Diaphragm fatigue: Similarities and differences between sexes.

Abstract

The inspiratory muscles of breathing are uniquely adapted for endurance. Nevertheless, akin to other striated muscles, inspiratory muscle fatigue occurs, even in the primary muscle of inspiration, during high-intensity exercise and inspiratory loading. Diaphragm fatigue has implications for respiratory system performance in health and disease. There are reports of sex differences in muscle fatigue characteristics in different muscle groups, including the inspiratory muscles, which is revealed as greater fatigue tolerance in women compared to men. Yet, interestingly, studies of diaphragm function in various species indicate similar force-generating and fatigue characteristics, suggesting that sex differences, where they exist, may reside at one or more sites within the complex integrative control of muscle behaviour and/or may be revealed in the (dys)functional response to stressors. Acute exposure to hypoxia can enhance diaphragm fatigue. There are reports of greater hypoxic tolerance in respiratory muscles of female rodents, purportedly as a result of the protective effects of oestrogen, particularly relevant to chronic exposure to hypoxia in the context of disease (O’Halloran & Lewis, 2017). In this issue of The Journal of Physiology, Archiza et al. (2021) sought to characterize diaphragm fatigue during inspiratory loading in acute hypoxia, aiming to determine whether differences exist between healthy men and women. In a technical tour de force, Archiza et al. (2021) elicited diaphragm fatigue in eight men and eight women by isocapnic inspiratory pressure-threshold loading at equivalent target workloads between sexes. Inspiratory loading trials were performed during exposure to normoxia and hypoxia (8%O2) performed on separate experimental days in a randomized fashion. Diaphragm fatigue was quantified by assessing the twitch transdiaphragmatic pressure elicited by cervical magnetic stimulation. Bilateral surface electromyogram recordings of the diaphragm allowed the assessment of M-waves to quantify diaphragm activation. Heart rate and non-invasive blood pressure were recorded to determine the cardiovascular consequences of the respiratory muscle metaboreflex. Peak transdiaphragmatic pressure at rest was equivalent between sexes. In normoxia, the magnitude of diaphragm fatigue was equivalent in men and women, confirming and extending previous work by this group (Geary et al. 2019). Conversely, and unexpectedly, greater fatigue was expressed in female diaphragm compared to males during equivalent cumulative work in hypoxia. Remarkably, the sex difference is characterized by robust hypoxic tolerance inmen, such that diaphragm fatiguewas not significantly greater in hypoxia compared to normoxia, whereas diaphragm fatigue in women was significantly enhanced in hypoxia compared to normoxia. The study by Archiza et al. (2021) contributes important observations and adds to the continued debate on similarities and differences in muscle fatigue between sexes, although this matter is far from settled. The hypoxic tolerance in men is curious given that a substantial enhancement of male diaphragm fatigue during hypoxia has been reported elsewhere (Verges et al. 2010). The difference may relate to temporal responses in acute hypoxia because Verges et al. (2010) used isocapnic hyperpnoea tests at 85% of maximum voluntary ventilation lasting 15 minutes. Indeed, during hypoxia, a linear decline in transdiaphragmatic twitch pressure has been described (Walker et al. 2016). The greater vulnerability of female diaphragm to fatigue during hypoxia, as described in Archiza et al. (2021), is interesting in light of the greater fatigue tolerance generally observed in female muscle, and is all the more curious, considering that time to exhaustion during repeated adductor pollicis muscle contractions was longer in females compared to males, both in normoxia and hypoxia, a finding that was maintained in a subset of participants matched for maximal voluntary contractile force and hence presumed ATP demand (Fulco et al. 2001). Thus, sex differences in fatigue tolerance during hypoxia may be muscle-specific, and there may be unique attributes of the inspiratory muscles, or at least of the diaphragm, compared to othermuscle groups. Recovery of transdiaphragmatic twitch pressure 60 min following inspiratory loading was incomplete, although equivalent between groups, suggesting no detrimental effect of preserved pressure-generation in hypoxic male diaphragm, and hence the greater fatigue in female diaphragm appears to be disadvantageous, at least for respiratory performance. Inspiratory loading provoked tachycardia and elevated mean arterial pressure. Interestingly, the pressor response to inspiratory loading was equivalent between sexes independent of oxygen availability. This points to a relatively blunted metaboreflex response in women during hypoxia. The finding contributes to a growing body of evidence suggesting sex differences in respiratory muscle metaboreflex control of blood pressure, which may reside in the afferent arm of the reflex pathway, although potential sex differences in sympathetic nervous responsiveness to a given sensory input carried in thin afferents cannot be discounted. The findings of Archiza et al. (2021) draw a focus on respiratory muscle fatigue, which may limit exercise performance at altitude or in hypoxaemic patients, highlighting hitherto unknown sex differences that lie therein. The findings encourage consideration of potential sex differences in diaphragm performance in the context of critical care, particularly against the backdrop of acute hypoxic stress. By extension, the study raises interesting questions pertaining to respiratory muscle responses to stressors in a host of conditions that are characterized by diaphragm dysfunction. In the fullness of time, a thorough understanding of sex-related similarities and differences in respiratory muscle physiology may serve to inform targeted therapeutic strategies.