Carotid body-mediated peripheral chemoreflex drive sets exercise tolerance in adult mice

Exercise tolerance (EXT) has been primarily explained by individual body/physical features, partly neglecting the complex cardiorespiratory response needed to cope with exercise. While in healthy conditions most people display good EXT, the presence of exercise intolerance (EXINT) has also been documented. More importantly, EXINT increases in several pathological conditions. Despite the precise mechanism underpinning EXINT is not fully understood. It is well known that exaggerated sympathetic outflow to skeletal muscle impairs proper muscle function and that activation of the carotid body (CB) chemoreceptors elicits a robust increase in sympathetic activity. Therefore, it is plausible to hypothesize that an exaggerated CB-chemoreflex drive may impair EXT. Accordingly, we aimed to determine: i) differences in CB-chemoreflex drive between EXT and EXINT mice, and ii) the role played by the CB-chemoreflex on setting EXINT. Male C57/BL6 mice (n=24) were used to study chemoreflex function using whole-body plethysmography. Exercise tolerance/intolerance was determined by a three-day maximal performance exercise test. CB-chemoreflex drive was assessed by allowing the mice to breathe hypoxic gas (FiO2~5%). We found that the incidence of EXINT among healthy mice was ~30%. Notably, compared to EXT mice, animals with EXINT exhibited a heightened CB-mediated chemoreflex drive as evidenced by larger increases in the hypoxic ventilatory responses (HVR). Indeed, HVR was ~1.4-fold larger in EXINT compared to the values obtained in EXT mice (VE: 17 ± 1.6 vs. 12 ± 3.2, mL/min, EXINT vs. EXT, respectively). Then, we tested whether high chemoreflex drive was associated with EXINT. For this, we reduced the chemosensory drive by using the Dejour´s maneuver (FiO2~35%) while EXINT mice continues to exercise. We found that chemoreflex unloading in EXINT markedly improves exercise tolerance. Indeed, exercise tolerance was almost fully restored by reducing chemoreflex drive in EXINT. Our findings underscore the potential role of heightened CB-chemoreflex on setting exercise tolerance. Supported by Fondecyt 1220950. This is the full abstract presented at the American Physiology Summit 2024 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.