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Background: The interaction of the exercise pressor reflex (EPR) and the carotid chemoreflex (CR) affects circulatory control during physical activity in health. It has been shown that patients with heart failure with reduced ejection fraction (HFrEF) have an abnormal cardiovascular response to EPR or CR activation, which contributes to impaired limb blood flow during exercise. However, the impact of the reflex interaction in HFrEF is unclear. Purpose: To evaluate the interaction between EPR and CR in HFrEF. Method: Five patients with HFrEF and 6 control subjects (Ctrl) completed two experimental sessions. In session 1, participants performed dynamic single-leg knee-extension at 60% of peak power output for 4 min while breathing room air (normoxia; NormC: SaO2~96%, PaO2~81 mmHg, PaCO2~33 mmHg, arterial pH~7.43) and pure O2 (hyperoxia; HyperC: SaO2~100%, PaO2~408 mmHg, PaCO2~35 mmHg, arterial pH~7.40). In session 2, following lumbar intrathecal fentanyl administration to attenuate group III/IV leg muscle afferent feedback, participants repeated the same exercise under normoxic and hyperoxic conditions (NormF and HyperF). Mean arterial pressure (MAP, radial artery catheter), heart rate (HR, 12-lead ECG), stroke volume (SV, finger photoplethysmography), cardiac output (CO), systemic vascular conductance (SVC), femoral blood flow of the working leg (LBF, Doppler ultrasound), and leg vascular conductance (LVC) were continuously quantified during exercise. Results: EPR activation (i.e., ΔHyperC-HyperF) in HFrEF resulted in no changes in MAP and HR, but significantly decreased SV (~10 mL), CO (~1 L min−1), SVC (~9 mL min−1 mmHg−1), LBF (~0.4 L min−1) and LVC (~4 mL min−1 mmHg−1). In contrast, EPR activation in Ctrl significantly increased MAP (~10 mmHg) and decreased LVC (~3 mL min−1 mmHg−1), but did not affect HR, SV, CO, SVC and LBF ( p≥0.20). CR activation in HFrEF (i.e., ΔNormF-HyperF) had no effects on any of the cardiovascular variables ( p≥0.12). CR activation in Ctrl significantly increased HR (~3 beats min−1) and SVC (~3 mL min−1 mmHg−1), but had no effects on MAP, SV, CO, LBF and LVC ( p≥0.10). During EPR:CR co-activation (i.e., ΔNormC-HyperF) in HFrEF, the observed responses were not significantly different from the sum of the responses evoked by each reflex individually. In Ctrl, MAP during EPR:CR co-activation was greater than the summated response (16±7 vs. 10±9 mmHg; p National Heart, Lung, and Blood Institute (HL-116579), U.S. Veterans Affairs Rehabilitation Research and Development (E3343-R) This is the full abstract presented at the American Physiology Summit 2023 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.

This study examined the impact of aging on the elastic and resistive components of the work of breathing (W(b)) during locomotor exercise at a given 1) ventilatory rate, 2) metabolic rate, and 3) operating lung volume. Eight healthy younger (25 ± 4 yr) and 8 older (72 ± 6 yr) participants performed incremental bicycle exercise, from which retrospective analyses identified similar ventilatory rates (approximately 40, 70, and 100 L·min(−1)), similar metabolic rates (V̇o(2): approximately 1.2, 1.6, and 1.9 L·min(−1)), and similar lung volumes [inspiratory and expiratory reserve volumes (IRV/ERV: approximately 25/34%, 16/33%, and 13-34% of vital capacity]. W(b) at each level was quantified by integrating the averaged esophageal pressure-volume loop, which was then partitioned into elastic and resistive components of inspiratory and expiratory work using the modified Campbell diagram. IRV was smaller in the older participants during exercise at ventilations of 70 and 100 L·min(−1) and during exercise at the three metabolic rates (P < 0.05). Mainly because of a greater inspiratory elastic and resistive W(b) in the older group (P < 0.05), total W(b) was augmented by 40%–50% during exercise at matched ventilatory and matched metabolic rates. When examined during exercise evoking similar lung volumes, total W(b) was not different between the groups (P = 0.86). Taken together, although aging exaggerates total W(b) during locomotor exercise at a given ventilatory or a given metabolic rate, this difference is abolished during exercise at a given operating lung volume. These findings highlight the significance of operating lung volume in determining the age-related difference in W(b) during locomotor exercise. NEW & NOTEWORTHY This study evaluated the impact of aging on the work of breathing (W(b)) during locomotor exercise evoking similar ventilatory rates, metabolic rates, and operating lung volumes in young and older individuals. Mainly because of a greater inspiratory elastic and resistive W(b) in older participants, total W(b) was higher during exercise at any given ventilatory and metabolic rate with aging. However, this age-related difference was abolished during exercise evoking similar operating lung volumes in both age groups. These findings highlight the significance of lung volumes in determining the age-related difference in total W(b).

This study investigated the impact of dietary nitrate supplementation on peripheral hemodynamics, the development of neuromuscular fatigue, and time to task failure during cycling exercise. Eleven recreationally active male participants (27 ± 5 yr, V̇o(2max): 42 ± 2 mL/kg/min) performed two experimental trials following 3 days of either dietary nitrate-rich beetroot juice (4.1 mmol NO(3)(−)/day; DNS) or placebo (PLA) supplementation in a blinded, counterbalanced order. Exercise consisted of constant-load cycling at 50, 75, and 100 W (4 min each) and, at ∼80% of peak power output (218 ± 12 W), to task-failure. All participants returned to repeat the shorter of the two trials performed to task failure, but with the opposite supplementation regime (iso-time comparison; ISO). Mean arterial pressure (MAP), leg blood flow (Q(L); Doppler ultrasound), leg vascular conductance (LVC), and pulmonary gas exchange were continuously assessed during exercise. Locomotor muscle fatigue was determined by the change in pre to postexercise quadriceps twitch-torque (ΔQ(tw)) and voluntary activation (ΔVA; electrical femoral nerve stimulation). Following DNS, plasma [nitrite] (∼670 vs. ∼180 nmol) and [nitrate] (∼775 vs. ∼11 μmol) were significantly elevated compared with PLA. Unlike PLA, DNS lowered both Q(L) and MAP by ∼8% (P < 0.05), but did not alter LVC (P = 0.31). V̇O(2) across work rates, as well as cycling time to task-failure (∼7 min) and locomotor muscle fatigue following the ISO-time comparison were not different between the two conditions (ΔQ(tw) ∼42%, ΔVA ∼4%). Thus, despite significant hemodynamic changes, DNS did not alter the development of locomotor muscle fatigue and, ultimately, cycling time to task failure. NEW & NOTEWORTHY This study sought to characterize the impact of dietary nitrate supplementation on the hemodynamic response, locomotor muscle fatigue, and time to task failure during cycling exercise. Although nitrate supplementation lowered mean arterial pressure and exercising leg blood flow, leg vascular conductance and oxygen utilization were unaffected. Despite significant hemodynamic changes, there was no effect of dietary nitrate on neuromuscular fatigue development and, ultimately, cycling time to task failure.

The cardiovascular response resulting from the individual activation of the muscle mechanoreflex (MMR) or the chemoreflex (CR) is different between men and women. Whether the haemodynamic consequence resulting from the interaction of these sympathoexcitatory reflexes is also sex-dependent remains unknown. MMR and CR were activated by passive leg movement (LM) and exposure to hypoxia (O

Although systemic hypercapnia is a common outcome of pulmonary disease, the relationship between hypercapnia and voluntary diaphragmatic activation (VAdi) is unclear. To examine whether hypercapnia independent of ventilatory work contributes to reduced central motor drive to the diaphragm in healthy humans, 14 subjects spontaneously breathed room air (NN) or a hypercapnic gas mixture (HH; 7% CO2 with air) while at rest. Thereafter, subjects volitionally hyperventilated room air (NH) matching the minute ventilation recorded during HH while maintained at eucapnic levels. Twitch interpolation with bilateral magnetic stimulation of phrenic nerves at functional residual capacity was used to assess VAdi during the three trials. Although PETCO2 was elevated during HH compared with NN and NH (52 vs 36 mmHg), VAdi was not altered across the trials (HH = 93.3 ± 7.0%, NN = 94.4 ± 5.0%, NH = 94.9 ± 4.6%, p = 0.48). Our findings indicate that the magnitude of hypercapnia acutely imposed may not be effective in inhibiting voluntary neural drives to the diaphragm in normal resting individuals.

We examined the interactive influence of the muscle reflex (MR) and the chemoreflex (CR) on the ventilatory response to exercise. Eleven healthy subjects (5 women/6 men) completed three bouts of constant-load single-leg knee-extension exercise in a control trial and an identical trial conducted with lumbar intrathecal fentanyl to attenuate neural feedback from lower-limb group III/IV muscle afferents. The exercise during the two trials was performed while breathing ambient air ([Formula: see text] ~97%, [Formula: see text] ~84 mmHg, [Formula: see text] ~32 mmHg, pH ~7.39), or under normocapnic hypoxia ([Formula: see text] ~79%, [Formula: see text] ~43 mmHg, [Formula: see text] ~33 mmHg, pH ~7.39) or normoxic hypercapnia ([Formula: see text] ~98%, [Formula: see text] ~105 mmHg, [Formula: see text] ~50 mmHg, pH ~7.26). During coactivation of the MR and the hypoxia-induced CR (O(2)-CR), minute ventilation (V̇e) and tidal volume (V(T)) were significantly greater compared with the sum of the responses to the activation of each reflex alone; there was no difference between the observed and summated responses in terms of breathing frequency (f(B); P = 0.4). During coactivation of the MR and the hypercapnia-induced CR (CO(2)-CR), the observed ventilatory responses were similar to the summated responses of the reflexes (P ≥ 0.1). Therefore, the interaction between the MR and the O(2)-CR exerts a hyperadditive effect on V̇e and V(T) and an additive effect on f(B), whereas the interaction between the MR and the CO(2)-CR is simply additive for all ventilatory parameters. These findings reveal that the MR:CR interaction further augments the ventilatory response to exercise in hypoxia. NEW & NOTEWORTHY Although the muscle reflex and the chemoreflex are recognized as independent feedback mechanisms regulating breathing during exercise, the ventilatory implications resulting from their interaction remain unclear. We quantified the individual and interactive effects of these reflexes during exercise and revealed differential modes of interaction. Importantly, the reflex interaction further amplifies the ventilatory response to exercise under hypoxemic conditions, highlighting a potential mechanism for optimizing arterial oxygenation in physically active humans at high altitude.

This review discusses evidence suggesting that group III/IV muscle afferents affect locomotor performance by influencing neuromuscular fatigue. These neurons regulate the hemodynamic and ventilatory response to exercise and, thus, assure appropriate locomotor muscle O2 delivery, which optimizes peripheral fatigue development and facilitates endurance performance. In terms of central fatigue, group III/IV muscle afferents inhibit motoneuronal output and thereby limit exercise performance.

Key points Although the exercise pressor reflex (EPR) and the chemoreflex (CR) are recognized for their sympathoexcitatory effect, the cardiovascular implication of their interaction remains elusive. We quantified the individual and interactive cardiovascular consequences of these reflexes during exercise and revealed various modes of interaction. The EPR and hypoxia-induced CR interaction is hyper-additive for blood pressure and heart rate (responses during co-activation of the two reflexes are greater than the summation of the responses evoked by each reflex) and hypo-additive for peripheral haemodynamics (responses during co-activation of the reflexes are smaller than the summated responses). The EPR and hypercapnia-induced CR interaction results in a simple addition of the individual responses to each reflex (i.e. additive interaction). Collectively, EPR:CR co-activation results in significant cardiovascular interactions with restriction in peripheral haemodynamics, resulting from the EPR:CR interaction in hypoxia, likely having the most crucial impact on the functional capacity of an exercising human. Abstract We investigated the interactive effect of the exercise pressor reflex (EPR) and the chemoreflex (CR) on the cardiovascular response to exercise. Eleven healthy participants (5 females) completed a total of six bouts of single-leg knee-extension exercise (60% peak work rate, 4 min each) either with or without lumbar intrathecal fentanyl to attenuate group III/IV afferent feedback from lower limbs to modify the EPR, while breathing either ambient air, normocapnic hypoxia (Sa O2 ∼79%, Pa O2 ∼43 mmHg, Pa CO2 ∼33 mmHg, pH ∼7.39), or normoxic hypercapnia (Sa O2 ∼98%, Pa O2 ∼105 mmHg, Pa CO2 ∼50 mmHg, pH ∼7.26) to modify the CR. During co-activation of the EPR and the hypoxia-induced CR (O2 -CR), mean arterial pressure and heart rate were significantly greater, whereas leg blood flow and leg vascular conductance were significantly lower than the summation of the responses evoked by each reflex alone. During co-activation of the EPR and the hypercapnia-induced CR (CO2 -CR), the haemodynamic responses were not different from the summated responses to each reflex response alone (P ≥ 0.1). Therefore, while the interaction resulting from the EPR:O2 -CR co-activation is hyper-additive for blood pressure and heart rate, and hypo-additive for peripheral haemodynamics, the interaction resulting from the EPR:CO2 -CR co-activation is simply additive for all cardiovascular parameters. Thus, EPR:CR co-activation results in significant interactions between cardiovascular reflexes, with the impact differing when the CR activation is achieved by hypoxia or hypercapnia. Since the EPR:CR co-activation with hypoxia potentiates the pressor response and restricts blood flow to contracting muscles, this interaction entails the most functional impact on an exercising human.

We sought to investigate the role of group III/IV muscle afferents in limiting endurance exercise performance, independently of their role in optimizing locomotor muscle O2 delivery. While breathing 100% O2 to ensure a similar arterial O2 content ([Formula: see text]) in both trials, eight male cyclists performed 5-km time trials under control conditions (HCTRL) and with lumbar intrathecal fentanyl (HFENT) impairing neural feedback from the lower limbs. After each time trial, common femoral artery blood flow (FBF) was quantified (Doppler ultrasound) during constant-load cycling performed at the average power of the preceding time trial. The assessment of end-tidal gases, hemoglobin content and saturation, and FBF facilitated the calculation of leg O2 delivery. Locomotor muscle activation during cycling was estimated from vastus lateralis EMG. With electrical femoral nerve stimulation, peripheral and central fatigue were quantified by pre- to postexercise decreases in quadriceps twitch torque (ΔQtw) and voluntary activation (ΔVA), respectively. FBF (~16 mL·min−1·W−1; P = 0.6), [Formula: see text] (~24 mL O2/dL; P = 0.9), and leg O2 delivery (~0.38 mL O2·min−1·W−1; P = 0.9) were not different during HCTRL and HFENT. Mean power output and time to completion were significantly improved by 9% (~310 W vs. ~288 W) and 3% (~479 s vs. ~463 s), respectively, during HFENT compared with HCTRL. Quadriceps muscle activation was 9 ± 7% higher during HFENT compared with HCTRL ( P < 0.05). ΔQtw was significantly greater in HFENT compared with HCTRL (54 ± 8% vs. 39 ± 9%), whereas ΔVA was not different (~5%; P = 0.3) in both trials. These findings reveal that group III/IV muscle afferent feedback limits whole body endurance exercise performance and peripheral fatigue by restricting neural activation of locomotor muscle. NEW & NOTEWORTHY Group III/IV muscle afferent feedback facilitates endurance performance by optimizing locomotor muscle O2 delivery but also limits performance by restricting neural drive to locomotor muscle. To isolate the performance-limiting effect of these sensory neurons, we pharmacologically attenuated their central projection during a cycling time trial while controlling for locomotor muscle O2 delivery. With no difference in leg O2 delivery, afferent blockade attenuated the centrally mediated restriction in motoneuronal output and improved cycling performance.

Motor point associative stimulation (MPAS) in hand muscles is known to modify motor cortex excitability and improve learning rate, but not plateau of performance, in manual dexterity tasks. Central stimulation of motor cortex, such as transcranial direct current stimulation (tDCS), can have similar effects if accompanied by motor practice, which can be difficult and tiring for patients. Here we asked whether adding tDCS to MPAS could improve manual dexterity in healthy individuals who are already performing at their plateau, with no motor practice during stimulation. We hypothesized that MPAS could provide enough coordinated muscle activity to make motor practice unnecessary, and that this combination of stimulation techniques could yield improvements even in subjects at or near their peak. If so, this approach could have a substantial effect on patients with impaired dexterity, who are far from their peak. MPAS was applied for 30min to two right hand muscles important for manual dexterity. tDCS was simultaneously applied over left sensorimotor cortex. The motor cortex input/output (I/O) curve was assessed with transcranial magnetic stimulation (TMS), and manual dexterity was assessed with the Purdue Pegboard Test. Compared to sham or cathodal tDCS combined with MPAS, anodal tDCS combined with MPAS significantly increased the plateau of manual dexterity. This result suggests that MPAS has the potential to substitute for motor practice in mediating a beneficial effect of tDCS on manual dexterity.

The specific internal environment in the body during exercise can influence the muscle hypertrophy and strength response. High altitude mediated hypobaric hypoxia creates many morphological and physiological changes. One study reported that thigh muscle cross-sectional area (CSA) decreased by 10% after sojourn at high altitude (Himalayas, greater than 5000 m for over 56 days), although whether changes in physical activity and food intake occurred is not clear. In that study, the loss of thigh muscle size was mainly due to a decrease in myofibrillar proteins.1 Mizuno et al2 also reported that muscle fiber CSA decreased at an average of 15% in the vastus lateralis and biceps brachii muscles in both active and less active men after 75 days of altitude (greater than 5250 m) exposure. Tanner and Stager found that energy intake, in part, accounts for changes in body composition variables during a 21-day expedition between 2200 m and 4300 m altitude.3 However, some studies have reported that no significant changes occur in muscle fiber CSA following ~8 weeks of high altitude exposure.4,5 In the study by Lundby et al4, subjects had free access to physical activities such as jogging, hiking, and soccer, which may have counteracted the acute disuse muscle atrophy. In addition, a recent study investigated the effects of chronic hypobaric hypoxia on muscle protein metabolism and suggested that whole body amino acid f lux is increased due to an elevated protein turnover. Furthermore, the myocontractile protein synthesis rate is elevated following chronic hypobaric hypoxia.6 Therefore, the large increase in protein degradation is the underlying mechanism for the loss of skeletal muscle mass under high altitude mediated hypobaric hypoxia;6,7 although total time of exposure, the degree of hypoxia, food intake, and physical activity levels may all be influencing factors. In contrast to chronic hypobaric hypoxia, one study found that muscle fiber size increased after exposure to intermittent normobaric hypoxia. In this study, subjects performed bicycle ergometer exercise (70-80% of VO2max; VO2max was measured in an ambient fractional oxygen concentration [FlO2] of 11.6%, equivalent to an altitude of 4800 m) for 3 weeks under normobaric hypoxia (ambient FlO2 decreasing from 12.7% to a f inal level of 10%) with recovery in normoxia.8 Furthermore, a recent study found that intermittent systemic