Not too much, not too little: crucial balance of muscle feedback on ventilation regulation

Despite more than a century of studies, the mechanisms underlying ventilatory responses to exercise remain an intriguing mystery. During exercise in the moderate- and heavy-intensity domain, ventilatory responses precisely match the rise in venous CO2 content generated by the metabolic demands of working muscles (i.e. hyperpnoea), thus maintaining arterial blood gas and acid–base homeostasis. Given that arterial CO2 levels remain unchanged at these intensities, brainstem chemoreceptors do not contribute to exercise hyperpnoea through CO2 detection. Moreover, no mechanism is known to directly sense CO2 in the venous circulation. In the severe-intensity exercise domain, ventilatory responses exceed metabolic demands (i.e. hyperventilation), reducing arterial CO2 pressure ( P aC O 2 ${P_{{\mathrm{aC}}{{\mathrm{O}}_2}}}$ ) to counteract exercise-induced metabolic acidosis by minimizing blood bicarbonate reductions. Notably, studies on McArdle disease patients and experiments manipulating blood H+ concentration or pH sensors (bicarbonate infusion or peripheral chemoreceptor ablation, respectively) suggest that these mechanisms alone do not fully account for exercise hyperventilation. Current evidence suggests that humoral and neural mechanisms probably interact to control ventilatory responses to exercise. Specifically, signals from premotor and motor brain areas (i.e. central command), peripheral and central chemosensors that mainly monitor substances such as O2, P aC O 2 ${P_{{\mathrm{aC}}{{\mathrm{O}}_2}}}$ and H+, and feedback from group III and IV muscle afferents sensitive to mechanical and metabolic changes in skeletal muscle interstitium probably work together to drive hyperpnoea and hyperventilation during exercise. The recent study by Iannetta et al. (2024) addresses two gaps in our understanding of these mechanisms. The authors explored the role of group III and IV muscle afferents in regulating pulmonary and alveolar ventilation and lung diffusion capacity during prolonged exercise (>5 min) in healthy participants. These questions are essential, as previous studies on the role of these afferents primarily used short-duration exercises, limiting their findings to initial ventilatory adjustments – namely, phases I and II. Phase I corresponds to the immediate increase in pulmonary ventilation during the first seconds of the rest-to-exercise transition, while phase II involves a slower, progressive rise until a steady-state level is reached. In addition, these previous studies suggested that group III and IV muscle afferents could play a role in gas exchange efficiency since the effect of attenuation of muscle afferents on pulmonary ventilation reduced over time and with increasing exercise intensity, but haemoglobin saturation remained unchanged throughout the exercise bout. Iannetta et al. (2024) used intrathecal fentanyl in 13 healthy participants to attenuate group III and IV muscle afferent feedback during cycling without directly affecting motor inputs to the lower limbs. Participants cycled sequentially at intensities representing 30% (moderate), 50% (heavy) and 80% (severe) of peak work rate (Wpeak) from a prior incremental test. The 30% and 50% Wpeak intensities were maintained for 20 min each, while the 80% Wpeak intensity lasted 5 min. The researchers found that attenuating the muscle afferent feedback, minute ventilation (V̇E) reduced significantly throughout exercise, supporting the sustained influence of group III and IV thin fibres in exercise hyperpnoea beyond initial ventilatory phases (I and II). Besides reduced V̇E, the study also reported a lower alveolar O2 pressure ( P A O 2 ${P_{{\mathrm{A}}{{\mathrm{O}}_2}}}$ ) at 30% and 50% Wpeak intensities but not at 80% Wpeak, alongside a widened alveolar–arterial oxygen difference (A-a D O 2 ${D_{{{\mathrm{O}}_2}}}$ ) throughout the exercise under fentanyl. While widened A-a D O 2 ${D_{{{\mathrm{O}}_2}}}$ at 30% and 50% Wpeak probably stems from hypoventilation (lower P A O 2 ${P_{{\mathrm{A}}{{\mathrm{O}}_2}}}$ ), the effect at 80% Wpeak suggests impaired gas exchange efficiency since P A O 2 ${P_{{\mathrm{A}}{{\mathrm{O}}_2}}}$ remained constant across conditions at this intensity. Interestingly, this gas exchange impairment was not due to changes in O2 diffusion capacity (DLCO), which remained unaffected by fentanyl. These results suggest that observed changes in gas exchange may result from other factors, such as impaired ventilation–perfusion matching or reduced sympathetic outflow, which could lower capillary permeability and interstitial fluid reabsorption. P a O 2 ${P_{{\mathrm{a}}{{\mathrm{O}}_2}}}$ and pH were significantly lower, while P aC O 2 ${P_{{\mathrm{aC}}{{\mathrm{O}}_2}}}$ and arterial K+ concentrations were higher across all exercise intensities under fentanyl. Furthermore, fentanyl exacerbated muscle fatigue, as indicated by the more significant decrease in maximal voluntary contraction from before to after exercise. Iannetta et al. (2024) argued that fentanyl probably attenuated about 50–60% of group III and IV muscle afferent feedback, resulting in a corresponding ventilatory reduction of 10–20%. Considering the magnitude of this fentanyl blockage, the authors contend that these afferents account for almost 50% of exercise hyperpnoea. As they highlight, their experimental model was designed not to isolate muscle afferent feedback but to examine its interaction with other mechanisms. Moreover, attenuating group III and IV muscle afferent feedback coincided with increased ventilatory drive from central and peripheral chemoreceptors during exercise in response to elevated P aC O 2 ${P_{{\mathrm{aC}}{{\mathrm{O}}_2}}}$ and arterial K⁺ and reduced P a O 2 ${P_{{\mathrm{a}}{{\mathrm{O}}_2}}}$ and pH. Additionally, increased fatigue in locomotor muscles probably heightened central command, further contributing to ventilatory drive. Collectively, these findings support a model in which humoral and neural signals interact to generate appropriate hyperpnoea and hyperventilation during exercise, with group III and IV muscle afferents playing a critical regulatory role. Further insights into this interaction model come from methods that isolate the contributions of metabo- and mechanosensitive thin sensory fibres to ventilatory control during exercise and their interactions with other mechanisms such as the central command and the peripheral chemoreflex. For instance, post-exercise circulatory occlusion (PECO), a nearly century-old manoeuvre used to stimulate metabosensitive afferents, shows that sustained metaboreflex activation at rest frequently does not affect pulmonary ventilation. However, the PECO manoeuvre in one leg significantly augmented ventilatory responses to exercise during another leg cycling at 60 W but not 40 W (Lam et al., 2019), suggesting that the metaboreflex relies on concurrent exercise-specific stimuli to modulate ventilation effectively and that exercise intensity may be relevant. The mechanisms that interact with the muscle metaboreflex remain unknown, and their interaction is likely to be complex. One recent study from our laboratory showed that ventilatory responses were similar during moderate-intensity voluntary and involuntary plantar flexor exercise when the PECO manoeuvre was applied to an arm (Gomes et al., 2024). These results suggest that the muscle metaboreflex does not interact with the central command during moderate-intensity exercise to generate the hyperpnoea. Whether such an interaction occurs at higher exercise intensities and/or with sizable muscle mass remains to be investigated. Conversely, both the metaboreflex and the mechanoreflex interact synergistically with the peripheral chemoreflex, as the coactivation of these reflexes produced ventilatory responses superior to the sum of their separated activation (de Oliveira et al., 2023). To conclude, group III and IV muscle afferents function as a critical regulatory mechanism for ventilatory responses to exercise, interacting with other neural mechanisms activated by exercise. In healthy individuals, muscle afferents provide adequate feedback about mechanical and metabolic-induced exercise stress; reducing this feedback leads to hypoventilation and poor gas exchange, resulting in hypoxaemia, hypercapnia, early acidosis, muscle fatigue and diminished exercise tolerance. Conversely, group III and IV muscle afferents – or their associated reflex arc – appear dysfunctional in pathological conditions such as chronic obstructive pulmonary disease as partial blockage with fentanyl reduced the response of pulmonary ventilation to the metabolic demand of exercise (i.e. improved ventilatory efficiency) without compromising pulmonary gas exchange (i.e. P a O 2 ${P_{{\mathrm{a}}{{\mathrm{O}}_2}}}$ and P aC O 2 ${P_{{\mathrm{aC}}{{\mathrm{O}}_2}}}$ ), ultimately reducing disproportionate dyspnoea and enhancing exercise tolerance (Gagnon et al., 2012). Thus, future studies should explore how humoral and neural mechanisms interact across exercise intensities to regulate ventilatory responses and identify strategies to address the dysfunctional role of such important regulatory mechanisms of ventilatory responses in pathological conditions. Please note: The publisher is not responsible for the content or functionality of any supporting information supplied by the authors. Any queries (other than missing content) should be directed to the corresponding author for the article. The authors declare no competing interest. All authors contributed equally. All authors approved the final version of the manuscript. F.G.S. received scholarships from CAPES and The São Paulo Research Foundation (FAPESP; processes: 22/10295-7 and 23/07135-0). The authors are grateful to Professor Bruno Silva, PhD, for his valuable insights into the original paper and the state-of-the-art in neural control of pulmonary ventilation, as well as his thorough review of the manuscript.