Bronchodilators, especially inhaled β2-agonists, which are the most commonly used treatments for exercise-induced asthma management, still spark concerns for sport competition. A frequent use of these products including salbutamol is reported in endurance sports like cycling or running involving high aerobic capacities. A larger prevalence of airway dysfunctions such as bronchial hyperresponsiveness and inflammation has been consistently reported in endurance athletes compared with sedentary controls (41,44). However, because of sympathomimetic properties of β2-agonists, concerns have been raised relative to the potential unfair competitive advantage provided by these products.
Oral β2-agonists administration in human has substantial effects on muscle function (25,34) and exercise performance (8–11,23,24,32). In animal models, β2-agonists were shown to increase muscle contractility (3,5,6), reduce muscle fatigue (4), and improve force recovery (14). Doses of inhaled β2-agonists of salbutamol, however, are more than 20 times smaller (100 µg per puff) than oral (2 mg per pill up to 12–20 mg·d−1) doses and are thought to act locally within the airways. Most studies, having tested the effect of inhalation of “therapeutic” (200 µg) or even “supratherapeutic” (up to 800–1000 µg) doses of β2-agonists on exercise performance, revealed no ergogenic effect (21,26,40). Our group showed in recreational sportsmen that acute inhalation of therapeutic (200 µg) or supratherapeutic (800 µg) doses of salbutamol did not significantly modify voluntary activation (VA), quadriceps contractility, and fatigue after whole-body or localized exercise (13).
Several arguments have led us to reappraise the effects of oral β2-agonists on neuromuscular function. First, salbutamol uptake was shown to induce some systemic effects, e.g., changes in resting heart rate (16), blood glucose concentration (36,37), ammonia (26), free fatty acids, glycerol, actate, and potassium (40). Thus, part of the inhaled β2-agonists dose may potentially reach the peripheral muscles. Second, effects in highly fit competitive sportsmen cannot be extrapolated from recreational athletes. Some recent results indicate for instance that oral doses of salbutamol are without any relevant ergogenic effect on muscle contractility and fatigability in nonasthmatic recreational male athletes (12), although it significantly enhances performance in highly fit sportsmen (32). Because it was less documented in literature, a potential ergogenic effect remains to be clarified in the most concerned population, i.e., in highly endurance-trained subjects. Third, some studies have shown weak positive effects of inhaled β2-agonists especially in maximal exercise and/or in endurance exercise, although a majority did not (2,35). Finally, it remains to be evaluated whether central versus peripheral muscle fatigue as well as high- versus low-frequency fatigue after exercise may be differentially affected by products acting on the CNS and/or the muscle itself.
Therefore, this study aimed to assess mechanisms potentially responsible for performance improvements after acute salbutamol inhalation in highly endurance-trained subjects. We hypothesized that salbutamol inhalation in endurance athletes may increase muscle contractility, reduce peripheral or central fatigability, and/or improve force recovery after an exhaustive isolated exercise. We used a local, intermittent incremental isometric quadriceps contraction task until exhaustion (1) to assess maximal strength, endurance, and resistance to fatigue. This kind of localized muscle exercise avoids large cardiorespiratory stimulation and permits to evaluate the effect of salbutamol specifically on the neuromuscular function. Femoral magnetic stimulation at various frequencies (1, 10, and 100 Hz) was used to assess both central and peripheral as well as “high-” versus “low-frequency” components of neuromuscular fatigue.
MATERIALS AND METHODS
Eleven healthy, nonasthmatic male athletes (age, 33 ± 6 yr; height, 176 ± 5 cm; weight, 68 ± 3 kg) with high aerobic capacities (maximal oxygen consumption, V˙O2max >65 mL·min−1·kg−1) gave written informed consent to participate in the study. The subjects were highly trained (two cyclists, three triathletes, and five runners; mean training = 12 ± 3 h·wk−1) and had no history of atopy, asthma, or other cardiorespiratory disorders. They were not allowed to eat or drink any caffeinated products and to perform any physical exercise 48 h before the day of the test. They had to keep their training activity constant during the whole testing period. Subjects took a high-carbohydrate meal (i.e., at least 800 kcal with 60% carbohydrates) at least 2 h before each test to load their energetic stores. The study was approved by the local ethics committee on human research and in accordance with the Declaration of Helsinki.
A prospective double-blind, randomized, three-way crossover design was used to compare two dose levels of salbutamol (200 and 800 μg) and a placebo (with the same packaging, indistinguishable by the subject; Spray® GlaxoSmithKline, Marly-le-Roi, France), administered by inhalation before a standardized quadriceps test (see the succeeding part of this article). Each test session was performed at least 96 h apart, within a maximum period of 3 wk. Salbutamol (Ventolin® 100 μg, GlaxoSmithKline) or placebo were administered using a meter-dose inhaler with an inhalation chamber (Volumatic, GlaxoSmithKline). One or four puffs of salbutamol or placebo were introduced into the chamber, and then the subject performed five respiratory cycles inside. This procedure was repeated twice (leading to inhalation of 200 and 800 µg of salbutamol). To ensure blinding, the technician who gave inhaled treatments in a random order was not involved in the other parts of the protocol. Lung function (forced vital capacity (FVC), forced expiratory volume in 1 s (FEV1), and forced expiratory flow at 25%–75% of FVC (FEF25–75)) was assessed 10 min after treatment administration (Medisoft, Dinant, Belgium).
Maximal incremental cycling test
Before performing the three experimental sessions, subjects performed a maximal incremental exercise test (80 W of initial power and 25 W·min−1 increment until subject exhaustion) on a computer-controlled electrically braked cycle ergometer (Ergometrics 800; Ergoline, Bitz, Germany) with electrocardiogram, breath-by-breath ventilation, and gas analysis (Medisoft) for the determination of maximal aerobic power and maximal oxygen uptake (V˙O2max) (Medisoft). A fingertip blood sample was obtained 3 min after exhaustion and was analyzed for lactate concentration ([La]max) (NOVA +; Nova Biomedical Corporation, Waltham, MA).
Experimental setup for quadriceps function assessment
Subjects lay supine on a customized quadriceps chair, the right knee was flexed at 90°, and the hip angle was 130° to allow good access to the femoral triangle. Voluntary strength and evoked responses to femoral nerve magnetic stimulation (FNMS) were measured with an inextensible ankle strap connected to a strain gauge (SBB 200 kg; Tempo Technologies, Taipei, Taiwan). Visual feedback of the torque produced and the target torque level (see the succeeding part of this article) was provided to the subjects. Extraneous movement of the upper body was limited by two belts across thorax and abdomen. Subjects were asked to keep their hands on their abdomen. Subjects rested for at least 20 min while the skin was prepared for EMG recordings and localization of optimal FNMS site (see the succeeding part of this article).
FNMS was performed with a 45-mm figure-of-eight coil powered by two linked Magstim 200 stimulators (peak magnetic field, 2.5 T; stimulation duration, 0.1 ms; Magstim, Whitland, Dyfed, UK). The linking circuitry (Bistim Module, Magstim) was capable of precisely controlling the interstimulus interval between 1 and 999 ms with an accuracy of less than 0.05 ms. One stimulator was used for single stimulations, whereas both stimulators were used for paired stimulations (doublets with interstimulus interval of 100 or 10 ms, i.e., 10 and 100 Hz, abbreviated Db10 and Db100). All stimuli were given at maximum stimulator output. The coil was positioned high in the femoral triangle in regard to the femoral nerve. Optimal stimulation site allowing maximal peak twitch and vastus lateralis (VL) M-wave amplitude was determined with minor adjustments and marked on the skin. The supramaximality of the stimulation was confirmed at each test session for all subjects, as previously reported in our laboratory (13,42).
Quadriceps EMG signal was recorded from the right VL, as a surrogate for whole quadriceps (29), with a pair of 20-mm-diameter silver chloride surface electrodes (Meditrace 100; Kendall, Mansfield, MA) positioned 25 mm apart. Low resistance (<10 kΩ) between the two electrodes was obtained by light abrasion of the skin and cleaning with alcohol. Recording electrode locations were based on SENIAM recommendations (20). A reference electrode was placed over the patella. EMG signals were amplified (BioAmp; AD Instruments, Medford, OR) with a bandwidth from 5 to 500 Hz. EMG data together with torque signals were digitized online at a sampling frequency of 2000 Hz and recorded on a dedicated device (PowerLab, ADInstruments).
Quadriceps test description
A graphic overview of the quadriceps test is provided in Figure 1. Forty minutes after treatment inhalation (to ensure maximal salbutamol plasmatic levels (27)), the subjects performed first 10 brief submaximal isometric quadriceps contractions to warm up and to familiarize themselves with visual feedback and the soundtrack instructions, and then three maximum voluntary contractions (MVC) with 1 min of rest in between (see “warm-up” in Fig. 1). After these initial warm-up and MVC providing full muscle potentiation (22), the initial neuromuscular assessment (Pre) was performed. It included a 4-s MVC superimposed with a doublet at 100 Hz (Db100,s) and followed after 2 s by two potentiated doublets at 100 and 10 Hz performed 4 s apart to assess low-frequency fatigue. After 15 s of rest, subjects performed a second MVC followed after 2 s by one potentiated single-pulse twitch (Twp). During all MVC, subjects were vigorously encouraged by the experimenter. After the initial neuromuscular assessment, a set of 10 intermittent contractions (5 s on/5 s off) at submaximal target torque was performed, starting at 20% MVC with 10% MVC increment from one set to another until exhaustion. Subjects had a visual torque feedback providing the target level, and a soundtrack indicated them the contraction–relaxation rhythm. Task failure was defined as two consecutive contractions 10 N below the target torque for more than 2.5 s. Immediately after the end of each set, at exhaustion (Exh) and after 10 (Post 10) and 30 min (Post 30) of recovery, neuromuscular assessment was performed similarly to Pre. The next set started 15 s after the end of the neuromuscular assessment. Right before the neuromuscular assessment at Post 10 and Post 30, the subjects performed two MVC 30 s apart to fully potentiate the quadriceps muscle.
The following parameters were calculated from the mechanical responses to FNMS: peak torque for Twp, Db100, Db100,s as well as the ratio Db10 over Db100 (Db10:100). Peak-to-peak M-waves amplitude (Mampl) and duration (Mduration) were calculated from potentiated single stimulation. For MVC, we considered the maximal value of the two MVC performed at Pre, after each set, at Exh, and at Post 10 and Post 30. Maximal VA was calculated as follows from high-frequency doublets, with a correction applied when the superimposed stimulation was administrated slightly before or after the real peak MVC (38):
We calculated the root mean square of the VL for each MVC normalized with the amplitude of M-wave (RMS/M). We also calculated the mean RMS/M of submaximal contractions during each set and the RMS/M difference between the three first contractions and the three last contractions of each set. We analyzed data (MVC, Twp, Db10, Db100, Db10:100, and VA) from the 10-contraction sets at 20% to 70% MVC because they were completed by all subjects. The following parameters were also studied from submaximal contractions of each set: total number of contractions (i.e., endurance index) and the total torque (force × time) calculated over each submaximal contraction.
All descriptive statistics are presented are mean values ± SD. Data recorded before, during, and after the quadriceps test were analyzed using a one-factor (i.e., treatment, for spirometric values, neuromuscular measurements at Pre, and total number of contractions) or two-factor (i.e., time × treatment, for neuromuscular measurements during and after the quadriceps test) ANOVA with repeated measures. Post hoc analyses with t-tests and Bonferroni correction were used to test differences over time and between treatments if a significant main effect or interaction was detected. The alpha level was set at 0.05 for all tests. All statistical calculations were performed using a statistical software package (NCSS, Kaysville, UT).
Because salbutamol can induce some cardiac function disturbances, subjects were carefully supervised during the 2 h after inhalation. No adverse effects were observed after treatment inhalation in all the subjects.
Lung function and maximal cycling test response
Subjects were normal weight, and their maximal cycling test responses (V˙O2max, 74 ± 4 mL·min−1·kg−1; maximal workload, 365 ± 25 W; heart rate, 186 ± 21 bpm; and [La]max, 11.6 ± 3.2 mmol·L−1) confirmed their highly trained status. As shown in Table 1, postinhalation FEV1 values were slightly but significantly higher after 200 and 800 µg of salbutamol inhalation (P = 0.036 and P = 0.042, respectively) than placebo. Similarly, FEF25–75 was slightly higher after 800 µg of salbutamol (P = 0.039).
Quadriceps strength and central activation
No significant differences were found between sessions at Pre (placebo vs 200 and 800 µg of salbutamol inhalation) in MVC (336 ± 51, 350 ± 60, and 360 ± 53 N·m, respectively, f = 1.64, P = 0.22) and evoked muscular responses to FNMS (Twp: 98 ± 14, 100 ± 15, and 99 ± 12 N·m, respectively, f = 0.23, P = 0.79; Db100: 146 ± 18, 148 ± 22, and 148 ± 17 N·m, respectively, f = 0.82, P = 0.19; Db10:100: 1.04 ± 0.08, 1.02 ± 0.09, and 1.04 ± 0.06, respectively, f = 0.55, P = 0.61). Volitional and evoked quadriceps strength during and after the quadriceps test are presented in Figure 2. MVC was significantly reduced at set 70% MVC (i.e., after 60 submaximal contractions) until exhaustion compared with Pre. After 10 and 30 min of recovery, MVC has returned to the same level of baseline. However, no significant difference was observed between placebo, 200 µg of salbutamol, and 800 µg of salbutamol (f = 0.46, P = 0.96). Twp, Db100, and Db10:100 were not significantly reduced until set 70% MVC during the quadriceps test, and no significant differences were found between treatments (Twp, f = 0.89, P = 0.59; Db100, f = 1.47, P = 0.10; Db10:100, f = 1.27; P = 0.21). No significant differences were observed overtime for M-wave amplitude and duration in all conditions (P > 0.05, data not shown). VA and RMS/M during MVC of the quadriceps test are shown in Figure 3. VA (f = 0.80, P = 0.70) as well as RMS/M (f = 0.81, P = 0.62) did not significantly change during the quadriceps test in all conditions. Mean RMS/M during sets of submaximal contractions did not differ between treatments (f = 1.21, P = 0.13; Fig. 4A). However, when considering RMS/M changes within sets of submaximal contractions, the increase in RMS/M from the first three to the last three contractions was significantly smaller with 800 µg of salbutamol compared with placebo at set 70% MVC (P = 0.002, Fig. 4B).
The total number of submaximal contractions until task failure significantly differed between treatments (72 ± 7, 78 ± 8, and 82 ± 7 for placebo, 200 and 800 µg of salbutamol, respectively; f = 6.77, P = 0.0063; Fig. 5A). Post hoc analysis revealed significant differences between placebo and 800 µg of inhaled salbutamol (P < 0.01) but not with 200 µg (P = 0.14). Furthermore, no significant differences were found between 200 and 800 µg of inhaled salbutamol (P = 0.42). The total torque (force × time) generated over the first 60 contractions at the end of the 70% MVC set (i.e., the set completed by all subjects in all sessions) was similar between treatments (36,688 ± 6637 vs 36,126 ± 7626 vs 35,722 ± 6882 N·m·s for placebo, 200 and 800 µg of salbutamol, respectively; P = 0.98). For this variable, intraclass coefficient correlation was 0.97 (95% CI, 0.92–0.99) and typical error was 3.7% (95% CI, 2.7–5.8). The overall total torque generated until exhaustion during the quadriceps test was significantly different between treatments (62,389 ± 10,044 vs 69,437 ± 10,184 vs 73,983 ± 7892 N·m·s for placebo, 200 and 800 µg of salbutamol, respectively; f = 5.32, P = 0.015; Fig. 5B). Post hoc analysis revealed significant differences between placebo and 800 µg of inhaled salbutamol only (P < 0.05).
The aim of this study was to evaluate the effect of inhaled β2-agonists on quadriceps strength, endurance, and fatigability in highly endurance-trained subjects. On the basis of our previous work (13) and data from the literature, we made the hypothesis that the effect of inhaled salbutamol on neuromuscular function, which was undetectable in recreational sportsmen, might be significant in endurance athletes regarding muscle strength, endurance, and on some aspects of neuromuscular fatigue. To test this hypothesis, we used an original quadriceps test validated by our team (1), including a maximal incremental exercise protocol under isometric conditions with multiple neuromuscular evaluations via FNMS. The main differences with previous neuromuscular assessment performed to evaluate potential effect of β2-agonists in our laboratory (13) are (i) the standardized and incremental strength developed during isometric contractions and (ii) a better monitoring of fatigue development because subjects were reevaluated at each set of increasing strength level. This allowed us to investigate endurance (i.e., the number of contractions or total torque achieved before exhaustion) and the kinetics of fatigue development and recovery. The main results of the present study confirm that inhaled β2-agonist does not lead to modified evoked or volitional strength, activation, and/or fatigability in endurance-trained men but reveal significant increase in muscle endurance (i.e., greater number of submaximal contractions and higher total torque generated to exhaustion).
Efficacy of salbutamol inhalation
As expected, the inhalation of salbutamol appeared to slightly improve lung function at rest (e.g., FEV1 and FEF25–75), as previously shown (13,18,28). These results are in accordance with the literature and confirm the bronchodilating effect of β2-agonists inhalation in nonasthmatic endurance athletes. However, if statistically significant effects have been noticed, this bronchodilating effect may have no overt consequence on localized muscle performance and cannot explain alone a possible improvement on muscle function (12,16).
Peripheral quadriceps function and fatigue
Some recent studies have suggested that acute β2-agonists have an effect on some processes in excitation–contraction coupling (7,17,35). Indeed, salbutamol might affect muscle torque and contractility by increasing Ca2+ reuptake by the sarcoplasmic reticulum. Hence, the hypothesis based on the improvement of excitation–contraction coupling induced by the enhancement of sarcoplasmic reticulum Ca2+ release (30) cannot be confirmed within the present study because no significant difference in evoked quadriceps responses was observed between different inhaled doses of treatment and placebo. Furthermore, M-wave characteristics did not change at rest, during the exercise protocol, and after 10 or 30 min of recovery, which indicates that impairment of action potential conduction is not involved during this type of exercise, at least in this population of athletes.
Effect of salbutamol on central activation
Salbutamol may increase neuromuscular function by stimulation of the CNS as suggested by Collomp et al. (11,31). We assessed the possible effect of salbutamol on VA by the twitch interpolation technique (33) combined with EMG recording during the quadriceps test and during recovery. VA did not differ between treatments as well as RMS/M before, during, and after the quadriceps test. These results indicate that salbutamol has no effect on central fatigue in these endurance-trained subjects, although this remains to be confirmed with exercise protocol inducing large amount of central fatigue. Moreover, the twitch interpolation does not quantify the descending drive to the lower motoneurons, nor does it take into account the source of this drive. The part of central fatigue resulting from deficient motor cortical output (i.e., supraspinal fatigue) is thus unknown. The twitch interpolation method has also some potential limitations (i.e., differential VA of synergists, antagonist activation, or lengthening of muscle fibers during contraction (39)) that may have led to no difference in VA between treatments. In our recent study dealing with the reliability of the quadriceps test used in the present work (1), typical error expressed as a coefficient of variation for VA was 2.3% and 4.3% at Pre and exhaustion, respectively, indicating the good reliability of this parameter. Nevertheless, other neurostimulation techniques are required to investigate the corticospinal component of fatigue like transcranial magnetic stimulation, which permit to explore the possible implication of salbutamol on the CNS leading to β2-activation pathway (19,45).
Interestingly, RMS/M increased significantly less from the beginning to the end of set 70% MVC (i.e., the last set completed by all subjects) with 800 µg of salbutamol compared with placebo. This could be the consequence of less peripheral fatigue development during this set with 800 µg of salbutamol, inducing a smaller increase in central command to compensate for peripheral fatigue and to maintain the target torque. Similar reductions in evoked quadriceps responses at the end of this step with salbutamol and placebo do not confirm however a smaller amount of fatigue development with salbutamol inhalation.
Effect of salbutamol on quadriceps endurance
As mentioned previously, the main findings of this study is that supratherapeutic (800 µg) doses of salbutamol appears to increase muscle endurance (i.e., greater number of submaximal contractions to exhaustion) without change in evoked or volitional strength and activation (Fig. 2). The comparison of the total torque (force × time) generated over 60 contractions from Pre to set 70% MVC between all conditions suggests that the quadriceps test was performed identically in the different sessions. On the basis of the increased total number of contractions (+10 contractions on average with 800 µg of salbutamol compared with placebo) and the larger overall total torque production (approximately +11,600 N·m·s with 800 µg of salbutamol compared with placebo) at exhaustion during the quadriceps test, 800 µg of salbutamol appears to induce greater endurance and therefore a genuine performance improvement compared with placebo. In our previous study in recreational sportsmen (13), we observed no change in muscular performance with similar doses of salbutamol inhalation. This contrasting result may have been due not only to differences in training status between the populations’ studies but also to differences in the exercise tests (five series of 10 MVC in our previous study). Hence, it appears that in endurance athletes, this treatment increases endurance capacities and delays task failure without significant changes in muscle strength and contractility at rest and during the fatiguing task. It is however of note that after 800 µg of salbutamol inhalation, longer exercise duration was performed with similar amount of quadriceps strength reduction at exhaustion, which can be interpreted as a slower development of muscle fatigue. Recent studies demonstrated no ergogenic effect of a high dose of salbutamol on aerobic capacity (15), and this may not explain the increased muscle endurance in the present study. However, β2-agonists induce changes in metabolism, leading to glycogenolysis stimulation as discussed by Voet and Voet (43). Salbutamol could activate the glycogenolysis (by stimulating adenylate cyclase), which in turn increases the intracellular cyclic AMP concentration leading to phosphorylation of phosphorylase. Acute administration of salbutamol was shown to increase blood glucose and lactate concentration at rest and after intense cycling exercise (32). Hence, during repetitive isometric contractions such as in the present study, stimulation of anaerobic glycolysis by salbutamol may underlie an increased performance. Metabolic measurements (e.g., blood lactate) are needed to confirm this statement.
In conclusion, supratherapeutic inhaled β2-agonists induced significant improvement of quadriceps endurance with similar amount of fatigue during a localized fatiguing task in healthy endurance-trained athletes. Consequently, inhaled β2-agonists seem to have some positive effect on physical performance in endurance-trained subjects regarding the capacity to maintain intermittent isometric contractions. Further studies in endurance athletes are needed to clarify the mechanisms underlying this effect, in particular, regarding the CNS and the metabolism, and to determine whether improved performance during a localized exercise would transfer to a true ergogenic aid during sporting competition.
The investigators wish to express their gratitude to the subjects for their dedicated performance and to the medical team of the Exercise Research Unit of the Grenoble University Hospital for their technical assistance. This work was carried out with the support of the French Anti-Doping Agency.
N. Decorte, M. Guinot, P. Flore, P. Levy, S. Verges, and B. Wuyam did the conception and design of the research; N. Decorte and B. Wuyam performed the experiments; N. Decorte, D. Bachasson, S. Verges, and B. Wuyam analyzed the data; N. Decorte, D. Bachasson, M. Guinot, P. Flore, S. Verges, and B. Wuyam interpreted the results of the experiments; N. Decorte, D. Bachasson, S. Verges, and B. Wuyam drafted the manuscript; N. Decorte, D. Bachasson, M. Guinot, P. Flore, P. Levy, S. Verges, and B. Wuyam edited and revised the manuscript; N. Decorte, D. Bachasson, M. Guinot, P. Flore, P. Levy, S. Verges, and B. Wuyam approved the final version of the manuscript; N. Decorte and D. Bachasson prepared the figures.
The authors report no conflicts of interest. The authors alone are responsible for the content and writing of the article.
The results of the present study do not constitute endorsement by the American College of Sports Medicine.
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