Dose-response relationship between muscle metaboreflex intensity and voluntary exercise intensity in regulating pulmonary ventilation and pulmonary gas exchange

Introduction: Pulmonary ventilation closely matches metabolic demand during exercise, yet its regulatory mechanisms remain incompletely understood. Metabolically sensitive muscle afferents (i.e., the muscle metaboreflex) activated via post-exercise circulatory occlusion (PECO) provoke inconsistent effects on pulmonary ventilation at rest. However, combining PECO with contralateral limb exercise elicits higher ventilatory response, suggesting interaction between the metaboreflex and exercise-related mechanisms. Whether this interaction depends on both the intensity of metaboreflex activation and other exercise mechanisms remains unclear. Emerging evidence implicates muscle afferent feedback in regulating pulmonary gas exchange during exercise, but the specific role of the muscle metaboreflex, alone or combined with other mechanisms, is unexplored. Aim: To investigate the dose-response relationship between muscle metaboreflex intensity and voluntary exercise intensity in regulating pulmonary ventilation and gas exchange. Methods: Seventeen adults (8 women, 28 ± 7 years) completed a familiarization session and three randomized visits. Each visit included rhythmic handgrip exercise at 30%, 50%, or 70% of the non-dominant hand's maximal voluntary contraction (MVC) for 2 minutes (or until exhaustion at 70%) to induce low, moderate, and high muscle metaboreflex activation. A cuff inflated on the non-dominant arm 20 seconds before exercise ended and stayed inflated during 1-min recovery (PECO). After recovery, participants performed incremental handgrip exercise with the dominant hand under PECO, starting at 30% MVC and increasing by 10% every 30 seconds until 60% or 70% MVC, when tolerated. Breath-by-breath airflow was measured with a bidirectional turbine, P ET CO 2 via an optoelectronic infrared reader. Earlobe blood samples were collected at rest, recovery, and at the end of dominant handgrip exercise to measure blood gases. Physiological dead space and alveolar ventilation were calculated using airflow and gas data. Results: Pulmonary ventilation was higher after non-dominant handgrip exercise at 70% MVC compared to 30% (P < 0.001) and 50% MVC (P = 0.002). P ET CO 2 decreased below baseline during non-dominant handgrip exercise at 50% (P < 0.001) and 70% MVC (P < 0.001) but not at 30% MVC (P = 0.112). During recovery, pulmonary ventilation remained elevated versus baseline at 50% (Δ 2.6 ± 2.7 L/min, P < 0.001) and 70% (Δ 2.8 ± 3 L/min, P < 0.001) MVC but not 30% MVC (Δ 0.4 ± 2 L/min, P = 0.445). P ET CO 2 remained lower than baseline at 50% (P = 0.012) and 70% MVC (P = 0.012). Pulmonary ventilation progressively increased during incremental dominant handgrip exercise without differences between conditions (lowest P = 0.069). P ET CO 2 decreased from recovery during the first incremental load in all conditions, increased after 30 s at 30% MVC, and stayed lower throughout 50% and 70% MVC. Consequently, P ET CO 2 was lower at 50% than 30% MVC for most of the exercise and at 70% than 30% at two points during incremental handgrip exercise. Physiological dead space and alveolar ventilation did not differ between conditions (lowest P = 0.24), but arterial CO 2 partial pressure (PaCO 2 ) was significantly lower at 50% (P < 0.001) but not at 70% (P = 0.108) than 30% MVC close to the end of incremental handgrip exercise. Conclusion: Moderate and high-intensity muscle metaboreflex activation, whether alone or combined with contralateral limb exercise, did not affect pulmonary or alveolar ventilation. However, it reduced alveolar and, to some extent, arterial CO 2 pressure, indicating a hyperventilatory response driven primarily by metaboreflex activation rather than other exercise-related mechanisms. Grant 2023/07135-0, São Paulo Research Foundation (FAPESP); Scientific production award (CNPq; Process: 310110/2019-0). This abstract was presented at the American Physiology Summit 2025 and is only available in HTML format. There is no downloadable file or PDF version. The Physiology editorial board was not involved in the peer review process.