Impact of Eccentric versus Concentric Cycling Exercise on Neuromuscular Fatigue and Muscle Damage in Breast Cancer Patients.

INTRODUCTION: This study investigated the magnitude and etiology of neuromuscular fatigue and muscle damage induced by eccentric cycling compared to conventional concentric cycling in patients with breast cancer. METHODS: After a gradual familiarization protocol for eccentric cycling, nine patients with early-stage breast cancer performed three cycling sessions in eccentric or concentric mode. The eccentric cycling session (ECC) was compared to concentric cycling sessions matched for power output (CONpower, 80% of concentric peak power output, 95 ± 23 W) or oxygen uptake (10 ± 2 mL.min.kg-1). Pre- to postexercise changes (30s through 10 min recovery) in knee extensor maximal voluntary contraction force (MVC), voluntary activation, and quadriceps potentiated twitch force (Qtw) were quantified to determine global, central, and peripheral fatigue, respectively. Creatine kinase (CK) and lactate dehydrogenase (LDH) activities were measured in the plasma before and 24 h postexercise as markers of muscle damage. RESULTS: Compared to CONpower (-11 ± 9%) and (-5 ± 5%), the ECC session resulted in a greater decrease in MVC (-25 ± 12%) postexercise (P < 0.001). Voluntary activation decreased only in ECC (-9 ± 6% postexercise, P < 0.001). The decrease in Qtw was similar postexercise between ECC and CONpower (-39 ± 21% and -40 ± 16%, P > 0.99) but lower in (P < 0.001). The CONpower session resulted in twofold greater compared to the ECC and sessions (P < 0.001). No change in CK or LDH activity was reported from preexercise to 24 h postexercise. CONCLUSIONS: The ECC session induced greater neuromuscular fatigue compared to the concentric cycling sessions without generating severe muscle damage. ECC is a promising exercise modality for counteracting neuromuscular maladaptation in patients with breast cancer.

Lactate and hydrogen ions play a predominant role in evoking the exercise pressor reflex during ischaemic contractions but not during freely perfused contractions.

We investigated the role played by lactate and hydrogen in evoking the exercise pressor reflex (EPR) in decerebrated rats whose hindlimb muscles were either freely perfused or ischaemic. Production of lactate and hydrogen by the contracting hindlimb muscles was manipulated by knocking out the myophosphorylase gene (pygm). In knockout rats (pygm-/-; n = 13) or wild-type rats (pygm+/+; n = 13), the EPR was evoked by isometrically contracting the triceps surae muscles. Blood pressure, tension, blood flow, renal sympathetic nerve activity and blood lactate concentrations were measured. Intramuscular metabolites and pH changes induced by the contractions were quantified by 31P-magnetic resonance spectroscopy (n = 5). In a subset of pygm-/- rats (n = 5), contractions were evoked with prior infusion of lactate (pH 6.0) in an attempt to restore the effect of lactate and hydrogen ions. Contraction of freely perfused muscles increased blood lactate and decreased muscle pH in pygm+/+ rats only. Despite these differences, the reflex pressor and sympathetic responses to freely perfused contraction did not differ between groups (P = 0.992). During ischaemia, contraction increased muscle lactate and hydrogen ion production in pygm+/+ rats (P < 0.0134), whereas it had no effect in pygm-/- rats (P > 0.783). Likewise, ischaemia exaggerated the reflex pressor, and sympathetic responses to contraction in pygm+/+ but not in pygm-/- rats. This exaggeration was restored when a solution of lactate (pH 6.0) was infused prior to the contraction in pygm-/- rats. We conclude that lactate and hydrogen accumulation in contracting myocytes play a key role in evoking the metabolic component of the EPR during ischaemic but not during freely perfused contractions. KEY POINTS: Conflicting results exist about the role played by lactate and hydrogen ions in evoking the exercise pressor reflex. Using CRISP-Cas9, we rendered the myophosphorylase gene non-functional to block the production of lactate and hydrogen ions. The exercise pressor reflex was evoked in decerebrated rats by statically contracting the triceps surae muscles with or without muscle ischaemia. Static contraction elevated the concentration of lactate and hydrogen ions in pygm+/+ but not in pygm-/- rats. Despite these differences, the exercise pressor reflex was not different between groups. Acute muscle ischaemia exaggerated the concentration of lactate and hydrogen ions in pygm+/+ but not in pygm-/- rats. Likewise, acute muscle ischaemia exaggerated the exercise pressor reflex in pygm+/+ but not in pygm-/- rats. We conclude that lactate and hydrogen play a key role in evoking the exercise pressor reflex during ischaemic but not during freely perfused contractions.

Paradoxical potentiation of the exercise pressor reflex by endomorphin 2 in the presence of naloxone.

When contracting muscles are freely perfused, the acid-sensing ion channel 3 (ASIC3) on group IV afferents plays a minor role in evoking the exercise pressor reflex. We recently showed in isolated dorsal root ganglion neurons innervating the gastrocnemius muscles that two mu opioid receptor agonists, namely endomorphin 2 and oxycodone, potentiated the sustained inward ASIC3 current evoked by acidic solutions. This in vitro finding prompted us to determine whether endomorphin 2 and oxycodone, when infused into the arterial supply of freely perfused contracting hindlimb muscles, potentiated the exercise pressor reflex. We found that infusion of endomorphin 2 and naloxone in decerebrated rats potentiated the pressor responses to contraction of the triceps surae muscles. The endomorphin 2-induced potentiation of the pressor responses to contraction was prevented by infusion of APETx2, an ASIC3 antagonist. Specifically, the peak pressor response to contraction averaged 19.3 ± 5.6 mmHg for control (n = 10), 27.2 ± 8.1 mmHg after naloxone and endomorphin 2 infusion (n = 10), and 20 ± 8 mmHg after APETx2 and endomorphin 2 infusion (n = 10). Infusion of endomorphin 2 and naloxone did not potentiate the pressor responses to contraction in ASIC3 knockout rats (n = 6). Partly similar findings were observed when oxycodone was substituted for endomorphin 2. Oxycodone infusion significantly increased the exercise pressor reflex over its control level, but subsequent APETx2 infusion failed to restore the increase to its control level (n = 9). The peak pressor response averaged 23.1 ± 8.6 mmHg for control (n = 9), 33.2 ± 11 mmHg after naloxone and oxycodone were infused (n = 9), and 27 ± 8.6 mmHg after APETx2 and oxycodone were infused (n = 9). Our data suggest that after opioid receptor blockade, ASIC3 stimulation by the endogenous mu opioid, endomorphin 2, potentiated the exercise pressor reflex.NEW & NOTEWORTHY This paper provides the first in vivo evidence that endomorphin 2, an endogenous opioid peptide, can paradoxically increase the magnitude of the exercise pressor reflex by an ASIC3-dependent mechanism even when the contracting muscles are freely perfused.

Inhibition and potentiation of the exercise pressor reflex by pharmacological modulation of TRPC6 in male rats.

We determined the role played by the transient receptor potential canonical 6 (TRPC6) channel in evoking the mechanical component of the exercise pressor reflex in male decerebrated Sprague-Dawley rats. TRPC6 channels were identified by quadruple-labelled (DiI, TRPC6, neurofilament-200 and peripherin) immunohistochemistry in dorsal root ganglion (DRG) cells innervating the triceps surae muscles (n = 12). The exercise pressor reflex was evoked by statically contracting the triceps surae muscles before and after injection of the TRPC6 antagonist BI-749327 (n = 11; 12 µg kg-1 ) or SAR7334 (n = 11; 7 µg kg-1 ) or the TRPC6 positive modulator C20 (n = 11; 18 µg kg-1 ). Similar experiments were conducted while the muscles were passively stretched (n = 8-12), a manoeuvre that isolated the mechanical component of the reflex. Blood pressure, tension, renal sympathetic nerve activity (RSNA) and blood flow were recorded. Of the DRG cells innervating the triceps surae muscles, 85% stained positive for the TRPC6 antigen, and 45% of those cells co-expressed neurofilament-200. Both TRPC6 antagonists decreased the reflex pressor responses to static contraction (-32 to -42%; P < 0.05) and to passive stretch (-35 to -52%; P < 0.05), whereas C20 increased these responses (55-65%; P < 0.05). In addition, BI-749327 decreased the peak and integrated RSNA responses to both static contraction (-39 to -43%; P < 0.05) and passive stretch (-56 to -62%; P < 0.05), whereas C20 increased the RSNA to passive stretch only. The onset latency of the decrease or increase in RSNA occurred within 2 s of the onset of the manoeuvres (P < 0.05). Collectively, our results show that TRPC6 plays a key role in evoking the mechanical component of the exercise pressor reflex. KEY POINTS: The exercise pressor reflex plays a key role in the sympathetic and haemodynamic responses to exercise. This reflex is composed of two components, namely the mechanoreflex and the metaboreflex. The receptors responsible for evoking the mechanoreflex are poorly documented. A good candidate for this function is the transient receptor potential canonical 6 (TRPC6) channel, which is activated by mechanical stimuli and expressed in dorsal root ganglia of rats. Using two TRPC6 antagonists and one positive modulator, we investigated the role played by TRPC6 in evoking the mechanoreflex in decerebrated rats. Blocking TRPC6 decreased the renal sympathetic and the pressor responses to both contraction and stretch, the latter being a manoeuvre that isolates the mechanoreflex. In contrast, the positive modulator increased the pressor reflex to contraction and stretch, in addition to the sympathetic response to stretch. Our results provide strong support for a role played by the TRPC6 channel in evoking the mechanoreflex.

Functional knockout of the TRPV1 channel has no effect on the exercise pressor reflex in rats.

The role played by the transient receptor potential vanilloid 1 (TRPV1) channel on the thin fibre afferents evoking the exercise pressor reflex is controversial. To shed light on this controversy, we compared the exercise pressor reflex between newly developed TRPV1+/+ , TRPV1+/- and TRPV1-/- rats. Carotid arterial injection of capsaicin (0.5 µg), evoked significant pressor responses in TRPV1+/+ and TRPV1+/- rats, but not in TRPV1-/- rats. In acutely isolated dorsal root ganglion neurons innervating the gastrocnemius muscles, capsaicin evoked inward currents in neurons isolated from TRPV1+/+ and TRPV1+/- rats but not in neurons isolated from TRPV1-/- rats. The reflex was evoked by stimulating the tibial nerve in decerebrated rats whose femoral artery was either freely perfused or occluded. We found no difference between the reflex in the three groups of rats regardless of the patency of the femoral artery. For example, the peak pressor responses to contraction in TRPV1+/+ , TRPV1+/- and TRPV1-/- rats with patent femoral arteries averaged 17.1 ± 7.2, 18.9 ± 12.4 and 18.4 ± 8.6 mmHg, respectively. Stimulation of the tibial nerve after paralysis with pancuronium had no effect on arterial pressure, findings which indicated that the pressor responses to contraction were not caused by electrical stimulation of afferent tibial nerve axons. We also found that expression levels of acid-sensing ion channel 1 and endoperoxide 4 receptor in the L4 and 5 dorsal root ganglia were not upregulated in the TRPV1-/- rats. We conclude that TRPV1 is not needed to evoke the exercise pressor reflex in rats whose contracting muscles have either a patent or an occluded arterial blood supply. KEY POINTS: A reflex arising in contracting skeletal muscle contributes to the increases in arterial blood pressure, cardiac output and breathing evoked by exercise. The sensory arm of the reflex comprises both mechanoreceptors and metaboreceptors, of which the latter signals that blood flow to exercising muscle is not meeting its metabolic demand. The nature of the channel on the metaboreceptor sensing a mismatch between supply and demand is controversial; some believe that it is the transient receptor potential vanilloid 1 (TRPV1) channel. Using genetically engineered rats in which the TRPV1 channel is rendered non-functional, we have shown that it is not needed to evoke the metaboreflex.

The Role of Contraction Mode in Determining Exercise Tolerance, Torque-Duration Relationship, and Neuromuscular Fatigue.

PURPOSE: Critical torque (CT) and work done above it ( W ') are key predictors of exercise performance associated with neuromuscular fatigue. The aim of the present study was to understand the role of the metabolic cost of exercise in determining exercise tolerance, CT and W ', and the mechanisms of neuromuscular fatigue. METHODS: Twelve subjects performed four knee extension time trials (6, 8, 10, and 12 min) using eccentric, isometric, or concentric contractions (3-s on/2-s off at 90°·s -1 or 30°·s -1 ) to modulate the metabolic cost of exercise. Exercise performance was quantified by total impulse and mean torque. Critical torque and W ' were determined using the linear relationship between total impulse and contraction time. Cardiometabolic, neuromuscular, and ventilatory responses were quantified. Neuromuscular function was evaluated by maximal voluntary contraction, resting potentiated single/doublet electrical stimulations, and superimposed single electrical stimulation to quantify neuromuscular, peripheral, and central fatigue, respectively. RESULTS: Compared with isometric exercise, total impulse (+36% ± 21%; P < 0.001), CT (+27% ± 30%; P < 0.001), and W ' (+67% ± 99%; P < 0.001) were increased during eccentric exercise, whereas total impulse (-25% ± 7%; P < 0.001), critical torque (-26% ± 15%; P < 0.001), and W ' (-18% ± 19%; P < 0.001) were reduced in concentric exercise. Conversely, the metabolic response and the degree of peripheral fatigue were reduced during eccentric exercise, whereas they were increased during concentric exercise. Critical torque was negatively associated with oxygen consumption gain ( R2 = 0.636; P < 0.001), and W ' was negatively associated with rates of neuromuscular and peripheral fatigue indices ( R2 = 0.252-0.880; P < 0.001). CONCLUSIONS: The contraction mode influenced both CT and W ', and consequently exercise tolerance, indicating that the metabolic cost of contraction played a key role.

Exercise-Induced Fatigue in Hamstring versus Quadriceps Muscles and Consequences on the Torque-Duration Relationship in Men.

PURPOSE: The present study investigated the mechanisms of neuromuscular fatigue in quadriceps and hamstring muscles and its consequences on the torque-duration relationship. METHODS: Twelve healthy men performed a 5-min all-out exercise (3-s contraction, 2-s relaxation) with either quadriceps or hamstring muscles on separate days. Central fatigue and peripheral fatigue were quantified via changes in pre- to postexercise voluntary activation (VA) and potentiated twitch (P Tw ) torque evoked by supramaximal electrical stimulation, respectively. Critical torque was determined as the mean torque of the last six contractions, whereas W ' was calculated as the torque impulse done above critical torque. RESULTS: After exercise, maximal voluntary contraction (MVC) decreased to a greater magnitude ( P < 0.001) in quadriceps (-67% ± 9%) compared with hamstring (-51% ± 10%). ∆P Tw was also greater in quadriceps compared with hamstring (-69% ± 15% vs 55% ± 10%, P < 0.01), whereas central fatigue only developed in quadriceps (∆VA, -25% ± 28%). Hamstring demonstrated reduced critical torque compared with quadriceps (60 ± 12 vs 97 ± 26 N·m, P < 0.001) as well as drastically lower W ' (1001 ± 696 vs 8111 ± 2073 N·m·s, P < 0.001). No correlation was found between quadriceps and hamstring for any index of neuromuscular fatigue (∆MVC, ∆P Tw , or ∆VA). CONCLUSIONS: These findings revealed that hamstring presented different etiology and magnitude of neuromuscular fatigue compared with quadriceps. The absence of correlation observed between quadriceps and hamstring fatigue parameters (∆MVC, ∆P Tw , or ∆VA) suggests no interrelation in fatigue etiology between these two muscle groups within individuals and, therefore, highlights the need to investigate specifically hamstring muscle fatigue.

Relationship between neuromuscular fatigue, muscle activation and the work done above the critical power during severe-intensity exercise.

NEW FINDINGS: What is the central question of this study? Does the work done above critical power (W') or muscle activation determine the degree of peripheral fatigue induced by cycling time trials performed in the severe-intensity domain? What is the main finding and its importance? Peripheral fatigue increased when power output and muscle activation increased, whereas W' did not change between the time trials. Therefore, no relationship was found between W' and exercise-induced peripheral fatigue such as previously postulated in the literature. In contrast, we found a significant association between EMG amplitude during exercise and exercise-induced reduction in the potentiated quadriceps twitch, suggesting that muscle activation plays a key role in determining peripheral fatigue during severe-intensity exercise. ABSTRACT: In order to determine the relationship between peripheral fatigue, muscle activation and the total work done above critical power (W'), 10 men and four women performed, on separated days, self-paced cycling time trials of 3, 6, 10 and 15 min. Exercise-induced quadriceps fatigue was quantified using pre- to postexercise (15 s to 15 min recovery) changes in maximal voluntary contraction (MVC) peak force, voluntary activation and potentiated twitch force (QT). Voluntary activation was measured using the interpolated twitch technique, and QT was evoked by electrical stimulations of the femoral nerve. Quadriceps muscle activation was determined using the root mean square of surface EMG of vastus lateralis (VLRMS ), vastus medialis (VMRMS ) and rectus femoris (RFRMS ). Critical power and W' were calculated from the power-duration relationship from the four time trials. Mean power output and mean VLRMS , VMRMS and RFRMS were greater during shorter compared with longer exercise periods (P < 0.05), whereas no significant between-trial change in W' was found. The magnitude of exercise-induced reductions in QT increased with the increase in power output (P < 0.001) and was associated with mean VLRMS, VMRMS and RFRMS (P < 0.001, r2  > 0.369) but not W' (P > 0.150, r2  < 0.044). Reduction in voluntary activation tended (P = 0.067) to be more pronounced with the lengthening in time trial duration, whereas no significant between-trial changes in MVC peak force were found. Our data suggest that peripheral fatigue is not related to the amount of work done above the critical power but rather to the level of muscle activation during exercise in the severe-intensity domain.

Recovery from Fatigue after Cycling Time Trials in Elite Endurance Athletes.

INTRODUCTION: We determined the recovery from neuromuscular fatigue in six professional (PRO) and seven moderately trained (MOD) cyclists after repeated cycling time trials of various intensities/durations. METHOD: Participants performed two 1-min (1minTT) or two 10-min (10minTT) self-paced cycling time trials with 5 min of recovery in between. Central and peripheral fatigue were quantified via preexercise to postexercise (15-s through 15-min recovery) changes in voluntary activation (VA) and potentiated twitch force. VA was measured using the interpolated twitch technique, and potentiated twitch force was evoked by single (QTsingle) and paired (10-Hz (QT10) and 100-Hz (QT100)) electrical stimulations of the femoral nerve. RESULTS: Mean power output was 32%-72% higher during all the time trials and decreased less (-10% vs -13%) from the first to second time trial in PRO compared with MOD (P < 0.05). Conversely, exercise-induced reduction in QTsingle and QT10/QT100 was significantly lower in PRO after every time trial (P < 0.05). Recovery from fatigue from 15 s to 2 min for QTsingle and QT10/QT100 was slower in PRO after every time trial (P < 0.05). In both groups, the reduction in QTsingle was lower after the 10minTTs compared with 1minTTs (P < 0.05). Conversely, VA decreased more after the 10minTTs compared with 1minTTs (P < 0.05). CONCLUSION: Our findings showed that excitation-contraction coupling was preserved after exercise in PRO compared with MOD. This likely contributed to the improved performance during repeated cycling time trials of various intensity/duration in PRO, despite a slower rate of recovery in its early phase. Finally, the time course of recovery from neuromuscular fatigue in PRO was dependent on the effects of prolonged low-frequency force depression.

Central and peripheral modulation of exercise pressor reflex sensitivity after nonfatiguing work.

Autonomic blood pressure control is fundamentally altered during a single bout of exercise, as evidenced by the downward resetting of the baroreflex following exercise (postexercise hypotension). However, it is unclear if an acute bout of exercise is also associated with a change in the sensitivity of the exercise pressor response to a controlled stimulus, such as a static contraction. This study tested the hypothesis that the blood pressure response to a controlled static contraction would be attenuated after unilateral cycling of the contralateral (opposite) leg, but preserved after cycling of the ipsilateral (same) leg. To test this, the blood pressure response to 90 s of isometric plantar flexion [50% maximal voluntary contraction (MVC)] was compared before and after 20 min of contralateral and ipsilateral single-leg cycling at 20% peak oxygen consumption and rest (control) in 10 healthy subjects (three males and seven females). The mean arterial pressure response was significantly attenuated after contralateral single-leg cycling (+9.8 ± 7.5% ∆mmHg vs. +6.7 ± 6.6% ∆mmHg pre and postexercise, respectively, P = 0.04) and rest (+9.0 ± 7.5% ∆mmHg vs. +6.6 ± 5.2% ∆mmHg pre and postexercise, respectively, P = 0.03). In contrast, the pressor response nonsignificantly increased following ipsilateral single-leg cycling (+5.5 ± 5.2% ∆mmHg vs. +8.9 ± 7.2% ∆mmHg pre and postexercise, respectively, P = 0.08). The heart rate, leg blood flow, and leg conductance responses to plantar flexion were not affected by any condition (P ≥ 0.12). These results are consistent with the notion that peripheral, but not central mechanisms promote exercise pressor reflex sensitivity after exercise.

Intrathecal injection of brilliant blue G, a P2X7 antagonist, attenuates the exercise pressor reflex in rats.

Purinergic 2X (P2X) receptors on the endings of group III and IV afferents play a role in evoking the exercise pressor reflex. Particular attention has been paid to P2X3 receptors because their blockade in the periphery attenuated this reflex. In contrast, nothing is known about the role played by P2X receptors in the spinal cord in evoking the exercise pressor reflex in rats. P2X7 receptors, in particular, may be especially important in this regard because they are found in abundance on spinal glial cells and may communicate with neurons to effect reflexes controlling cardiovascular function. Consequently, we investigated the role played by spinal P2X7 receptors in evoking the exercise pressor reflex in decerebrated rats. We found that intrathecal injection of the P2X7 antagonist brilliant blue G (BBG) attenuated the exercise pressor reflex (blood pressure index: 294 ± 112 mmHg·s before vs. 7 ± 32 mmHg·s after; P < 0.05). Likewise, intrathecal injection of minocycline, which inhibits microglial cell output, attenuated the reflex. In contrast, intrathecal injection of BBG did not attenuate the pressor response evoked by intracarotid injection of sodium cyanide, a maneuver that stimulated carotid chemoreceptors. Moreover, injections of BBG either into the arterial supply of the contracting hindlimb muscles or into the jugular vein did not attenuate the exercise pressor reflex. Our findings support the hypothesis that P2X7 receptors on microglial cells within the spinal cord play a role in evoking the exercise pressor reflex.

ASIC1a does not play a role in evoking the metabolic component of the exercise pressor reflex in a rat model of peripheral artery disease.

The role of the ASIC1a in evoking the exercise pressor reflex in rats with simulated peripheral artery disease is unknown. This prompted us to determine whether ASIC1a plays a role in evoking the exaggerated exercise pressor reflex in decerebrated rats with simulated peripheral artery disease. To simulate peripheral artery disease, we ligated the left femoral artery 72 h before the experiment. The right femoral artery was freely perfused and used as a control. To test our hypothesis, we measured the effect of injecting two ASIC1a blockers into the arterial supply of the triceps surae muscles with and without the femoral artery ligated on the reflex pressor responses to 1) static contraction of the triceps surae muscles, 2) calcaneal tendon stretch, and 3) intra-arterial injection of diprotonated phosphate (pH 6.0). We found that the ASIC1a blockers psalmotoxin-1 (200 ng/kg) and mambalgin-1 (6.5 µg/kg) decreased the pressor responses to static contraction as well as the peak pressor responses to injection of diprotonated phosphate when these responses were evoked from the freely perfused hindlimb. In contrast, ASIC1a blockers only decreased the peak pressor responses evoked by injection of diprotonated phosphate in the hindlimb circulation with simulated peripheral artery disease. This inhibitory effect was less than the one measured from the healthy hindlimb. Independently of the hindlimb of interest, ASIC1a blockers had no effect on the pressor responses to tendon stretch. Our results do not support the hypothesis that ASIC1a play a role in evoking the exercise pressor reflex arising from a hindlimb with simulated peripheral artery disease.NEW & NOTEWORTHY The role of ASIC1a in evoking the metabolic component of the exercise pressor reflex in peripheral artery disease is unknown. Using a within-rat experimental design, we found that the contribution of ASIC1a decreased in a rat model of peripheral artery disease. These results have key implications to help finding better treatments and improve morbidity, quality of life, and mortality in patients with peripheral artery disease.

Functional knockout of ASIC3 attenuates the exercise pressor reflex in decerebrated rats with ligated femoral arteries.

The exercise pressor reflex arises from contracting muscle and is manifested by increases in arterial pressure, heart rate, and cardiac contractility. In patients with peripheral artery disease, the exercise pressor reflex is exaggerated. This effect is believed to be caused by a metabolite whose concentration is increased when the working muscles are inadequately perfused. Previous work in rats with simulated peripheral artery disease has shown that pharmacological blockade of acid-sensing ion channel 3 (ASIC3), which is found on group III and IV afferents, prevented the exaggeration of the exercise pressor reflex. Blockade of ASIC3, however, may have off-target effects that preclude a conclusion that ASIC3 plays a role in evoking the reflex in rats with simulated peripheral artery disease. In the present experiments performed in decerebrated rats with simulated peripheral artery disease, we compared the exercise pressor reflex in rats with a functional knockout of the ASIC3 (KO) with the reflex in their wild-type counterparts (WT). We found that the exercise pressor reflex in ASIC3 KO rats was significantly lower than the exercise pressor reflex in their WT counterparts (P < 0.05). ASIC 3 KO rats demonstrated lower pressor responses to intra-arterial injection of diprotonated phosphate (86 mM; pH 6.0), lactic acid (12 mM; pH 2.85), and capsaicin (0.2 µg; pH 7.2) (P < 0.05). In contrast, both ligated WT and ASIC3 KO rats displayed similar pressor responses to tendon stretch (P > 0.05). We conclude that ASIC3 play an important role in evoking the exaggerated exercise pressor reflex in rats with peripheral artery disease.NEW & NOTEWORTHY We used a genetic approach to test the hypothesis that the magnitude of the exercise pressor reflex evoked in ligated ASIC3 KO rats was significantly lower than the magnitude of the exercise pressor reflex evoked in their ligated wild-type (WT) counterparts. The pressor response to contraction in ligated ASIC3 KO rats was significantly smaller than was the pressor response to contraction in ligated WT rats.

Inorganic phosphate and lactate potentiate the pressor response to acidic stimuli in rats.

NEW FINDINGS: What is the central question of this study? What is the contribution of the main acidic compounds accumulated during contractions, namely H+ , lactic acid and inorganic phosphate, to evoke the metabolic component of the exercise pressor reflex? What is the main finding and its importance? We found that the pressor response to acidic stimuli is driven by the concentration of hydrogen ions and that lactate and inorganic phosphate act as potentiating agents. ABSTRACT: H+ ions, lactate and inorganic phosphate are produced by contracting skeletal muscles and evoke, in part, the metabolic component of the exercise pressor reflex. Owing to their disparate dissociation constants (i.e. pKa ), the contribution of each acid to the muscle metaboreflex is unclear. This lack of information prompted us to determine the reflex pressor responses to injection of acidic saline, lactate (24 mm) and inorganic phosphate (86 mm) at various values of pH (from 2.66 to 7.5), alone or in combination, into the arterial supply of hindlimb skeletal muscle of decerebrate rats. In particular, we tested the hypothesis that the pressor response to an injection of a combination of lactate and phosphate at an acidic pH is greater than that evoked by injection of either phosphate or lactate alone at the same pH. We found that injection of acidic saline produced a pressor response only at a pH of 2.66 (7 ± 4 mmHg), an effect that was potentiated when the solution contained lactate (50 ± 20 mmHg). At a pH of 6.0, however, this effect was lost. At a pH of 6.0, only the injection of inorganic phosphate produced a significant pressor response (23 ± 12 mmHg). A large potentiating effect was found when lactate was added to the inorganic phosphate solution (39 ± 18 mmHg), an effect that was lost at a pH >7.0. Our findings led to the conclusion that the pressor response to injection of acidic solutions was driven by H+ ions and that inorganic phosphate and lactate functioned as sensitizing agents.

Similar Cardioventilatory but Greater Neuromuscular Stimuli With Interval Drop Jump Than With Interval Running.

CONTEXT: Drop jumps and high-intensity interval running are relevant training methods to improve explosiveness and endurance performance, respectively. Combined training effects might, however, be achieved by performing interval drop jumping. PURPOSE: To determine the acute effects of interval drop jumping on oxygen uptake (V˙O2)-index of cardioventilatory/oxidative stimulation level and peripheral fatigue-a limiting factor of explosiveness. METHODS: Thirteen participants performed three 11-minute interval training sessions during which they ran 15 seconds at 120% of the velocity that elicited maximal V˙O2 (V˙O2max) (ITrun), or drop jumped at 7 (ITDJ7) or 9 (ITDJ9) jumps per 15 seconds, interspersed with 15 seconds of passive recovery. V˙O2 and the time spent above 90% of V˙O2max (V˙TO2max) were collected. Peripheral fatigue was quantified via preexercise to postexercise changes in evoked potentiated quadriceps twitch (ΔQT). Power output was estimated during ITDJs using optical sensors. RESULTS: All participants reached 90% of V˙O2max or higher during ITrun and ITDJ9, but only 11 did during ITDJ7. V˙TO2max was not different between ITrun and ITDJ9 (145 [76] vs 141 [151] s; P = .92) but was reduced during ITDJ7 (28 [26] s; P = .002). Mean ΔQT in ITDJ9 and ITDJ7 was not different (-17% [9%] vs -14% [8%]; P = .73) and greater than in ITrun (-8% [7%]; P = .001). No alteration in power output was found during ITDJs (37 [10] W·kg-1). CONCLUSION: Interval drop jumping at a high work rate stimulated the cardioventilatory and oxidative systems to the same extent as interval running, while the exercise-induced increase in fatigue did not compromise drop jump performance. Interval drop jumping might be a relevant strategy to get concomitant improvements in endurance and explosive performance.

ASIC1a plays a key role in evoking the metabolic component of the exercise pressor reflex in rats.

The role of the acid-sensing ion channel 1a (ASIC1a) in evoking the exercise pressor reflex is unknown, despite the fact that ASIC1a is opened by decreases in pH in the physiological range. This fact prompted us to test the hypothesis that ASIC1a plays an important role in evoking the exercise pressor reflex in decerebrated rats with freely perfused hindlimb muscles. To test this hypothesis, we measured the effect of injecting two ASIC1a blockers into the arterial supply of the triceps surae muscles on the reflex pressor responses to four maneuvers, namely 1) static contraction of the triceps surae muscles (i.e., the exercise pressor reflex), 2) calcaneal tendon stretch, 3) intra-arterial injection of lactic acid, and 4) intra-arterial injection of diprotonated phosphate. We found that the 2 ASIC1a blockers, psalmotoxin-1 (200 ng/kg) and mambalgin-1 (6.5 µg/kg), decreased the pressor responses to static contraction as well as the peak pressor responses to injection of lactic acid and diprotonated phosphate. In contrast, neither ASIC1a blocker had any effect on the pressor responses to tendon stretch. Importantly, we found that ASIC1a blockade significantly decreased the pressor response to static contraction after a latency of at least 8 s. Our results support the hypothesis that ASIC1a plays a key role in evoking the metabolic component of the exercise pressor reflex.NEW & NOTEWORTHY The role played by acid-sensing ion channel 1a (ASIC1a) in evoking the exercise pressor reflex remains unknown. In decerebrated rats with freely perfused femoral arteries, blocking ASIC1a with psalmotoxin-1 or mambalgin-1 significantly attenuated the pressor response to static contraction, lactic acid, and diprotonated phosphate injection but had no effect on the pressor response to stretch. We conclude that ASIC1a plays a key role in evoking the exercise pressor reflex by responding to contraction-induced metabolites, such as protons.

The magnitude of the exercise pressor reflex is influenced by the active skeletal muscle mass in the decerebrate rat.

The exercise pressor reflex is composed of two components, namely the muscle mechanoreflex and the muscle metaboreflex. The afferents evoking the two components are either thinly myelinated (group III) or unmyelinated (group IV); in combination they are termed "thin fiber afferents." The exercise pressor reflex is often studied in unanesthetized, decerebrate rats. However, the relationship between the magnitude of this reflex and the number of thin fiber afferents stimulated by muscle contraction is unknown. This lack of knowledge prompted us to test the hypothesis that the magnitude of the exercise pressor reflex was directly proportional to the amount of muscle mass activated. Muscle mechanoreceptors were stimulated by stretching the calcaneal tendon. Likewise, muscle metaboreceptors were stimulated by injecting lactic acid into the arterial supply of the hindlimb muscles. In addition, both muscle mechanoreceptors and metaboreceptors were stimulated by statically contracting the hindlimb muscles. We found that simultaneous bilateral (both hindlimbs) stimulation of thin fiber afferents with stretch, lactic acid, and static contraction evoked significantly greater pressor responses than did unilateral (one hindlimb) stimulation of these afferents. In addition, the magnitude of the pressor responses to bilateral simultaneous stimulation of thin fiber afferents evoked by stretch, lactic acid, and contraction was not significantly different from the magnitude of the sum of the pressor responses evoked by unilateral stimulation of these afferents by stretch, lactic acid, and contraction. We conclude that the magnitude of the exercise pressor reflex and its two components is dependent on the number of afferents stimulated.

Blocking the transient receptor potential vanilloid-1 does not reduce the exercise pressor reflex in healthy rats.

Controversy exists regarding the role played by transient receptor potential vanilloid-1 (TRPV1) in evoking the exercise pressor reflex. Here, we determine the role played by TRPV1 in evoking this reflex while assessing possible confounding factors arising from TRPV1 antagonists or from the vehicle in which they were dissolved. The exercise pressor reflex was evoked in decerebrated, anesthetized Sprague-Dawley rats by electrical stimulation of the tibial nerve to contract the triceps surae muscles statically. This procedure was repeated before and after injection of the TRPV1 blockers: capsazepine (100 µg/100 µL), ruthenium red (100 µg/100 µL), or iodoresiniferatoxin (IRTX; 1 µg/100 µL). We found that capsazepine decreased the exercise pressor reflex when the drug was dissolved in DMSO (-10 ± 9 mmHg; P = 0.015; n = 7). However, similar reduction was found when DMSO alone was injected (-8 ± 5 mmHg; P = 0.023; n = 5). Capsazepine, dissolved in ethanol (2 ± 6 mmHg; P = 0.49; n = 7), ruthenium red (-4 ± 12 mmHg; P = 0.41; n = 7), or IRTX (4 ± 18 mmHg; P = 0.56; n = 7), did not significantly decrease the exercise pressor reflex. In addition, we found that capsazepine and ruthenium red had "off-target" effects. Capsazepine decreased the pressor response evoked by intra-arterial injection of bradykinin (500 ng/kg; -12 ± 13 mmHg; P = 0.028; n = 9) and α-ß-methylene ATP (10 µg/kg; -7 ± 8 mmHg; P = 0.019; n = 10), whereas ruthenium red decreased the ability of the muscle to produce and sustain force (-99 ± 83 g; P = 0.020; n = 7). Our data therefore suggest that TRPV1 does not play a role in evoking the exercise pressor reflex. Additionally, given their strong off-target effects, capsazepine and ruthenium red should not be used for studying the role played by TRPV1 in evoking the exercise pressor reflex.

Increased Fatigue Response to Augmented Deceptive Feedback during Cycling Time Trial.

PURPOSE: This study aimed to investigate the effect of different magnitudes of deception on performance and exercise-induced fatigue during cycling time trial. METHODS: After three familiarization visits, three women and eight men performed three 5-km cycling time trials while following a simulated dynamic avatar reproducing either 100% (5K100%), 102% (5K102%), or 105% (5K105%) of the subject's previous fastest trial. Quadriceps muscle activation was quantified with surface electromyography. Fatigue was quantified by preexercise to postexercise (10 s through 15 min recovery) changes in quadriceps maximal voluntary contraction (MVC) force, potentiated twitch force evoked by electrical femoral nerve stimulation (QTSingle) and voluntary activation (VA, twitch interpolation technique). RESULTS: Greater quadriceps muscle activation in 5K102% versus 5K100% (12% ± 11%) was found in parallel with a 5% ± 2% and 2% ± 1% improvement in power output and completion time, respectively (P < 0.01). Exercise-induced reduction in MVC force and VA were 14% ± 19% and 28% ± 31% greater at exercise termination (at 10 s), whereas QTSingle recovery (from 10 s to 15 min) was 5% ± 5% less in 5K102% versus 5K100% (P < 0.01). No difference in performance or fatigue indices measured at exercise termination was found between 5K100% and 5K105%. CONCLUSIONS: Muscle activation and performance improvements during a deceptive cycling time trial were achieved only with a 2% magnitude of deception and were associated with a further impairment in MVC force, QTSingle recovery and VA compared to control. Performance improvement during cycling time trial with augmented deceptive feedback therefore resulted in exacerbated exercise-induced peripheral and central fatigue.