the homeostatic equilibrium occurs during breath-holding, because oxygen flow from ambient air to mitochondria is interrupted. No coupling at all is possible between respiration and metabolism in this case.

This definition implies that in blood, \({\dot{V}}_{R}{O}_{2}\) and \({\dot{V}}_{R}{CO}_{2}\) are not the flow of the respective gases in arterial or in mixed venous blood, but the difference between these two flows; analogously, in the lungs, \({\dot{V}}_{R}{O}_{2}\) and \({\dot{V}}_{R}{CO}_{2}\) are not the flow of the respective gases in inspired or in expired air, but the difference between these two flows.

\({\dot{V}}_{R}{O}_{2}\) and \({\dot{V}}_{R}{CO}_{2}\) are flows along the respiratory system, oriented in opposite directions. Equations (5a) and (5b) clearly show that, since \({C}_{a}{O}_{2}\) > \({C}_{\stackrel{-}{v}}{O}_{2}\), whereas \({C}_{a}{CO}_{2}<{C}_{\overline{v}}{CO}_{2}\), \({\dot{V}}_{R}{O}_{2}\) results positive and \({\dot{V}}_{R}{CO}_{2}\) turns out negative. This implies that RQ_L is negative as well. This concept carries along a notation differing from the usual notation, wherein the modulus of these flows is used.

Since \({\dot{V}}_{R}{CO}_{2}\) is in STPD and \({\dot{V}}_{A}\) in BTPS, expressing both variables in standard condition, so that \({F}_{A}{CO}_{2} = \frac{{P}_{A}{CO}_{2} }{{P}_{B}{-47}}\), yields \(\frac{{\dot{V}}_{A[{BTPS}]}}{{\dot{V}}_{R}{{CO}_{2}}_{[{STPD}]}}=-\frac{{P}_{B}-47 \, \mathrm{mmHg }}{{P}_{A}{CO}_{2}} \frac{760 \, \mathrm{mmHg}}{273 \, ^\circ \mathrm{K}}\frac{310 \, ^\circ \mathrm{K}}{{P}_{B}-47 \, \mathrm{mmHg}}=-\frac{863 \, \mathrm{mmHg }}{{P}_{A}{CO}_{2}}\). This means that, for \({P}_{A}{CO}_{2}=\) 40 mmHg, \(\frac{{\dot{V}}_{A[{BTPS}]}}{{\dot{V}}_{R}{{\mathrm{CO}}_{2}}_{[{STPD}]}}=-\frac{863 }{40}=-21.6\). This value does not vary at exercise, because \({\dot{V}}_{A}\) and \({\dot{V}}_{R}{CO}_{2}\) increase in direct proportion.

The extraordinary stability of \({P}_{A}{CO}_{2}\) and \({P}_{a}{CO}_{2}\) around 40 mmHg throughout life has to do with the fact that the ventilatory response to carbon dioxide (actually to the H+ concentration in the cerebrospinal fluid) is a threshold phenomenon, with threshold at an H+ concentration compatible with \({P}_{a}{CO}_{2}=\) 40 mmHg. The phenomenon is a consequence of how the acid-sensing ion channels interact with H+ . Bound H+ is in dynamic equilibrium with free H+ . When a sufficiently high number of H+ units are bound to the extracellular region of the channel, the transmembrane domain 2 of the channel undergoes conformational changes leading to channel opening. An influx of sodium ions, and thus cell depolarization, occur, leading to activation of voltage-gated calcium channels. The ASIC 1 and ASIC 2 channels are widely expressed in the ventro-lateral medulla. For details, see e.g. Hanukoglu (2017), Song et al. (2016) and Zha (2013). On the role of central chemoreceptors in regulating pH and \({P}_{a}{CO}_{2}\), see Guyenet (2014), and Nattie and Li (2012).

It is important to mention that the arterial blood concentrations are weighed by perfusion to each unit, whereas the alveolar gas concentrations are weighed by the ventilation to each unit. The heterogeneity of perfusion distribution across the lungs is much more accentuated than the heterogeneity of ventilation distribution. Therefore, the number of alveolar units with low \({\dot{V}}_{A}/\dot{Q}\) values is by far larger than that of alveolar units with high \({\dot{V}}_{A}/\dot{Q}\) values, so that the former units contribute more than the latter to the formation of arterial blood.

In fact \({\dot{V}}_{A}=-\frac{\frac{760 }{{P}_{B}-47} \frac{310}{273} {RQ}_{L } \, {\dot{V}}_{R}{O}_{2}}{ \frac{{P}_{A}{CO}_{2}}{{P}_{B}-47}}\). Since the two terms (\({P}_{B}-47\)) cancel out, the proportionality constant in Eq. (16) (Cg) turns out equal to 760*310/273, i.e., 863 mmHg if \({\dot{V}}_{R}{CO}_{2}\) is expressed in L min⁻¹, or 0.863 mmHg if \({\dot{V}}_{R}{CO}_{2}\) is expressed in ml min⁻¹.

Throughout the text, the acronym \({\dot{V}}_{R}{O}_{2}\) is used for oxygen flow, because it is the oxygen flow along the respiratory system. However, since these are steady-state relationships, wherein \({\dot{V}}_{R}{O}_{2}=\dot{V}{O}_{2}\), we could also use \(\dot{V}{O}_{2}\) instead, as Cerretelli and di Prampero (1987) did.

It is fair to acknowledge that the piezo ion channel hypothesis on baroreceptors has been scrutinized and challenged by other authors (Stocker et al. 2019).

Equation (35) does not include dissolved oxygen, which at a \({P}_{a}{O}_{2}\) of 100 mmHg contributes only 3 mL of oxygen per litre of blood, i.e., about 1.5% of the overall amount of oxygen in arterial blood: a negligible quantity indeed.

In this case, expressing \(\left[{Hb}\right]\) in g L⁻¹, \({\dot{V}}_{A}\) in L min⁻¹, \({P}_{A}{CO}_{2}\) in mmHg and \({C}_{a}{O}_{2}-{C}_{\overline{v}}{O}_{2}\) in mL L⁻¹, \({\dot{V}}_{R}{O}_{2}\) turns out in mL min⁻¹.

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Title: A century of exercise physiology: key concepts on coupling respiratory oxygen flow to muscle energy demand during exercise
Authors: Guido Ferretti
Nazzareno Fagoni
Anna Taboni
Giovanni Vinetti
Pietro Enrico di Prampero
Publication date: 26-02-2022
Publisher: Springer Berlin Heidelberg
Published in: European Journal of Applied Physiology / Issue 6/2022
Print ISSN: 1439-6319
Electronic ISSN: 1439-6327
DOI: https://doi.org/10.1007/s00421-022-04901-x

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A century of exercise physiology: key concepts on coupling respiratory oxygen flow to muscle energy demand during exercise

Abstract

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Abstract

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