Sex differences in diaphragmatic fatigue and the metaboreflex following inspiratory pressure‐threshold loading

During inhalation, inspiratory muscles contract to expand the ribcage, creating negative intrathoracic pressure with respect to atmospheric pressure; this enables air from the atmosphere to flow into the lungs. The development of this pressure gradient is primarily due to the contribution of the diaphragm during inspiration. The diaphragm supports airway maintenance during expulsive manoeuvres (like coughing and sneezing) and contributes to movements separate from respiration, such as swallowing and vocalization. Ultimately, this means the diaphragm is rarely at rest. Respiratory muscle fatigue can be defined as the reduced ability to exert force or power from respiratory muscles (and as a result to generate flow) in response to a voluntary effort. This can occur from impairments in contractile function of the muscle fibres and neuromuscular transmission (collectively peripheral fatigue), or from a decrease in respiratory drive (central fatigue). Despite being well equipped to handle high work intensities, the diaphragm unfortunately is not completely fatigue resistant. In a laboratory setting, to minimize the systemic effects of exercise, diaphragmatic fatigue (DF) can be induced by increasing inspiratory resistance. Evoking DF in this manner elicits a sympathetically mediated metaboreflex. This metaboreflex is the result of increased afferent feedback from the working inspiratory muscles, which in turn increases heart rate, mean arterial blood pressure and limb vascular resistance, theoretically prompting a redistribution of blood towards respiratory muscles. Smith and colleagues (2016) recently reported that women have a blunted metaboreflex compared to males. However, diaphragmatic force production (estimated by the change in transdiaphragmatic pressure) was not quantified during this particular study; thus DF could not be assessed. Without estimating the fatigue-related decrease in contractile capability of the diaphragm, it is uncertain whether the blunted metaboreflex in women was due to DF or simply due to males and females performing at different relative workloads. Recently, Welch and colleagues (2018) aimed to determine whether a relationship exists between previously observed sex differences in DF and the magnitude of the metaboreflex that follows. The authors hypothesized that women would be more resistant to DF, leading to blunted cardiovascular responses compared to males. Nine young healthy men and women performed a single bout of isocapnic, inspiratory resistance loading (pressure-threshold loading; PTL) at 60% of the individual's predetermined maximal inspiratory mouth pressure, until task failure. Each participant was instrumented with one oesophageal and one gastric balloon (positioned above and below the level of the diaphragm) to assess transdiaphragmatic pressure, as an estimate of diaphragmatic contractile function. In order to measure DF, cervical magnetic stimulation was used to stimulate the phrenic nerve, which elicited pressure twitches, while M-waves were recorded via surface electromyography (EMG) of the left and right costal diaphragm. Women were able to perform the PTL task longer and displayed an attenuated cardiovascular response, as hypothesized. Contrary to the hypothesis, DF was not different between males and females at task failure. However, with the same DF in face of longer time to task failure, the rate of DF was considerably lower in females. This is the first study to show that females compared to males report greater inspiratory muscle endurance time, but no difference in end-task DF, in association with an attenuated respiratory metaboreflex. Despite having larger ventilatory constraints (decreased lung diffusion capacity and smaller airways when matched for lung volume), the fact that females were able to perform the PTL task longer compared to males, with the same degree of DF, is interesting. Intuitively, the attenuated metaboreflex in response to DF in females seems plausible, given that a constant upregulation of sympathetic activity in response to greater respiratory work (from increased airway resistance owing to relatively smaller airways than males) would be considerably disadvantageous. The authors do indicate, however, that without direct recordings of muscle sympathetic nerve activity, the causal link between the estimated magnitude of the metaboreflex and sympathetic activation from DF requires further investigation. In addition, the slower rate of development of DF in females than males may also have influenced the results. It is important to note (which the authors have done) that task failure can still occur without the presence of DF. Meaning, additional factors may have contributed to task failure, such as central fatigue or dyspnoea. Exploring neural activation patterns during varying levels of dyspnoea may provide insight into the mechanisms responsible for longer time until task failure in females than males. With no change in the compound muscle action potential (M-wave) and a reduction in transdiaphragmatic pressure following PTL, the indicated mechanism most likely resides in the excitation-contraction coupling rather than in sarcolemmal propagation. The lack of impairment in neuromuscular transmission (i.e. decline in M-wave amplitude) coincides with findings from McKenzie and colleagues (1992), who found pseudofacilitation in the amplitude of the M-wave (as in Welch et al. 2018, see Table 2), in association with little central fatigue when tested during the Mueller manoeuvre (same manoeuvre used in Welch et al. 2018) across a fatiguing protocol. The possible mechanisms responsible for peripheral fatigue of the diaphragm at task failure in Welch et al. (2018) should be of future interest, as the diaphragm is highly vascularized and even less susceptible to peripheral fatigue compared to limb muscles. In another recent study, females exhibited a greater reliance on accessory inspiratory muscles during high intensity cycling as a way perhaps, to minimize DF (Mitchell et al. 2018). Therefore, whether sex differences exist in the recruitment patterns and contribution of accessory muscles during inspiratory muscle fatiguing tasks (specifically targeting the diaphragm) should be of future interest. If a change in recruitment occurs as fatigue develops, such that accessory muscles bear a greater proportion of the workload, this may result in less DF during an iso-time and iso-load task. Additional EMG recordings of the diaphragm (i.e. gastroesophageal electrodes) and of accessory inspiratory muscles may provide useful information for interpretation of the results when DF is involved. Another aspect to consider for future studies is the standardization of testing conditions. From previous findings, area under the curve and size of the M-wave recorded from surface electrodes when stimulating the phrenic nerve were highly variable with changing lung volumes and body positions (Gandevia & McKenzie 1986). In this particular study, Gandevia and McKenzie electrically stimulated the phrenic nerve with an electrode fixed to a neck brace to ensure reliable maximal stimulation of the phrenic nerve, and thus less variability in the size of the M-wave. Welch and colleagues (2018) controlled for this by ensuring the location of phrenic nerve stimulation remained consistent throughout testing and only occurred at functional residual capacity with a closed glottis to prevent changes in lung volume. Welch and colleagues have provided important insights for the emerging field of sex differences in DF. Specifically, they showed females have a greater inspiratory muscle time to task failure and lower metaboreflex-related cardiovascular responses to PTL compared to males, with the same DF. Future studies could include additional measures to: (1) determine and examine whether the rate of fatigue of respiratory muscles, rather than discrete end-task peripheral fatigue, relates to the magnitude of the sympathetic metaboreflex; (2) explore the contribution dyspnoea has on time to task failure; (3) better differentiate the central and peripheral contributions to the decline in voluntary function of the diaphragm; and (4) characterize neural activation and recruitment patterns between sexes during fatiguing tasks of the respiratory muscles. None declared. All authors have approved the final version of the manuscript and agree to be accountable for all aspects of the work. All persons designated as authors qualify for authorship, and all those who qualify for authorship are listed. None. The authors regret having to exclude a number of relevant citations due to Journal Club formatting limitations. The authors would like to acknowledge Dr Chris McNeil and Dr Jonathan Smirl for their guidance and support.

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