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

Exercise tolerance (EX T ) 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 EX T , the presence of exercise intolerance (EX INT ) has also been documented. More importantly, EX INT increases in several pathological conditions. Despite the precise mechanism underpinning EX INT 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 EX T . Accordingly, we aimed to determine: i) differences in CB-chemoreflex drive between EX T and EX INT mice, and ii) the role played by the CB-chemoreflex on setting EX INT . 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 (F i O 2 ~5%). We found that the incidence of EX INT among healthy mice was ~30%. Notably, compared to EX T mice, animals with EX INT 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 EX INT compared to the values obtained in EX T mice (V E : 17 ± 1.6 vs. 12 ± 3.2, mL/min, EX INT vs. EX T , respectively). Then, we tested whether high chemoreflex drive was associated with EX INT . For this, we reduced the chemosensory drive by using the Dejour´s maneuver (F i O 2 ~35%) while EX INT mice continues to exercise. We found that chemoreflex unloading in EX INT markedly improves exercise tolerance. Indeed, exercise tolerance was almost fully restored by reducing chemoreflex drive in EX INT . 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.