Reply from Luca Ruggiero, Alexandra F. Yacyshyn, Jane Nettleton and Chris J. McNeil

In their letter to the Editor regarding our recent paper, Finn and colleagues propose that the heightened motoneurone responsiveness in chronic hypoxia (CH) compared to acute hypoxia (AH) may relate primarily to greater peripheral fatigue in AH than CH, rather than motoneuronal adaptations to hypoxia. This is an astute observation and, based on the reduction of maximal torque and increase in EMG at the end of the fatigue protocol, an interpretation that could have been addressed in the original article. However, for the reasons described below, we do not believe peripheral fatigue to be a driving influence for our results. We also take this opportunity to discuss the issue of study design (i.e. matched torque vs. matched EMG). Of note, all of the values we report refer to a relative increase or decrease from baseline. After 3 min of exercise, there is a ∼35% reduction in motoneurone excitability (as measured by the cervicomedullary motor evoked potential, CMEP) during a matched EMG contraction in both AH and normoxia (N), whereas the CMEP in CH is reduced only 3% (see Fig. 5B of Ruggiero et al. 2018). Just prior to this time point, the absolute increase in integrated EMG (iEMG) during a matched torque contraction is 13% for AH, 5% for N, and 4% for CH. This AH iEMG is similar to the end-exercise value in CH (+11%), yet the reduction in the CMEP is 36% for AH at 3 min but only 23% for CH at 16 min. Further, despite the absence of a meaningful increase in iEMG from 3 min to 5 min (+3%) in CH, the CMEP at 5 min is reduced 18% and relatively stable thereafter. In N, the CMEP is stable beyond 3 min, despite a continued, gradual increase in iEMG (22% at 16 min). In AH, the CMEP nears its lowest value at 7 min, when the increase in iEMG (28%) is less than half that at task termination (58%). Based on these findings, it is clear that the size of the CMEP is influenced strongly by factors other than the level of peripheral fatigue inferred by EMG. Moreover, the (non-significant) greater reduction in maximal torque in CH compared to N, without a decrease in CMEP size in CH, weakens the link between motoneurone excitability and this alternative index of fatigue. The iEMG data described above argue against a tight relationship between the CMEP and peripheral fatigue; this argument is strengthened if the voluntary EMG data (either integrated or root mean square) are normalized to account for fatigue-related changes to the maximal M-wave (Mmax). When normalized in this fashion, the increase in EMG is equivalent for CH and N and the separation between these conditions and AH is reduced. Although none of the changes are statistically significant (see Fig. 5A of Ruggiero et al. 2018), Mmax size increases with fatigue in N and AH but decreases in CH. To compensate for this reduction in peripheral excitability, greater descending drive would be required in CH compared to N and AH to achieve a targeted level of iEMG. Hence, in a protocol of matched EMG instead of torque, there is the potential to simply flip which condition is likely to experience the greatest fatigue-related increase in motoneurone activation. In the work that compared CMEPs of different sizes (McNeil et al. 2011), the conditions of the fatigue task were identical across the two sessions. With the current study, there were three different conditions (N, AH and CH) and, given the dearth of similar experiments, a limited ability to tailor our design according to previous findings. The nature of the expedition to 5050 m permitted only one attempt to address our research question. After weighing the benefits and limitations of various experimental protocols, we opted for a design that aligned with the acclimatization studies of whole-body exercise (e.g. Goodall et al. 2014); i.e. we chose a submaximal, intermittent protocol with a target (torque) that relates to muscle performance outside of a laboratory setting. As suggested by Finn and colleagues (2018), we agree that it would be prudent for future work to investigate the impact of hypoxia (acute and chronic) on motoneurone excitability during a fatiguing task with only an EMG target. However, based on our novel findings, it is advisable to adjust the EMG target to account for real-time changes to the Mmax. This would be true not only for the environmental conditions considered here, but for any experimental design in which multiple conditions are compared. We thank Finn and colleagues for their interest in our study. It provided us the opportunity to expand on our rationale and interpretations of the data and also make a recommendation for future study design. None declared.

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