FATIGUE-INDUCED DECREASE IN MOTONEURON EXCITABILITY: ROLE OF REPETITIVE ACTIVATION AND GROUP III/IV MUSCLE AFFERENT FEEDBACK

Vincent P Georgescu, Joshua C Weavil, Taylor S Thurston, Nathaniel M Birgenheier, Scott R Junkins, Markus Amann

INTRODUCTION: Although fatiguing exercise is recognized to decrease motoneuronal excitability, the underlying mechanisms responsible for this impact remain unclear. The purpose of this study was to investigate the roles of repetitive motoneuron activation and group III/IV muscle afferent feedback in determining the decrease in motoneuronal excitability as a result of fatiguing exercise.

METHODS: On 3 separate days, 7 healthy young subjects (25 ± 5 yrs) performed intermittent isometric knee extensions (at 20% of maximal voluntary quadriceps torque): 1) voluntarily (VOL; i.e. requiring repetitive motoneuron activation), 2) electrically-evoked (EVO, femoral motor nerve stimulation at 40 Hz; no motoneuron activation), 3) electrically-evoked with group III/IV muscle afferent feedback attenuated via lumbar (L3-L4) intrathecal fentanyl (EVO+FENT, no motoneuron activation and attenuated neural feedback from the lower limbs). Exercise consisted of 50-s quadriceps contractions followed by 10-s breaks during which potentiated quadriceps twitches (Qtw) were assessed to monitor the development of peripheral fatigue during each trial. Exercise continued until the goal of achieving a similar reduction in Qtw (ΔQtw ~40%) was reached in each trial. Before and immediately after exercise, a transcranial magnetic stimulation was followed by a cervicomedullary stimulation with a 100 ms inter-stimulus interval to elicit conditioned cervicomedullary motor-evoked potentials (cond.CMEP). All cond.CMEPs were normalized to M-waves (maximal compound muscle action potentials) and evoked during a constant electromyographic (EMG) activity corresponding to 20% of the EMG obtained during pre-exercise maximal voluntary contractions. A priori planned comparisons of cond.CMEPs were made between VOL and EVO via to assess the influence of repetitive activation, and between EVO and EVO+FENT to assess the influence of group III/IV muscle afferent feedback on motoneuron excitability.

RESULTS: Per study design, ΔQtw was not different between all 3 trials (-45±1%). During VOL, cond.CMEP fell by 79±6% from pre to post fatiguing quadriceps contractions (p < 0.01). Although the exercise-induced decrease in cond.CMEP was also significant during EVO (-51±10%), the reduction was substantially smaller compared to VOL. The exercise-induced decrease in cond.CMEP during EVO+FENT (-42±10%) was not different compared with that observed during EVO (p = 0.5).

CONCLUSION: Voluntary fatiguing muscle contractions compromise motoneuron excitability. While repetitive motoneuron activation accounts for part of the decrease, group III/IV muscle afferent feedback does not contribute to this depression. Importantly, the observation that the fall in motoneuron excitability is still significant during fatiguing muscle contractions performed without repetitive motoneuron activation suggests that other factors, such as extrasynaptic serotonin spillover and afterhyperpolarization, may play a role in the fatigue-related decrease in motoneuron excitability.

Autonomic Control of Cardiovascular Function: Group III/IV Muscle Afferents Regulate the Hemodynamic Response to Locomotor Exercise

TS Thurston, VP Georgescu, RM Broxterman, H Wan, NM Birgenheier, JE Jessop, CK Morrissey, M Amann

BACKGROUND: Group III/IV muscle afferents respond to mechanical and chemical stimuli occurring in skeletal muscle during exercise and contribute, via their feedback to cardiovascular control centers in the brainstem, to the circulatory response to physical activity. In healthy young individuals, feedback from these afferents facilitate leg blood flow during single-joint exercise. However, their exact role in determining peripheral hemodynamics during locomotor exercise (large active muscle mass), which is characterized by larger sympathetically-mediated vasoconstriction compared to single-joint exercise (small active muscle mass), has yet to be I d.

METHODS: Separated by 2 h of rest, 6 healthy males (Age 23 ± 3 yrs) completed three 4-min bouts of cycling exercise [75 W: ~45% of VO₂max, 100 W: ~55% VO₂max, and 80% of peak power output (246 ± 37.4 W): ~98% VO₂max] under both control conditions (CTRL) and with lumbar intrathecal fentanyl (FENT) blocking μ-opioid receptor-sensitive group III/IV muscle afferents. To avoid different respiratory muscle metaboreflex and/or chemoreflex effects on leg vascular resistance (LVR) and blood flow, subjects’ breathing (V_E) during FENT (usually characterized by hypoventilation and asphyxia) was guided to be similar to that in CTRL. Femoral arterial blood flow (Q_L; Doppler Ultrasound), LVR, and leg perfusion pressure (PP; intravascular catheter, arterial – venous blood pressure) were continuously determined; cardiac output (CO), stroke volume (SV), heart rate (HR), femoral arterial and venous blood samples were collected during the final minute of each workload. 

RESULTS: There were no hemodynamic differences between conditions at rest. Arterial blood gases and V_E were, per design, not different between conditions. During FENT exercise, PP was, compared to CTRL, significantly lower at all intensities (up to 26%). Without affecting HR (P = 0.41), CO and SV were significantly lower during FENT compared to CTRL at 75 and 100 W (~10%), but not at 80% W_peak.  Q_L was, however, not different between conditions (P = 0.43) as LVR was up to 25% lower during FENT compared to CTRL (P < 0.05). Additionally, arterial oxygen content, leg oxygen uptake and leg oxygen delivery were similar in both conditions (P > 0.15).   

CONCLUSION: The current findings obtained from humans during leg cycling suggest that group III/IV-mediated afferent feedback from locomotor muscle facilitates blood pressure, LVR and CO during whole body exercise. These effects of group III/IV muscle afferents are likely secondary to their role in regulating autonomic control of the heart and vasculature. Interestingly, the effect of these sensory neurons on leg vascular resistance differs between exercise characterized by large vs small active muscle mass. While afferent blockade decreases leg vascular resistance and MAP (with no changes in Q_L) during locomotor exercise, it increases leg vascular resistance (relatively larger fall in Q_Lcompared to fall in MAP) during single-joint exercise.

Group III/IV muscle afferents determine arterial oxygenation and gas exchange efficiency during prolonged locomotor exercise

Weavil JC, Georgescu VP, Jenkinson RH, Chang J, Junkins SR, and Amann M 

Introduction: Via their projections to the ventilatory control areas of the brain stem, feedback from mechano- and metabosensitive group III/IV skeletal muscle afferents has been identified as a key determinant of the ventilatory response during relatively short (~3 minutes) bouts of locomotor exercise executed at different intensities ranging from 30-100% of VO₂max. However, the influence of these muscle afferents on arterial oxygenation during physical activities of longer duration (>15 minutes) is unknown. It was therefore the purpose of this study to evaluate the role of group III/IV muscle afferent feedback in determining arterial oxygenation and gas exchange efficiency during long duration leg cycling exercise.

Methods: Five healthy males (24±6 yrs) performed an incremental maximal leg cycling test for the determination of peak power (W_peak, 315±54 W). After a familiarization session, participants returned to the laboratory on two additional days. All subjects performed 20 minutes of leg cycling at 30% of W_peak (92±19 W) immediately followed by 20 min at 50% of W_peak (155±34 W) under a) control conditions (i.e. intact neural feedback from group III/IV muscle afferents from the legs; CTRL), and b) with lumbar intrathecal fentanyl (attenuated group III/IV muscle afferent feedback from the legs; FENT). Metabolic and ventilatory responses were continuously monitored throughout exercise. Blood samples were taken from a radial catheter to determine the partial pressure of arterial O₂ and CO₂ (P_aO₂ and P_aCO₂) at rest and every 5 min during the exercise. The alveolar PO₂ was calculated (P_AO₂ = P_iO₂ - (P_aCO₂/RER)) and used to determine pulmonary gas exchange efficiency, i.e. the alveolar-to-arterial O₂ difference (A-aDO₂). Variables are presented as the average over the last 5 minutes of each of the two 20-min stages. A priori statistical comparisons were made between CTRL and FENT within each condition via Student’s T-tests corrected for family-wise comparisons.

Results: Fentanyl had no effect on A-aDO₂, minute ventilation (V_E), hemoglobin saturation, and pulmonary O₂ uptake (VO₂) and CO₂ production (VCO₂) at rest. While VCO₂ was similar during the last 5 minutes of exercise (30% W_peak: ~1.5±0.2 L/min; 50% W_peak: ~2.5±0.4 L/min, P>0.11), VO₂ was significantly higher during FENT (30% W_peak: 1.8±0.3 vs 1.6±0.2 L/min; 50% W_peak: 2.7±0.4 vs 2.5±0.3 L/min), and the ventilatory equivalent for O₂ (V_E/VO₂) was significantly lower during FENT compared to CTRL (30% W_peak: 25±2 vs 28±2; 50% W_peak: 29±5 vs 31±5, P<0.05). Finally, without affecting P_AO₂ (30% W_peak: ~84±5 mmHg; 50% W_peak: ~92±1 mmHg),  P_aO₂ (30% W_peak:71±3 vs 80±4 mmHg; 50% W_peak: 73±6 vs 80±5 mmHg, P<0.05) and hemoglobin O₂ saturation (30% W_peak: 94±1 vs 96±1%; 50% W_peak: 94±1 vs 95±1% , P<0.05) were significantly lower, and the A-aDO₂ significantly wider (30% W_peak: 12±3 vs 6±1 mmHg; 50% W_peak: 19±1 vs 12±2 mmHg, P<0.05) during FENT compared to CTRL.

Conclusions: In addition to their previously documented critical contribution to the cardiopulmonary response to the first few minutes of locomotor exercise, feedback from group III/IV muscle afferents remains an important determinant of arterial oxygenation during prolonged physical activities. The current data also emphasize the continuous significance of sensory feedback in matching the ventilatory response to the oxygen cost of prolonged human locomotion and in perpetually optimizing gas exchange efficiency during longer physical activity.

On the circulatory interaction of the chemoreflex and the muscle mechanoreflex

Hsuan-Yu Wan, Joshua C. Weavil, Taylor S. Thurston, Vincent P. Georgescu, Markus Amann

Introduction: Although the chemoreflex (CR) and the muscle mechanoreflex (MR) are recognized as strong, independent sympatho-excitatory feedback mechanisms, the interaction of these reflexes and the resulting effect upon the circulatory response remains unclear. This study evaluated the cardiovascular consequence of the interaction of the CR and MR in healthy men.

Methods: We administered a hypoxic and a hypercapnic inspirate to activate the CR at rest and during passive leg movement (PLM) activating the MR. Eight male volunteers completed 2 experimental sessions. With subjects at rest, one session included normoxic control conditions (Norm^Rest; S_pO₂ ~98%, P_ETO₂ ~84 mmHg, P_ETCO₂ ~34 mmHg), isocapnic hypoxia (Hypo^Rest; S_pO₂ ~85%, P_ETO₂ ~46 mmHg, P_ETCO₂ ~35 mmHg), and hyperoxic hypercapnia (Hyper^Rest; S_pO₂ ~100%, P_ETO₂ ~527 mmHg, P_ETCO₂ ~45 mmHg). In the other session, PLM was performed for 1 min under the same conditions of normoxia (Norm^PLM), isocapnic hypoxia (Hypo^PLM), and hyperoxic hypercapnia (Hyper^PLM). Norm^Rest was considered the condition with no reflexes activated. Hypo^Rest and Hyper^Rest were considered to activate the CR alone; Norm^PLM was considered to activate the MR alone; Hypo^PLM and Hyper^PLM were considered to simultaneously activate the CR and the MR. All sessions and conditions were conducted in a randomized order. Mean arterial blood pressure (MAP), cardiac output (CO), and femoral blood flow (Q_L) were continuously quantified using finger photoplethysmography and Doppler ultrasound.

Results: CR activation via hypoxia (i.e., ΔHypo^Rest-Norm^Rest) and CR activation via hypercapnia (i.e., ΔHyper^Rest-Norm^Rest) significantly, but similarly, increased CO (~0.7 L⋅min^-1). MR activation by PLM (i.e., ΔNorm^PLM-Norm^Rest) decreased MAP (~7 mmHg; p < 0.05), but significantly increased CO (~1.6 L⋅min^-1), Q_L (~1.4 L⋅min^-1), and leg vascular conductance (LVC, ~14 ml⋅min^-1⋅mmHg^-1). During co-activation of the CR via hypoxia and the MR (i.e., ΔHypo^PLM-Norm^Rest), the observed Q_L and LVC responses were significantly lower compared to the summated responses evoked by each reflex alone (Q_L: 1.1 ± 0.1 vs. 1.5 ± 0.1 L⋅min^-1; LVC: 11 ± 1 vs. 15 ± 2 ml⋅min^-1⋅mmHg^-1); there were no differences between the observed and summated responses of MAP and CO. During co-activation of the CR via hypercapnia and the MR (i.e., ΔHyper^PLM-Norm^Rest), only the observed LVC response was significantly lower than the summation of the responses to each reflex alone (LVC: 12 ± 1 vs. 14 ± 1 ml⋅min^-1⋅mmHg^-1), whereas the observed MAP, CO, and Q_L did not differ from the summated responses.

Conclusion: With CR activation by hypoxia, the CR:MR interaction is additive in terms of MAP and CO, but hypo-additive in terms of Q_L and LVC (i.e., impeded leg muscle perfusion). In contrast, with CR activation by hypercapnia, the CR:MR interaction is additive in terms of MAP, CO, and Q_L, but hypo-additive in terms of LVC. These outcomes indicate that the different modes of the chemoreflex engaged and interacting with the MR result in different impacts on the peripheral hemodynamic regulation. Taken together, despite different cardiovascular consequences, the LVC-based findings suggest that the interaction between the CR and the MR further augments sympathetically-mediated vasoconstriction in healthy men.