When sex is not the reason for your breathlessness: clinical insights into exertional dyspnoea from dead space loading during exercise

The respiratory system of otherwise healthy humans is optimized for efficient breathing with little or no sensation of breathing difficulty under resting conditions. Accordingly, the sensation of dyspnoea, or shortness of breath, is typically an extremely uncomfortable, if not debilitating, experience that negatively impacts the activities of daily life and therefore the quality of life. In patients with cardiorespiratory diseases, the greater perception of dyspnoea is due to ‘neuro-mechanical dissociation’ which is defined as a ‘mismatch between the outgoing motor command and the mechanical/muscular response of the respiratory system’ (Laviolette & Laveneziana, 2014). Dyspnoea can be a primary cause of exercise termination in those individuals with respiratory diseases such as chronic obstructive pulmonary disease (COPD) (Laviolette & Laveneziana, 2014). Additionally, dyspnoea is a better predictor of mortality in COPD and left heart disease than forced expiratory volume in 1 s (FEV1) and angina, respectively (Laviolette & Laveneziana, 2014). This highlights the clinical importance of dyspnoea and the need to better understand the causes of dyspnoea in healthy humans as well as various clinical populations where dyspnoea is a limiting factor. There are well defined sex differences in respiratory system anatomy, mechanics and in the sensation of dyspnoea during exercise. Importantly, when matching for relative exercise intensity, differences in dyspnoea quality remain though absolute dyspnoea ratings often disappear. Thus, the role of increasing ventilatory demand on these sex differences is not well defined. In this issue of The Journal of Physiology, Mitchell and colleagues employed a moderate level of dead space loading (15% of forced vital capacity) using a single-blind, counterbalanced design to increase ventilatory demand during exercise (Mitchell et al., 2025). In this well-controlled study at rest and during relative workload intensities, the investigators used a multidimensional assessment of perceptions of inspiratory and expiratory effort including breathing work/effort, difficulty breathing in, and difficulty breathing out. To the authors’ surprise, there were no sex differences in any of the perceptions of dyspnoea despite significant increases in ventilatory work induced by moderate dead space loading to increase ventilatory demand and neuromechanical uncoupling. As with all good studies, these investigations have addressed a physiologically and clinically important question that has given rise to additional avenues for investigation. The authors correctly note that their data can only be generalized to young, healthy and recreationally active individuals and not populations with respiratory disease. Nevertheless, by eliminating the role of increased ventilatory demand as a cause of perceptual differences in dyspnoea between males and females, the authors have advanced the field, moving one step closer to understanding this clinically relevant contributor to exercise and quality of life. So, if increased ventilatory demand and neuromechanical uncoupling are not the cause of the sex differences in dyspnoea perception and quality with exertion, what else may be contributing and how do we measure it? Interestingly, not all groups with respiratory limitations have a greater degree of dyspnoea with exercise. For example, adults with a history of preterm birth with and without bronchopulmonary dysplasia have impaired pulmonary function and reduced aerobic exercise capacity. However, they do not have a higher dyspnoea rating than age-, height- and sex-matched controls (Lovering et al., 2014). These individuals with lung disease from birth have lifelong respiratory disease, and although speculative, it is possible that they perceive dyspnoea differently because they have never experienced exertion without respiratory limitations to exercise. Accordingly, the afferent feedback received is perceived as ‘appropriate’ for the effort so there is no sensory mismatch leading to exaggerated dyspnoea despite their significant respiratory limitations. To the contrary, those who have relatively healthy lungs at birth live part of their life knowing what it is like to exercise without significant respiratory limitations until they develop lung disease later in life like those with COPD. The change in lung health with respiratory disease then leads to a mismatch from the motor command and afferent feedback. This highlights the importance of better understanding the neural aspects of dyspnoea, which may also be different between sexes. Pfeifer and colleagues examined brain activation using positron emission tomography with and without relief of dyspnoea (Peiffer et al., 2008). They found not only a reduction of activity in dyspnoea-activated areas with relief of symptoms but also activation of other areas associated with the relief of symptoms. Notably, this study was done in males only, so whether these same areas are inactivated and activated the same in females remains unknown. Known sex differences in perceptions of pain and relief are associated with differences in neural network dynamics at rest (Galli et al., 2016). Thus, it is possible that sex differences in neural activation, deactivation and network dynamics may contribute to perceptual differences in afferent and proprioceptive feedback leading to dyspnoea, but this information would not be ascertainable using gold standard exercise physiology approaches alone. Clearly more work needs to be done within the realm of sex differences and dyspnoea perception. There are many experiences in our lives that can ‘take our breath away’, but not all of them are enjoyable as is the case with exertional dyspnoea. Future work exploring dead space loading in older adults and/or populations with cardiorespiratory disease would provide clinically relevant insight into understanding if there were an interaction between age, sex and cardiorespiratory diseases. Fundamentally, it would be important to understand if one sex perceives a given change in ventilatory work differently from another. Using a combination of gold standard exercise physiology approaches with neuroimaging may help get to the next level of understanding when, and why, sex is, or is not, the reason for taking our breath away. 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 have no conflicts to disclose. Both authors have read and approved the final version of this manuscript and agree to be accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved. All persons designated as authors qualify for authorship, and all those who qualify for authorship are listed. This work was funded by the Wu Tsai Human Performance Alliance at the University of Oregon (A.T.L.); Ken and Kenda Singer Human Physiology Research Support (A.T.L.); and a Fulbright Scholar Award (J.W.D.).