Enhancement of self-sustained muscle activity through external dead space ventilation appears to be associated with hypercapnia
Introduction
In the chemical control of breathing, changes in CO2 pressure (PaCO2) and O2 pressure (PaO2) in arterial blood are important factors for modulating breathing through stimulation of central and peripheral chemoreceptors (Nattie and Li, 2012; Whipp and Ward, 1998). In this process, the respiratory center in the medulla receives inputs from each chemoreceptor and generates depolarizing currents called central respiratory drive potentials (CRDPs) in spinal motoneurons (MNs) of the respiratory muscles (Butler, 2007).
It has been reported in decerebrate anesthetized cats that plateau potentials are induced in hindlimb MNs when CRDPs are potentiated by CO2 addition (Kirkwood et al., 2002, 2005). Plateau potentials are self-sustained depolarizations of spinal MNs caused by persistent inward currents (PICs). PICs are a powerful intrinsic property of MNs that are activated via voltage-gated channels in MN dendrites (Heckman et al., 2005; Hounsgaard and Kiehn, 1993) and modulated by the action of monoaminergic drives (i.e., serotonin: 5-HT) onto the MNs (Lee and Heckman, 2000). Serotonergic raphe neurons, which project to the spinal cord (Hultborn et al., 2013; Jacobs and Azmitia, 1992), are a part of the central chemoreceptors (da Silva et al., 2011; Hennessy et al., 2017; Ray et al., 2011) that are activated in response to changes in PaCO2 (Corcoran et al., 2013; Mitchell et al., 2008; Veasey et al., 1995, 1997). Taken together, the phenomenon observed by Kirkwood et al. (2002, 2005) is considered to suggest that increased PaCO2 can induce not only an increase in breathing but also facilitatory modulation into limb MNs. We (Hatano et al., 2018) have recently shown that external dead space ventilation (EDSV) with hypercapnia and hypoxia enhances self-sustained muscle activity (SSMA) in the soleus muscle, which was measured as an indirect estimation of PIC behavior (Collins et al., 2001; Nozaki et al., 2003), supporting the above possibility.
Self-sustained firing of MNs due to PICs has been considered to provide the baseline tone for fundamental behavior such as maintenance of posture (Heckman et al., 2008; Hounsgaard et al., 1988; Lee and Heckman, 1998), locomotion (Brownstone et al., 1992; Heckman et al., 2009; Jacobs and Fornal, 1993), and even production of maximal levels of muscular force (Trajano et al., 2014). Therefore, EDSV has the potential to be an intervention to improve fundamental motor function and would be clinically important to explore in detail the mechanism by which EDSV leads to increased SSMA. Nonetheless, the study by Hatano et al. (2018) leaves open the possibility that CRDPs themselves (Kirkwood et al., 2005) or respiratory afferent activity (Balzamo et al., 1997; Morélot-Panzini et al., 2007), which would be enhanced with increased ventilation by EDSV, could affect motor neuron excitability of limb muscles. Furthermore, hypoxia has been suggested to cause a form of serotonin-dependent motoneuronal enhancement in limb muscles (Christiansen et al., 2018; Hayes et al., 2014; Trumbower et al., 2012). In addition, hypercapnia may contribute to the enhancement of neural activity by hypoxia (Mateika et al., 2018). As mentioned above, EDSV leads to hypoxia as well as hypercapnia. Therefore, the EDSV-induced increase in SSMA observed in our previous study (Hatano et al., 2018) may have been due to hypoxia rather than hypercapnia or due to a combined effect of both. Thus, the relationship between hypercapnia and SSMA remains to be elucidated.
SSMA is one of the indirect indicators of PICs (Collins et al., 2001; Mesquita et al., 2020; Nozaki et al., 2003; Trajano et al., 2014; Walton et al., 2002). Nozaki et al. (2003) confirmed that SSMA is neither due to the primary motor cortex nor due to reverberating activity within closed neuronal circuits involving MNs, demonstrating that it is due to autonomous motor neuron activity involved in the plateau potential. Therefore, in the present study, our primary purpose was to investigate the possibility that hypoxia and / or increased ventilation equivalent to EDSV may be involved in the enhancement of SSMA in the soleus muscle. If hypoxia and increased ventilation are involved in SSMA, it is predicted that SSMA will be enhanced during hypoxia and / or hyperventilation. This possibility was examined in Experiment 1 in this study. Furthermore, if hypercapnia contributes independently to the increase in SSMA, SSMA may be enhanced by hypercapnia without hypoxia. This possibility was examined in Experiment 2 in this study.
Section snippets
Subjects
A total of 11 healthy males (mean ± SD: age, 22 ± 2 years; height, 173.1 ± 5.0 cm; body weight, 68.6 ± 7.9 kg) participated in the present study. All of the subjects received detailed and standardized explanations on the experimental procedure and potential risks involved before they provided informed consent for participation in the study. All 11 subjects participated in Experiment 1, and 9 of the 11 subjects also participated in Experiment 2. The exclusion criteria for subjects used in order
Results
In Experiment 1, ANOVA showed a main effect of respiratory conditions on PETCO2 (F2, 30 = 41.06, P < 0.001) and V̇E (F2, 30 = 82.21, P < 0.001). As shown in Table 1, PETCO2 was significantly higher in the EDSV condition than in the NB (P < 0.001, d = 3.63), HX (P < 0.001, d = 3.88) and VH (P < 0.001, d = 2.34) conditions. There was no significant difference in PETCO2 between the NB, HX, and VH conditions. V̇E was significantly higher in the EDSV and VH conditions than in the NB (vs. EDSV: P <
Discussion
The main finding of Experiment 1 was that SSMA increased in the external dead space ventilation (EDSV) condition compared to that in the normal breathing (NB) condition but did not significantly change in the hypoxia (HX) and voluntary hyperventilation (VH) conditions. SpO2 in the HX condition and V̇E in the VH condition were equivalent to those in the EDSV condition. In Experiment 2, SSMA was higher in the normoxic hypercapnia (NH) condition than in the NB condition. Therefore, it is likely
Data availability
The data associated with the paper are not publicly available but are available from the corresponding author upon reasonable request.
Authors’ contribution
KH, MR, and TY conceived and designed the study. KH, OY, and TY conducted the experiments. KH and TY analyzed the data. KH performed the statistical analyses. KH and TY wrote the manuscript. All authors read and approved the manuscript.
Declaration of Competing Interest
The authors declare that they have no conflict of interest.
Acknowledgments
This study was supported by a Grant-in-Aid for Scientific Research from the Japanese Ministry of Education, Culture, Sports, Science and Technology (JSPS KAKENHI Grant Number 17K01612).
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