Separate and Combined Effects of Local and Systemic Hypoxia In

European Journal of Applied Physiology (2019) 119:2313–2325 https://doi.org/10.1007/s00421-019-04217-3

ORIGINAL ARTICLE

Separate and combined efects of local and systemic hypoxia in resistance exercise

Olivier Girard1,2 · Sarah J. Willis2 · Marin Purnelle2 · Brendan R. Scott1 · Grégoire P. Millet2

Received: 8 May 2019 / Accepted: 21 August 2019 / Published online: 29 August 2019 © Springer-Verlag GmbH Germany, part of Springer Nature 2019

Abstract Purposes This study quantifed performance, physiological, and perceptual responses during resistance exercise to task failure with blood fow restriction (BFR), in systemic hypoxia, and with these stimuli combined. Methods Fourteen young men were tested for 1-repetition maximum (1RM) in the barbell biceps curl and lying triceps extension exercises. On separate visits, subjects performed exercise trials (4 sets to failure at 70% 1RM with 90 s between sets) in six separate randomized conditions, i.e., in normoxia or hypoxia (fraction of inspired oxygen = 20.9% and 12.9%, respectively) combined with three diferent levels of BFR (0%, 45%, or 60% of resting arterial occlusion pressure). Muscle activation and oxygenation were monitored via surface electromyography and near-infrared spectroscopy, respectively. Arte- rial oxygen saturation, heart rate, and perceptual responses were assessed following each set. Results Compared to set 1, the number of repetitions before failure decreased in sets 2, 3, and 4 for both exercises (all P < 0.001), independently of the condition (P > 0.065). Arterial oxygen saturation was lower with systemic hypoxia (P < 0.001), but not BFR, while heart rate did not difer between conditions (P > 0.341). Muscle oxygenation and activation during exercise trials remained unafected by the diferent conditions (all P ≥ 0.206). A signifcant main efect of time, but not condition, was observed for overall perceived discomfort, difculty breathing, and limb discomfort (all P < 0.001). Conclusion Local and systemic hypoxic stimuli, or a combination of both, did not modify the fatigue-induced change in performance, trends of muscle activation or oxygenation, nor exercise-related sensations during a multi-set resistance exercise to task failure.

Keywords Vascular occlusion · Systemic hypoxia · Muscle activation · Muscle oxygenation · Strength training · Task failure

Abbreviations RTH Resistance training in systemic hypoxia 1RM 1-Repetition maximum TSI Tissue saturation index BFR Blood fow restriction [FiO2] Fraction of inspired oxygen HR Heart rate Introduction NIRS Near-infrared spectroscopy SpO2 Pulse oxygen saturation Resistance exercise with loads over 60% of an individual’s RSH Repeated sprints in hypoxia 1-repetition maximum (1RM) is commonly used for improving strength and skeletal muscle mass (Chodzko-Zajko et al. 2009) as well as subsequent athletic performance. In recent years, scientists have begun to implement hypoxic stimuli Communicated by Philip D. Chilibeck. during resistance exercise training in an attempt to augment * Olivier Girard these responses (Scott et al. 2014). This was initially studied [email protected] via blood fow restriction (BFR) techniques, involving the application of an infatable cuf around the proximal end 1 Murdoch Applied Sports Science (MASS) Laboratory, of a limb to occlude venous return while partially preserv- Murdoch University, Perth, Australia ing arterial infow (Loenneke et al. 2014). The resulting 2 Faculty of Biology and Medicine, Institute of Sport Sciences, alteration in limb hemodynamics causes a localized hypoxic University of Lausanne, Lausanne, Switzerland

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intramuscular environment during exercise (Ganesan et al. oxygen [FiO2] = 16%) compared to normoxic air (Scott 2015). This ischemia facilitates increased production of et al. 2017). Similar fndings have been reported for high- metabolites, due to a greater reliance on anaerobic metabo- load resistance exercise circuits, whereby blood oxygena- lism, which may impact on several downstream processes tion and markers of metabolic stress were increased when (i.e., muscle cell swelling, intramuscular anabolic/anti-cat- undertaking exercise in more severe (FiO2 = 13%), but not abolic signaling, and muscle fber recruitment) thought to in moderate (FiO2 = 16%), levels of hypoxia vs. normoxia contribute to hypertrophy (Schoenfeld 2013). In addition, (Ramos-Campo et al. 2017a). the hypoxic environment may increase the activation and To date, only one study has directly compared resistance proliferation of satellite cells (Nielsen et al. 2012), which training using BFR and systemic hypoxia (Manimmanakorn would further enhance muscle growth. et al. 2013). These authors observed that both strategies were While exercise with BFR has been demonstrated to be more efective for improving muscular strength, hypertro- feasible and efective in training the limb muscles, trunk and phy, and performance in several running-based assessments hip muscles (i.e., not under fow restriction) are unlikely to than the same training without any additional hypoxia stimu- adapt to the same extent (Yasuda et al. 2011). Considering lus. An interesting question that remains unanswered, how- this, researchers have recently begun to investigate the use- ever, is whether the addition of local to systemic hypoxia fulness of performing resistance exercise under normobaric during resistance exercise provides a means to further aug- hypoxic conditions to magnify the metabolic responses in ment the muscle adaptation for a given physical training an attempt to augment subsequent muscle mass development dose. Practically, it is, therefore, important to verify that this (Ramos-Campo et al. 2018a). Systemic hypoxic environ- resistance training strategy does not adversely afect physical ments are created via nitrogen dilution or oxygen reduction performance and the potential training dose by a too large and exercise is performed in an environmental chamber or magnitude. breathing a gas mixture through a face mask (Millet et al. Due to increased fatigability, BFR limits the number of 2010). Participants can, therefore, undertake multi-joint repetitions that can be performed in a set of resistance exer- compound exercises with the same hypoxic stimulus being cise (Wernbom et al. 2009; Loenneke et al. 2014). Previ- applied to all contributing musculature. Although the picture ous researchers have reported no efect of systemic hypoxia is still emerging and debated (Scott et al. 2014), several stud- (FiO2 = 13–16%) on performance during high-load (Scott ies have reported that resistance training in systemic hypoxia et al. 2015) or moderate-load resistance exercises (Scott et al. (RTH) ofers greater hypertrophic and strength benefts than 2018a) and on the time course of recovery for neuromuscular the equivalent normoxic exercise (Nishimura et al. 2010; performance following training (Scott et al. 2018b). How- Manimmanakorn et al. 2013), in conjunction with improved ever, other researchers have shown that when performing muscular endurance (Kon et al. 2014). These benefts may high-load resistance exercise in a circuit style, adding severe improve physical performance, for instance, aerobic capac- hypoxia (FiO 2 = 13%) can be detrimental for force and power ity and repeated-sprint ability (Ramos-Campo et al. 2018b). production during exercise (Ramos-Campo et al. 2017a). These augmented adaptations to RTH are likely driven partly These divergent fndings may arise from the diferences in by similar mechanisms to those underpinning BFR exercise exercise type and intensity between these research groups; but diferences are also possible. some authors (Scott et al. 2015, 2018a) implemented sub- In systemic hypoxia, the limited oxygen availability maximal exercise by prescribing pre-determined sets and induces vasodilation for increasing blood fow and oxygen repetitions, while others (Ramos-Campo et al. 2017a, 2018b) delivery, while when external pressure is applied (vascular employed circuits comprising of exercises performed for 6 occlusion, BFR), blood fow is impaired via vascular resist- repetitions each with 100% of 6RM. It is, therefore, pos- ance and venous return is nearly eliminated (Casey and sible that performance decrements resulting from breathing Joyner 2011). Both of these local and systemic methods hypoxic air during resistance exercise are only realized when create diferent intrinsic mechanisms (metabolic vasodila- each set is performed to failure. tion and vascular resistance) for a hypoxic environment, Therefore, our aim was to assess the separate and com- which may alter conductance and blood fow (Scott et al. bined acute efects of BFR and systemic hypoxia (both com- 2014). Specifcally, with repeated sprints during BFR con- pared with controls) during resistance exercise to task failure ditions, there is limited oxygen delivery, but also increased on exercise capacity, muscle oxygenation/activation levels, vascular resistance due to nearly no venous return, thereby and exercise-related sensations. It was hypothesized that increasing local blood volume (Willis et al. 2018). Previous resistance exercise with BFR would cause higher metabolic/ research has observed signifcantly elevated blood lactate neuromuscular stress than systemic hypoxia, yet with no concentrations (a marker of metabolic stress) in conjunc- measurable efect on performance (i.e., the number of rep- tion with increased motor unit recruitment during resist- etition to task failure within a set). We further hypothesized ance exercise when breathing hypoxic (fraction of inspired that, compared to each modality alone, BFR and systemic

1 3 European Journal of Applied Physiology (2019) 119:2313–2325 2315 hypoxia when combined would augment metabolic, neuro- curl and lying triceps extension), each with 4 sets to exhaus- muscular, and perceptual stress causing an earlier exercise tion under six conditions. These conditions included two cessation. levels of inspired oxygen (normoxia and hypoxia; i.e., fraction of inspired oxygen = 20.9% and 12.9%, respectively) and three diferent levels of BFR (0%, 45%, and 60% of the Methods arterial occlusion pressure): normoxia combined with 0% BFR (N 0), 45% BFR (N45), and 60% BFR (N60); and hypoxia Participants combined with 0% BFR (H0), 45% BFR (H45), and 60% BFR (H60) (Fig. 1). During experimental trials, participants were Fourteen male participants (age 22.6 ± 1.3 years; body assessed for the number of repetitions performed, muscle height 1.79 ± 0.8 m; body mass 72.3 ± 6.6 kg volunteered oxygenation, muscle activation, and perceived discomfort. to participate in this study. All were physically active with Participants were asked to refrain from cafeine and alcohol recreational resistance training experience, but none were consumption for at least 24 h before each testing session and involved in regular resistance training within 6 months prior strenuous upper body activity for 48 h prior. to the study. At time of testing, none of the participants were smokers, all were injury free and not on any medications or Familiarization and baseline testing dietary supplements. Participants reported taking no sub- stances that could afect the study’s results (i.e., anabolic Participants received instructions regarding the perceptual steroids, creatine, and sympathoadrenal drugs). In addition, scales to be used in the research at the beginning of the all participants were living near sea-level during the study familiarization session, before being assessed for arterial and reported no exposure to an altitude of > 3000 m within occlusion pressure. Participants rested in a seated posi- 3 months before investigation and no history of severe acute tion, shoulder at about 85°, with a 5-cm wide cuf (SC10D mountain sickness. Participants were encouraged to maintain Rapid Version Cuf, D.E. Hokansson Inc., Bellevue, WA, regular dietary habits during the course of the study and USA) applied proximally on the dominant upper limb. Arte- replicate the daily diet (from the frst trial) for 24 h before rial occlusion pressure was measured by gradually infat- subsequent testing sessions. A priori power analysis using ing the cuf until the point at which arterial blood fow was G*Power software (version 3.1.9.3) was conducted to deter- occluded, which was determined via Doppler ultrasound mine the appropriate sample size. Based on the data from a (EchoWave II 3.4.4, Telemed Medical Systems, Telemed previous study (Willis et al. 2019) on arm-cycling using the Ltd. Lithuania, Milano, Italy) of the brachial artery. This same combination between systemic hypoxia (FiO 2 = 13%) procedure was repeated three times for accuracy (i.e., val- and BFR (45% of the arterial occlusion pressure), 12 partici- ues were averaged), with 2 min between trials, and the pants per group were required to yield the targeted analysis seated resting arterial occlusion pressure corresponded to power of β = 0.8 at α = 0.05 for total work until exhaustion. 208 ± 18 mmHg. To our knowledge, there is no previous study using the same Following arterial occlusion pressure assessment, partici- environmental conditions for resistance training in hypoxia pants were instructed on correct technique for the barbell either with arms or with legs. To reach the appropriate biceps curl and lying triceps extension, before undertaking sample size with potential risks of drop-out or injuries, the 1-repetition maximum (1RM) testing of these exercises. present sample was n = 14. The study was approved by the Specifcally, the participants performed a warm-up of 8–10 local ethical committee (Commission Cantonale Vaudoise repetitions at 50% of estimated 1RM, followed by two heav- d’Ethique de la Recherche sur l’Etre Humain, CCER-VD ier warm-up sets of 2–5 repetitions with loads increasing by 308/13) in accordance with the Declaration of Helsinki, and 10–20% for each set. Subjects then performed single repeti- signed written consent was obtained from the participants tions with increasing loads until unable to lift the weight. before inclusion. The heaviest load successfully lifted through the entire range of motion was denoted as the 1RM (barbell biceps Study design curl: 39.8 ± 5.0 kg; lying triceps extension: 34.6 ± 5.8 kg), which was determined in ≤ 4 trials for all participants. At A randomized, single-blinded, repeated measures crossover least 3 min of rest was allowed between successive warm- design, in which participants were blinded toward the envi- up sets and 1RM attempts, and testing was conducted in ronmental conditions, was used for this study. Participants normoxia without BFR. frst completed a familiarization session before six experi- Throughout 1RM testing and subsequent trials, any mental trials, which were all separated by 5–10 days and bouncing of the weight or changes in body posture were conducted at the same time of day (± 2 h). The exercise regarded as incorrect technique, and if participants failed protocol comprised two resistance exercises (barbell biceps to adhere to these criteria during a repetition, the lift was

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Visit 0 Barbell Lying triceps biceps curl extension (1 (1) (2)

(1)

Determinationof arterial occlusion Demonstrationand practice of (1) and (2) 1 RM testingof (1) and (2) pressure

Visits 1-6

Warm-up 2min 30 s5Warm-up min 30 s1Resistance exercise 0 min Resistance exercise Instrumentation (1) (2) (1) (2)

10 repetitionsof (1) and (2) 4 sets of (1) and (2) to failureat70% of 1RM (randomorder) at 30% 1RM (randomorder) Climatic room entrance (1) (1) (1) ( ( (

90 s … 90 s … 90 s … 90 s …

NIRS and EMG

HR, SpO2,perceptualratings

N, 0% BFR (N0); N, 45% BFR (N45); N, 60% BFR (N60); H, 0% BFR (H0); H, 45% BFR (H45); H, 60% BFR (H60)

Fig. 1 Experimental protocol overview. Normoxia, 0% BFR or blood fow restriction (N0); normoxia, 45% BFR (N 45); normoxia, 60% BFR (N60); hypoxia, 0% BFR (H0); hypoxia, 0% BFR (H45); hypoxia, 0% BFR (H60) deemed unsuccessful. For the barbell biceps curl, partici- instrumented with near-infrared spectroscopy (NIRS) and pants stood with the back against a wall and a supinated electromyography (EMG) equipment to monitor muscle oxy- shoulder width grip on the bar. The movement started with genation and activation characteristics, respectively. Follow- elbows extended and alongside the trunk, before fexing the ing this, participants began an exercise protocol in one of the elbows until the barbell reached the level of the anterior del- six experimental conditions. All sessions were completed in toid. For the lying triceps extension, participants lay supine a hypoxic chamber (ATS Altitude, Sydney, Australia) at an on the bench with elbows fully extended and gripping the elevation of 380 m above sea level (Lausanne, Switzerland). dumbbell in front of the body. Participants maintained the Chamber temperature was maintained constant at ~ 22 °C, upper arm in this position while fexing at the elbows to and FiO2 for the normoxic and hypoxic conditions was set lower the weight just behind the head, before extending the at 20.9% and 12.9%, respectively. The BFR stimulus was elbows to return to the start position. A customized elas- applied using infatable cufs around both upper arms. The tic string line was set so that participant’s upper arm/elbow pressures used for BFR (0, 45, and 60% arterial occlusion came in contact with the string at all times for the triceps pressure) corresponded to 20 mmHg (similar for all par- extension exercise to maintain shoulder angle during the ticipants and arbitrarily defned as 0%), 94 ± 8 mmHg and range of motion. Participants were given continuous signals 125 ± 11 mmHg, respectively. The cufs were infated 10 s and reminders of start and end positions for both exercises before each set of exercise, and were defated for the rest to execute the appropriate range of motion. periods between the sets and the two exercises. The exercise protocol commenced with two standardized Experimental trials warm-up sets of 10 repetitions at 50% 1RM for the barbell biceps curl or lying triceps extension, which were separated The structure of experimental visits is depicted in Fig. 1. by 2.5 min of rest. The order in which the exercises were Upon arriving at the laboratory, participants entered performed was randomized across participants, but held con- the climatic chamber, and stood for 15 min while being stant for each individual during the six visits. Participants

1 3 European Journal of Applied Physiology (2019) 119:2313–2325 2317 then recovered for 5.5 min, before performing 4 sets of the Before electrode placement, the skin was lightly abraded frst exercise to task failure with 70% of 1RM and 90 s rest and washed to remove surface debris and oil, and electrodes between sets. Participants then rested for 10 min before per- were secured with elastic adhesive bandage to reduce move- forming the same warm-up and sets to task failure for the ment during exercise. The position of the EMG electrodes second exercise. Participants were instructed to perform the was marked with pen (as described for NIRS assessment) concentric and eccentric phases corresponding with each to ensure consistent electrode placement. The myoelectric tick of a metronome (2 s concentric and 2 s eccentric). Ver- signals were amplifed (gain = 1000 × ) using a diferential bal encouragement was provided to encourage participants amplifer (EMG 100, Biopac Systems, Inc., Santa Barbara, to reach task failure, which was defned as the inability to CA, USA, bandwidth 1–5000 Hz) with a common mode complete another concentric muscle action throughout the rejection ratio of 110 dB min and an impedance of 2 MΩ, full range of motion. During each visit, participants were and digitally fltered (zero-phase shift fourth-order Butter- blinded to the hypoxic and BFR conditions. worth flter) with a bandpass of 20–450 Hz. Surface EMG signals were sampled simultaneously at 2 kHz with a Biopac Physiological responses to exercise data acquisition system (MP150WSW, Biopac Systems, Inc., Santa Barbara, CA, USA), and recorded on a personal com- Near‑infrared spectroscopy puter for of-line processing with AcqKnowledge 4.2 software (Biopac Systems, Inc., Santa Barbara, CA, USA). The Muscle oxygenation profles of the right biceps brachii and activity of each muscle was determined by measuring the triceps brachii muscles were assessed using portable NIRS mean value of the RMS signal for the whole set. apparatus (PortaMon and PortaLite, Artinis, Medical Sys- tem, Zetten, The Netherlands). Devices were wrapped in Heart rate and pulse oxygen saturation transparent plastic to create a water-proof barrier, before being afxed with double sided tape and wrapped with a Heart rate (HR) and pulse oxygen saturation (SpO2) were dark bandage to reduce movement during exercise. Perma- monitored via a Polar transmitter–receiver (Polar RS400, nent pen was used to mark the position of the device and Kempele, Finland) and non-invasive pulse oximetry using an ensure reproducible placement in subsequent visits. earlobe probe (8000Q2 Sensor, Nonin Medical Inc., Amster- All NIRS signals were acquired at the maximum sam- dam, The Netherlands), respectively. These values were pling frequency of each device, 50 Hz (PortaLite) and 10 Hz recorded 10 s after reaching exhaustion in the four exercise (PortaMon), and down sampled to 1 Hz for analysis. Muscle sets for both exercises, in a manner to not allow participants oxygenation was assessed as the percentage of tissue satura- to view any data, according to the blinding procedure. tion index (TSI; oxyhemoglobin/[oxyhemoglobin + deoxy- hemoglobin] × 100). For analysis, a moving average (3 s) Perceived discomfort scales was applied to smooth the signal. Baseline TSI was established before the warm-up, with participants standing with Based on modifed Borg CR10 scales, overall perceived arms relaxed by the body for 30 s. During exercise, abso- exertion, upper limb discomfort, and difculty breathing lute maximal and minimal TSI values (TSImax and TSI min) were recorded (invariant order) at the same time as HR were calculated for each set, and each post-exercise recovery and SpO 2. During the familiarization, participants were interval. We further calculated the de-oxygenation amplitude instructed that the “perceived discomfort” scales were used during each set of exercise (∆TSIexercise) as the diference to evaluate the subjective perception of (1) overall perceived between TSImax and TSImin values within the set. Similarly, exertion (‘How uncomfortable do you feel overall?’), (2) re-oxygenation amplitude during the post-exercise recov- upper limb discomfort (‘How uncomfortable do your arms ery (∆TSIrecovery) was determined as the diference between feel?’), and (3) difculty breathing (‘How uncomfortable TSI min within a set and TSImax at the end of the subsequent does it feel to breathe?’). Participants were instructed to 90-s recovery period. refect on perceptions during the whole preceding exercise set. Electromyography Statistical analysis Surface EMG signals from the left biceps brachii and triceps brachii were recorded using bipolar Ag/AgCl elec- Values are expressed as means ± SD. Two-way repeated trodes (Covidien-Kendall 100 Foam electrodes, Covidien, measures ANOVAs (Time [Set 1, Set 2, Set 3, Set 4] × Con- Mansfeld, MA, USA; inter-distance electrode = 20 mm) dition [N0, N45, N60, H0, H45, H60]) were used. To assess fxed lengthwise over the muscle belly, with the reference assumptions of variance, Mauchly’s test of sphericity was electrode was attached to the left elbow (lateral epicondyle). performed using all ANOVA results. A Greenhouse–Geisser

1 3 2318 European Journal of Applied Physiology (2019) 119:2313–2325 correction was performed to adjust the degree of freedom if A –Barbell biceps curl C = 0.155 (0.11) N0 N45 N60 H0 H45 H60 an assumption was violated, while post hoc pairwise com- T= <0.001 (0.94) 16 parisons with Bonferroni-adjusted P values were performed I = 0.065 (0.11) if a signifcant main efect was observed. For each ANOVA, 14 partial eta-squared was calculated as measures of efect size. 12 Values of 0.01, 0.06, and values above 0.14 were considered 10 as small, medium, and large, respectively. All statistical cal- * 8 culations were performed using SPSS statistical software * * 6 V.24.0 (IBM Corp., Armonk, NY, USA). Statistical signif- Repetitions cance was set at P < 0.05. 4

0 1234 Results B –Lying triceps extension C = 0.009 (0.21) T= <0.001 (0.91) Performance 16 I = 0.108 (0.10)

14 Compared to set 1, the number of repetitions to task fail- biceps 12 ure decreased in sets 2, 3, and 4 for both the barbell * curl (− 44 ± 6%, − 59 ± 7%, and − 63 ± 6%, respectively) 10 and lying triceps extension (− 39 ± 10%, − 56 ± 7%, and 8 * * − 62 ± 7%, respectively) exercises (all P < 0.001; η > 0.93), 6 independently of the condition (P > 0.065; η > 0.11) (Fig. 2). Repetitions 4

2 Responses to exercise 0 1234 For both the barbell biceps curl and the lying triceps exten- Sets number sion exercise, SpO2 values were lower with normobaric (P < 0.001; η > 0.78), but not localized hypoxia (BFR) vs. Fig. 2 Performance across four sets to task failure for the barbell biceps triceps normoxia, while HR (P > 0.341; η > 0.08) did not difer curl (a, b) and lying extension (c, d) resistance exercises. normoxia, 0% BFR or blood fow restriction (N 0); normoxia, between conditions (Fig. 3). For each exercise, a signifcant 45% BFR (N45); normoxia, 60% BFR (N60); hypoxia, 0% BFR main efect of time was observed for overall perceived dis- (H0); hypoxia, 0% BFR (H45); hypoxia, 0% BFR (H60). Data are comfort, difculty breathing, and upper limb discomfort (all mean ± SD. C, T, and I, respectively refer to ANOVA main efects P < 0.001; η > 0.85); however, no diference between condi- of condition, time, and interaction between these two factors with P value and partial eta-squared into brackets. *Signifcantly difer- tions (all P > 0.369; η > 0.06) nor any interaction was present ent from set 1 (P < 0.05). †Signifcantly diferent from previous set (all P > 0.235; η > 0.03) (Table 1). (P < 0.05)

Muscle oxygenation and activation responses Discussion

There was main efect of time (all P < 0.001; η > 0.38) but Summary of main fndings not condition (all P > 0.206; η > 0.08) on ∆TSI values during exercise and subsequent recovery (Fig. 4). Only ∆TSI recov- The main fnding is that the expected decrease in number ery values during the barbell biceps curl exercise displayed a of repetitions from the frst to the second set with smaller signifcant interaction efect (P < 0.046; η = 0.12). changes thereafter occurred in a similar way between all Compared to set 1, EMG RMS activity increased across conditions; i.e., independently of the cuf pressure applied sets for barbell biceps curl and lying triceps extension or the hypoxia severity. Moreover, while systemic hypoxia P P η η exercises ( = 0.022 and = 0.008; = 0.22 and = 0.26, decreased SpO2 compared with exercise in normoxia, HR respectively), whereas there was no main efect of condition and perceptual responses did not differ between condi- (P = 0.508 and P = 0.908; η = 0.05 and η = 0.03, respectively) tions. Markers of muscle oxygenation and muscle acti- or any significant interaction (P = 0.705 and P = 0.377; vation were not afected diferently by local or systemic η = 0.06 and η = 0.08, respectively) (Table 2). hypoxia, or a combination of both stimuli (contradictory

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Barbell biceps curl C = <0.001 (0.84) C = <0.001 (0.78) A T=0.167 (0.13) C Lying triceps extension T=0.634 (0.63) I = 0.715 (0.06) I = 0.825 (0.83) N0 N45N60 H0 H45H60 N0 N45N60 H0 H45H60 100 100 ) ) 95 95

90 90 saturation (% saturation (% † † † † en en † † † 85 85 † yg ox ox yg

80 80 terial terial Ar Ar 75 75 1234 1234 B C= 0.341 (0.08) D C= 0.396 (0.08) 170 N0 N45N60 H0 H45H60 T= <0.001 (0.49) 170 N0 N45N60 H0 H45H60 T= 0.016 (0.28) I = 0.329 (0.08) I = 0.580 (0.06)

160 160 * * ) 150 150 bpm) (

140 140 ate (bpm rate * t tr 130 130 Hear Hear

120 120

110 110 1234 1234 Sets number Sets number

Fig. 3 Arterial oxygen saturation and heart rate immediately follow- hypoxia, 0% BFR (H 60). Data are mean ± SD. C, T, and I, respectively ing each set to task failure for the barbell biceps curl (a, b) and lying refer to ANOVA main efects of condition, time, and interaction triceps extension (c, d) resistance exercises. normoxia, 0% BFR or between these two factors with P value and partial eta-squared into † blood fow restriction (N 0); normoxia, 45% BFR (N 45); normoxia, brackets. *Signifcantly diferent from set 1 (P < 0.05). Signifcantly 60% BFR (N60); hypoxia, 0% BFR (H0); hypoxia, 0% BFR (H45); diferent from previous set (P < 0.05) to the hypothesis). Overall, fatigue-induced performance et al. (2009) also reported signifcantly less repetitions in decrement and exercise responses were essentially similar each set when BFR was applied to the proximal thigh, which between barbell biceps curl and lying triceps extension exer- the current study did not observe. Furthermore, presently, cises and between local and systemic hypoxia conditions. there was no impact of systemic hypoxia on the number of repetitions performed in sets of either exercise. These results Exercise performance are somewhat surprising, considering that applying BFR reduces the time to task failure during low-load resistance The present results showed that for both the barbell biceps exercise (Loenneke et al. 2012). In addition, while this is the curl and lying triceps extension exercises, the number of rep- frst study to examine the impact of hypoxia on the number etitions decreased by ~ 60% from the frst to the last set, with of repetitions to task failure in resistance exercise, the previ- approximately three quarters of this decrease seen from set 1 ous work has reported earlier and larger performance decre- to set 2. Similar results have been observed previously across ments during repeated sprints in hypoxia (RSH) compared three sets of low-load knee extension exercise to task failure to normoxia (Girard et al. 2017). For example, Willis et al. (30% 1RM) when performed with BFR (100 mmHg) and (2017) reported a decrease of 27% and 49% for the total without (Wernbom et al. 2009); i.e., larger decreases were work performed to exhaustion during repeated cycling sprint observed in the number of repetitions performed between exercise in hypoxia for FiO 2 = 16.5 and 13.3%, respectively, sets 1 and 2 than between sets 2 and 3. However, Wernbom when compared to normoxia.

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Table 1 Difculty breathing, N N N H H H upper limb discomfort, and 0 45 60 0 45 60 overall perceived discomfort Barbell biceps curl immediately following each set Difculty breathing to task failure for the barbell biceps curl and lying triceps Set 1 3.7 ± 1.0 4.0 ± 1.0 4.0 ± 1.1 3.8 ± 1.0 3.9 ± 1.2 4.0 ± 1.0 extension exercises Set 2 4.3 ± 1.0* 4.4 ± 0.9* 4.7 ± 0.8* 4.3 ± 1.1* 4.5 ± 1.3* 4.6 ± 1.0* Set 3 4.7 ± 1.1*† 4.8 ± 0.9*† 5.1 ± 1.0*† 4.7 ± 1.1*† 4.8 ± 1.3*† 5.0 ± 1.0*† Set 4 4.9 ± 0.9*† 4.9 ± 1.0*† 5.4 ± 0.9*† 4.9 ± 1.2*† 5.0 ± 1.6*† 5.2 ± 1.0*† Upper limb discomfort Set 1 5.0 ± 0.9 4.8 ± 1.3 5.2 ± 1.1 4.8 ± 1.1 5.1 ± 1.2 4.9 ± 0.9 Set 2 5.9 ± 0.8* 5.9 ± 1.1* 6.3 ± 0.9* 5.8 ± 1.1* 6.2 ± 1.3* 5.9 ± 0.8* Set 3 6.5 ± 1.0*† 6.5 ± 1.1*† 7.0 ± 0.9*† 6.6 ± 1.1*† 6.6 ± 1.2*† 6.4 ± 1.0*† Set 4 7.3 ± 1.0*† 7.3 ± 1.2*† 7.5 ± 0.9*† 6.9 ± 1.1*† 7.3 ± 1.2*† 7.1 ± 1.0*† Overall perceived exertion Set 1 4.4 ± 1.0 4.6 ± 1.0 4.6 ± 0.8 4.5 ± 1.1 4.4 ± 1.2 4.4 ± 0.8 Set 2 5.3 ± 1.0* 5.3 ± 1.0* 5.5 ± 0.9* 5.3 ± 1.0* 5.2 ± 1.3* 5.1 ± 0.8* Set 3 5.6 ± 1.0*† 5.8 ± 0.9*† 5.9 ± 1.0*† 6.1 ± 0.9*† 5.9 ± 1.3*† 5.7 ± 0.8*† Set 4 6.2 ± 0.9*† 6.4 ± 0.9*† 6.5 ± 0.9*† 6.3 ± 0.9*† 6.2 ± 1.3*† 6.2 ± 0.9*† Lying triceps extension Difculty breathing Set 1 3.7 ± 1.2 3.6 ± 1.2 3.8 ± 1.0 3.5 ± 1.2 3.6 ± 1.5 3.7 ± 1.3 Set 2 4.0 ± 1.2* 4.3 ± 1.4* 4.4 ± 1.0* 4.0 ± 1.2* 4.3 ± 1.3* 4.4 ± 1.2* Set 3 4.5 ± 1.3*† 4.7 ± 1.6*† 4.9 ± 1.3*† 4.5 ± 1.2*† 4.5 ± 1.5*† 4.9 ± 1.1*† Set 4 4.7 ± 1.4*† 5.1 ± 1.9*† 5.1 ± 1.5*† 4.8 ± 1.1*† 4.9 ± 1.7*† 5.0 ± 1.0*† Upper limb discomfort Set 1 5.0 ± 1.2 5.1 ± 1.3 4.6 ± 1.4 4.6 ± 1.3 5.0 ± 1.6 4.7 ± 1.4 Set 2 5.8 ± 1.1* 6.0 ± 1.3* 5.8 ± 1.2* 5.8 ± 1.1* 5.7 ± 1.3* 5.7 ± 1.2* Set 3 6.5 ± 1.0*† 6.9 ± 1.3*† 6.6 ± 1.2*† 6.6 ± 0.9*† 6.8 ± 1.3*† 6.5 ± 1.1*† Set 4 7.1 ± 1.0*† 7.4 ± 1.5*† 7.3 ± 1.3*† 7.1 ± 0.9*† 7.5 ± 1.4*† 7.0 ± 1.0*† Overall perceived exertion Set 1 4.4 ± 1.4 4.5 ± 1.4 4.3 ± 0.9 4.2 ± 1.3 4.4 ± 1.4 4.3 ± 0.9 Set 2 5.0 ± 1.3* 5.3 ± 1.4* 5.2 ± 1.0* 5.1 ± 1.1* 5.1 ± 1.1* 5.0 ± 0.8* Set 3 5.6 ± 0.9*† 6.1 ± 1.3*† 5.8 ± 0.9*† 5.9 ± 0.9*† 5.9 ± 1.2*† 5.7 ± 0.7*† Set 4 6.0 ± 1.0*† 6.2 ± 1.2*† 6.3 ± 0.7*† 6.4 ± 1.0*† 6.0 ± 1.2*† 6.1 ± 0.6*†

Data are mean ± SD. normoxia, 0% BFR or blood fow restriction (N0); normoxia, 45% BFR (N45); normoxia, 60% BFR (N 60); hypoxia, 0% BFR (H0); hypoxia, 0% BFR (H45); hypoxia, 0% BFR (H60). Note that there was an efect of time (P < 0.001) but not of condition (P > 0.369) or any interaction (P > 0.235) *Signifcantly diferent from set 1 (P < 0.05) † Signifcantly diferent from previous set (P < 0.05)

A potential explanation for the lack of between-condi- (Laurentino et al. 2008). Considering the findings from tion differences in the present study may be the inherent Laurentino et al. (2008) in conjunction with the current demands of the exercise implemented; it is likely that observations, the application of BFR seems secondary to the volume of each set was not large enough to induce exercise load and/or volume considerations when lifting any additional potent metabolic stimulus induced by sys- heavy loads. In addition to this, both exercises involve temic hypoxia and/or BFR (Scott et al. 2014). This is small muscle mass, which may have been insufficient to contradictory to whole-body cycling exercise, where the stress metabolic processes to the point where localized severity of hypoxia affected the repeated-sprint perfor- or systemic hypoxia became a limiting factor for exercise mance and led to large muscle deoxygenation level (Wil- performance. In normoxia, the ‘central’ resistances (i.e., lis et al. 2017). Moreover, applying BFR during low-vol- alveolo-capillary diffusion and O2 transport convective ume heavy resistance exercise does not seem to augment factor) are more important than ‘peripheral’ resistances muscular development compared to unrestricted training (i.e., O2 diffusion from capillary blood to mitochondria

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A Barbell biceps curl C Lying triceps extension C= 0.285 (0.09) C= 0.254 (0.09) T= <0.001 (0.38) 60 N0 N45N60 H0 H45H60 T= <0.001 (0.79) 42 N0 N45N60 H0 H45H60 I = 0.169 (0.10) I = 0.381 (0.08) * * 50 * 35 * * ) %)

40 (% 28 e( e is 30 21 xerc exercis e 20 14 ∆TSI ∆TSI 10 7

0 0 1234 1234

C= 0.206 (0.10) C= 0.344 (0.08) B D N0 N45N60 H0 H45H60 T= <0.001 (0.48) 60 N0 N45N60 H0 H45H60 T= <0.001 (0.63) 42 I = 0.046 (0.12) I = 0.775 (0.05)

50 35 * * * * * *** * * ) * %) (% 40 28 y( ry er ve 30 21 ecov reco

r 20 14 ∆TSI ∆TSI 10 7

0 0 1234 1234 Sets numberSets number

Fig. 4 Delta tissue saturation index (∆TSI) during exercise and BFR (H45); hypoxia, 0% BFR (H 60). Data are mean ± SD. C, T, and recovery across four sets to task failure for the barbell biceps curl (a, I, respectively refer to ANOVA main efects of condition, time, and b) and lying triceps extension (c, d) resistance exercises. normoxia, interaction between these two factors with P value and partial eta- 0% BFR or blood fow restriction (N0); normoxia, 45% BFR (N45); squared into brackets. *Signifcantly diferent from set 1 (P < 0.05). † normoxia, 60% BFR (N 60); hypoxia, 0% BFR (H 0); hypoxia, 0% Signifcantly diferent from previous set (P < 0.05)

Table 2 Root mean square N N N H H H (RMS) of the electromyography 0 45 60 0 45 60 signal for muscle activation Barbell biceps curl for sets 2–4 (expressed as Set 2 5 ± 3 5 ± 4 8 ± 3 5 ± 3 4 ± 3 5 ± 3 percentage increments in reference to set 1) for the barbell Set 3 12 ± 4 7 ± 5 13 ± 4 6 ± 4 7 ± 4 7 ± 4 biceps curl and lying triceps Set 4 14 ± 3* 10 ± 5* 15 ± 4* 11 ± 4* 10 ± 4* 11 ± 4* extension exercises (biceps Lying triceps extension and triceps brachii muscles, Set 2 3 ± 6 1 ± 3 5 ± 4 1 ± 4 1 ± 6 2 ± 3 respectively) Set 3 6 ± 8* 3 ± 5* 7 ± 6* 5 ± 7* 6 ± 6* 11 ± 4* Set 4 16 ± 10*† 14 ± 6*† 13 ± 6*† 14 ± 7*† 16 ± 6*† 12 ± 4*†

Data are mean ± SD. normoxia, 0% BFR or blood fow restriction (N0); normoxia, 45% BFR (N45); normoxia, 60% BFR (N 60); hypoxia, 0% BFR (H0); hypoxia, 0% BFR (H45); hypoxia, 0% BFR (H60) Note that there was an efect of time (P = 0.022 and P = 0.008, respectively) but not of condition (P = 0.508 and P = 0.908, respectively) or any interaction (P = 0.705 and P = 0.377, respectively) for barbell biceps curl and lying triceps extension exercises, respectively *Signifcantly diferent from set 1 (P < 0.05) † Signifcantly diferent from the previous set (P < 0.05)

1 3 2322 European Journal of Applied Physiology (2019) 119:2313–2325 and mitochondrial capacity) in large muscle groups exer- Muscle activation cise, while the difference is reduced in small muscle mass groups exercise (di Prampero et al. 2003). In hypoxia, The present muscle activation increased progressively despite being reduced, convection remains the main fac- across sets, indicating greater motor unit recruitment, tor for both large and small muscle groups’ exercises. fring rate, and/or synchronization throughout the exer- This may explain the differences observed on the effects cise (Pincivero et al. 2006). An unexpected fnding from of hypoxia on performance and muscle deoxygenation the current study, however, was the lack of diference in between whole body and local exercises. As discussed muscle activation between conditions. We have previously below, this may also explain why the effects of systemic observed increased muscle activation for vastus lateralis and/or local hypoxia on all physiological and perceptual and vastus medialis muscles during squats and deadlifts measures were not measureable. (3 sets of 10 repetitions at 60% 1RM, 60 s inter-set rest) in hypoxia vs. normoxia (Scott et al. 2017). Furthermore, several studies have reported increased muscle activation Cardiovascular and perceptual responses to exercise when lifting light loads with BFR compared with the same exercise unrestricted (Yasuda et al. 2008, 2009). However, The present study observed lower SpO2 but unchanged conflicting findings of non-augmented muscle activa- HR values following sets in systemic hypoxia compared to tion have also been reported when performing resistance normoxia, while BFR across the range of pressures tested training with systemic (Filopoulos et al. 2017; Scott et al. had no infuence on these responses. These results are 2018b) and localized (Wernbom et al. 2009) hypoxia. As similar to several previous reports (Ramos-Campo et al. mentioned previously, both Wernbom et al. (2009) and the 2017a, b; Scott et al. 2017), where oxygen saturation but current study required participants to exercise to task fail- not HR were afected by hypoxia during resistance exer- ure with and without BFR; it may be that by maximizing cise (FiO2 of 13–16%). While HR decreased with time in the efort applied in each set by instructing participants to the current study (likely as a side-efect of less repetitions exercise to exhaustion, any between-condition diferences being completed in successive sets), the lack of BFR-medi- in muscle activation were blunted. ated HR increases may relate to the heavier loads used in Performing resistance exercise in systemic hypoxia vs. this investigation compared to previous BFR work; heavy normoxia with short (60 s) (Kon et al. 2012), but not long weights result in lower exercise volumes during each set (90 s) (Ho et al. 2014), recoveries accentuates metabolic and, therefore, lower impact on cardiovascular function. stress (i.e., blood lactate concentration). The addition Regarding the perception of exercise, there have been of a normobaric hypoxic stress (FiO 2 = 12%) to a single divergent results reported for the impacts of BFR and high-intensity (85% 1RM), low-volume resistance exer- systemic hypoxia. While some researchers have observed cise session had no measurable efect on neuromuscular BFR (Wernbom et al. 2006, 2009) and hypoxia (Scott et al. activation patterns (Filopoulos et al. 2017). Arguably, a 2015; Innes et al. 2016) to have no impact on perceived lack of diference between conditions in the present study exertion during resistance exercise, others have shown that may relate, at least partially, to relatively long recover- resistance exercise either with BFR (Yasuda et al. 2009; ies (90 s) due to the exhaustive nature of the task. It is, Scott et al. 2018c) or in simulated altitude environments therefore, plausible that muscle activation patterns during (Filopoulos et al. 2017; Ramos-Campo et al. 2017b) yields resistance exercise to task failure would difer when inter- larger increases in exercise-related sensations. Current set durations (shorter) and loads (lower) are appropriately results indicated no efect for BFR or systemic hypoxia manipulated to maximize the efects of a hypoxic stimu- on perceptions of exercise, which may be explained by lus. In addition, it cannot be ruled out that calculating the exercise design. Indeed, all sets were performed to muscle activity during only the concentric phase (Scott task failure during exercise trials, which likely resulted et al. 2017) and/or for specifc time periods within each in the similar levels of exertion irrespective of experi- set (initial, middle vs. last repetitions) (Jenkins et al. 2015) mental condition. Indeed, similar results were observed could present a diferent fatigue manifestation pattern than when comparing BFR with non-BFR low-load exercise a mean activation value obtained for each entire exercise performed to task failure (Wernbom et al. 2006, 2009). set. Overall, the present muscle activation results suggest Interestingly though, perceptual ratings never exceeded that local and/or systemic hypoxic stress during resistance 7 on CR10 scales despite exercising to exhaustion, which exercise had no efect on the increased rate of motor unit may refect the small muscle mass used in the present exer- recruitment in response to peripheral fatigue development cises. Further work is needed to elucidate the impacts of (not measured directly). combined BFR and systemic hypoxia on perceived exertion during resistance exercise using greater muscle mass.

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Muscle oxygenation study did not demonstrate performance (evaluated by number of repetitions) diferences for combining localized and

TSI reflects the dynamic balance between O2 supply systemic hypoxia during resistance exercise on two small and consumption and has been reported as the most reli- muscle groups’ upper body exercises. Further research is able NIRS variable during resistance exercise (Scott et al. needed to investigate the manipulation of BFR cuf pressure 2014). The present ∆TSI results demonstrated no difer- and systemic hypoxia severity in conjunction with diferences between conditions, although muscle de-oxygena- ent structures of resistance exercise. Higher volume, shorter tion (during exercise periods) and re-oxygenation (during rest periods, and/or greater muscle mass used during resist- recovery periods) responses changed across sets. These fnd- ance exercise create a more potent metabolic stress (Scott ings concur with some previous reports which have shown et al. 2014). This, during low-intensity resistance exercise that moderate- or high-load resistance exercise in hypoxia (e.g., < 50% 1RM) when local and systemic hypoxia are (FiO 2 = 13–16%) results in lower levels of SpO2 than the combined, may aggravate muscle oxygenation and activa- equivalent normoxic exercise, without impacting on mus- tion responses, in turn accelerating task failure. cle oxygenation responses measured by NIRS (Scott et al. 2017, 2018b). Nevertheless, Kon et al. (2010) observed lower values in mean minimum muscle oxygenation during Conclusion moderate-load resistance bench press and leg press exercises performed in hypoxia (FiO = 13%) compared with 2 Local and systemic hypoxic stimuli, or a combination of normoxia. Similarly, low-load resistance exercise with BFR both, did not modify the fatigue-induced change in per- has been shown to cause signifcantly greater increases in formance, trends of muscle activation or oxygenation, nor deoxygenated hemoglobin than the equivalent unrestricted exercise-related sensations during a multi-sets’ resistance exercise (Lauver et al. 2017). The lack of signifcant inter- exercise to task failure. Contradictory to our hypothesis, conditions efects in the present study are, therefore, difcult these two stressors when combined also did not augment to explain. The diferences with previous investigations may metabolic, neuromuscular, and perceptual load and, there- come from factors such as: (1) the limbs occluded (upper vs. fore, did not cause premature fatigue. In addition, responses lower limbs); (2) the nature of the resistance exercise (single were similar between the barbell biceps curl and lying tri- vs. multiple joints, repetitions-to-failure vs. pre-established ceps extension exercises. number of sets/repetitions); (3) participant characteristics (power vs. endurance trained) which infuence tissue oxy- Acknowledgements The authors thank the participants for their dedi- genation; and (4) the use of diferent NIRS indices (TSI vs. cation, commitment, and cooperation with this study. oxygenated hemoglobin). Finally, as expected, the muscle re-oxygenation during Author contributions OG, SW, MP, and GPM conceived and designed recovery periods became progressively slower across sets. research. OG, SW, and MP conducted experiments. OG, SW, MP, and GPM analyzed data. All authors interpreted results of experiments. OG The smaller ∆TSI observed during sets 3 and 4 compared drafted manuscript and prepared fgures/tables. All authors edited and to set 1 (except for N 60 and H45 for the barbell biceps curl) revised manuscript. All authors approved fnal version of manuscript. is indicative of an impaired O2 delivery at the muscle level (Perrey and Ferrari 2018). However, it is questionable Compliance with ethical standards whether these changes represent a limiting factor during resistance exercise performed to task failure. Indeed, larger Conflict of interest The authors have no confict of interest to disclose. performance decrements occurred between set 1 and set 2 in the present study, which was not accompanied by signifcant diference for ∆TSI values. Under the present circumstances, References these fndings demonstrate that the muscle oxygenation sta- tus to resistance exercise is minimally afected by exposure Casey DP, Joyner MJ (2011) Local control of skeletal muscle blood to local and/or systemic hypoxia. Future studies should fow during exercise: infuence of available oxygen. J Appl Physiol verify if lower limb exercises (e.g., squat, knee extension) 111(6):1527–1538 Chodzko-Zajko WJ, Proctor DN, Fiatarone Singh MA, Minson C, Nigg would yield to similar muscle oxygenation responses. CR, Salem GJ, Skinner JS (2009) American College of Sports Medicine position stand. Exercise and physical activity for older Perspective adults. Med Sci Sports Exerc 41(7):1510–1530 di Prampero PE (2003) Factors limiting maximal performance in humans. Eur J Appl Physiol 90(3–4):420–429 Although the benefts of "systemic hypoxia" and "BFR" have Filopoulos D, Cormack SJ, Whyte DG (2017) Normobaric hypoxia been previously verifed separately, our approach focusing increases the growth hormone response to maximal resistance on combined efects of these two stressors is novel. This exercise in trained men. Eur J Sport Sci 17(7):821–829

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