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Medicine & Science in Sports & Exercise:
doi: 10.1249/MSS.0b013e3182a54ee3
Basic Sciences

Actions of β2-Adrenoceptor Agonist Drug on Neuromuscular Function after Fatigue


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1Institute of Sport Sciences, University of Lausanne, Lausanne, SWITZERLAND; and 2Neuromuscular Research Laboratory, Schulthess Clinic, Zurich, SWITZERLAND

Address for correspondence: Giacomo Crivelli, Institute of Sport Sciences, University of Lausanne, Bâtiment Géopolis, quartier UNIL, Mouline, CH-1015 Lausanne, Switzerland; E-mail:

Submitted for publication April 2013.

Accepted for publication July 2013.

Supplemental digital content is available for this article. Direct URL citations appear in the printed text and are provided in the HTML and PDF versions of this article on the journal’s Web site (

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Purpose: The effects of β2-agonists on human skeletal muscle contractile function are unclear, more particularly in the presence of fatigue. Moreover, it remains to be ascertained whether central motor drive during voluntary contractions could counter for eventual contractile alterations induced by β2-agonists. This study explored central and peripheral neuromuscular adjustments of the quadriceps induced by β2-agonist terbutaline after fatiguing exercise.

Methods: On 2 d, nine men performed 120 intermittent (5-s contraction/5-s relaxation) submaximal (50% maximal voluntary contraction [MVC]) voluntary contractions, 2 h after having ingested a terbutaline (8 mg) or placebo capsule, in a double-blind randomized order. The isometric knee extension peak torque of single twitch and tetanic (10 and 100 Hz) contractions and of MVC was recorded before (PRE) and after (POST) the fatiguing exercise. Twitch maximal rate of torque relaxation (−dT/dt) was also calculated. Central motor drive was estimated via quadriceps electromyogram recorded during the submaximal voluntary contractions.

Results: In PRE and POST conditions, MVC and twitch peak torque were not modified by terbutaline. PRE twitch −dT/dt was 22% higher in terbutaline compared with placebo (P < 0.005), but it did not differ significantly between treatments at POST. The evoked torque of 10- and 100-Hz tetanus were significantly lower in terbutaline compared with placebo, regardless of time (−16% and −17% respectively, P < 0.05). Central motor drive during voluntary exercise did not differ between treatments.

Conclusions: These results demonstrate that terbutaline affected the contractile function of the quadriceps muscle during electrically evoked contractions both before and after fatiguing exercise. However, this did not impair the maximal voluntary force-generating capacity of the knee extensors and did not result in any compensatory adjustments of the central nervous system.

β2-Adrenergic agonists are powerful bronchodilators that are widely used for treating asthma and exercise-induced asthma. In addition to the bronchodilatory action, β2-adrenergic agonists have also been shown to increase muscle strength and to improve exercise performance in nonasthmatic individuals (12,14,31,44). Even if the exact mechanism by which β2-agonists enhance human performance is still a matter of debate, a specific potentiating effect on the skeletal muscle contractility is often invoked. Indeed, a potentiating action of β2-agonists on twitch and tetanic tension has been clearly established in anesthetized animals as well as in isolated muscles and fiber bundles (5,7,8,26). Such positive inotropic effect has been mainly related to enhanced release of Ca2+ from the sarcoplasmic reticulum (8,11,26).

There are, nevertheless, studies in which an acute administration of β2-agonists failed to improve muscle strength (16,17) and exercise performance (13). For example, adrenaline or β2-agonists have been shown to exert a weakening action on human skeletal muscle during submaximal contractions evoked by electrical stimulation (16,33). Marsden and Meadows (33) reported a reduction of unfused tetanic force of the adductor pollicis and calf muscles in response to an intravenous injection of the β-adrenergic agonist adrenaline. Similarly, an acute administration of the β2-adrenergic agonist terbutaline decreased the force generation capacity of the soleus muscle during unfused and fused tetanic responses (16). The weakening effect was in most of the cases observed in the presence of a shortening of the twitch response due to enhanced relaxation rate (16,33). Such positive lusitropic effect elicited by β-agonists, which mainly affects slow muscle fibers (5,8,26), induces a weakening action because shorter twitches result in a reduction of their degree of fusion and summation, thus lowering average force level during repetitive activation (5,37,38). Besides these effects on relaxation rate, terbutaline administration increased soleus EMG activity during submaximal voluntary contractions (16). This was interpreted as an augmentation of the neural drive to the muscle to compensate for the reduced force-generating capacity because of the terbutaline-induced reduction in half-relaxation time (16). According to this idea, it was speculated that such an increase of the motor drive during voluntary exercise could exaggerate metabolic cost and thus muscle fatigue (16).

To the best of our knowledge, only one study has investigated the effect of β2-agonists on human skeletal muscle contractile function in the presence of fatigue (17). The β2-agonist salbutamol did not modify fatigability of the quadriceps femoris muscle, although unfused tetanic force was less affected by fatigue (17). It must, nevertheless, be emphasized that in this previous study, muscle fatigue was elicited by intermittent electrical stimulation, which differs “physiologically” from the fatigue induced by voluntary contractions (4). The action of acute β2-agonists intake on the extent and time course of human muscle fatigue induced by voluntary exercise has never been investigated.

Therefore, the primary purpose of this study was to explore the effects induced by an acute oral therapeutic administration of the β2-agonist terbutaline (8 mg) on the contractile function of the knee extensor muscles fatigued by intermittent submaximal voluntary contractions. Second, given that terbutaline has been shown to reduce the tetanic force-generating capacity of human skeletal muscles (16), we also examined whether the accelerated rate of force relaxation elicited by terbutaline would be associated to a higher central motor drive compared with placebo as a compensatory strategy to preserve voluntary force output (16). This could in turn increase the extent of muscle fatigue in the terbutaline condition compared with placebo (16).

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Nine recreationally active men volunteered for the study (age = 30 ± 7 yr, height = 181 ± 6 cm, body mass = 75 ± 7 kg). They were involved in different sport activities (running, cycling, climbing, or soccer) in the last 2 yr, with a frequency of two to four exercise sessions per week. All the participants declared that they had never taken β2-agonists and any prescribed or over-the-counter medications that may have interfered with β2-agonist action (e.g., β-blockers). The study was approved by the University of Lausanne’s Human Research Ethics Committee and conformed to the principles expressed in the Declaration of Helsinki. All participants gave their written informed consent to participate after being fully informed about the procedures and the possible related risks.

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Experimental Design

Participants reported to the laboratory on three separate occasions: once for the familiarization session followed by two identical experimental sessions. Before each visit, they were asked to refrain from caffeinated beverages, alcohol, and strenuous physical exercise for at least 24 h. At the familiarization session, participants were acclimated to the testing procedure; isometric knee extension maximal voluntary contraction (MVC) torque was measured, and subjects were subsequently trained to produce submaximal intermittent isometric contractions of the knee extensors. They received visual feedback of knee extension torque on a computer monitor with a target line at ∼50% MVC.

During the two experimental sessions, participants performed an identical fatigue protocol (see next section) after having ingested either a single 8-mg dose of terbutaline (terbutaline sulfate; AstraZeneca, Zug, Switzerland) or a placebo (mannitol) in a double-blind, counterbalanced, and randomized order. The experimental session started with the baseline (BSL) assessment of the neuromuscular function of the right knee extensors (Fig. 1A) that consisted of a series of stimulated and voluntary contractions, during which isometric knee extension torque and surface EMG activity were recorded. Then, either placebo or terbutaline, which were packaged in identical capsules, was administered. Two hours after ingestion, which coincides with terbutaline peak plasma concentration (18), the neuromuscular function of the knee extensors was assessed both before (PRE) and immediately after (POST) the fatigue protocol, and again after 30 min of recovery (REC). The testing procedure was identical through the entire experimental protocol. A standardized warm-up of 5 min was conducted before both BSL and PRE test and consisted of several submaximal voluntary isometric contractions of the knee extensors. Participants rested for 1 min between the end of the warm-up and the beginning of neuromuscular testing. The fatigue protocol began 1 min after PRE test and consisted of 120 submaximal intermittent voluntary contractions of the knee extensors. The intensity of the contractions was ∼50% MVC, as measured during the familiarization session, and the duration of both contraction and relaxation phases was 5 s. The two experimental sessions were separated by 7 d and were completed at the same time of day to minimize the effects of diurnal biological variation on the neuromuscular properties of the knee extensors (41).

Figure 1
Figure 1
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Experimental Set-up
Torque recordings.

During the entire test period, participants were seated in the chair of a custom-built device with the right knee positioned at 90° and a trunk-thigh angle of 100° to facilitate access to the femoral nerve. The participants were secured firmly with two shoulder harnesses and a belt across the abdomen to stabilize the upper body, and they were also asked to cross their arms over the chest throughout testing. Isometric knee extension torque was recorded using an S-shaped load cell (Universal cell load [linear range = 0–250 N·m, sensitivity = 0.05 V·(N·m)−1], model 9363-C3; Vishay, Shelton, CT), with the participant’s right shank attached by a noncompliant strap to the lever arm, 3–5 cm above the tip of the lateral malleolus. During the protocol, participants received visual feedback of the knee extensors torque on a computer monitor with a target line at ∼50% MVC. Room temperature remained constant (21°C–22°C) during each experimental session.

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EMG recordings.

Surface EMG activity of the right vastus lateralis (as a surrogate for the quadriceps muscles) was recorded using self-adhesive bipolar Ag/AgCl electrodes (EL503; Biopacs Systems, Santa Barbara, CA) with a diameter of 10 mm and an interelectrode (center-to-center) distance of 25 mm. The two electrodes were placed lengthwise over the muscle belly on a line two-thirds of the distance from the anterosuperior iliac spine to the lateral femoral condyle. The reference electrode was placed over the right knee cap. Low interelectrode impedance (<5 kΩ) was obtained by abrading the skin with emery paper and cleaning with alcohol. The EMG signals were amplified 1000 times and band-pass filtered at 10–500 Hz (EMG 100C; Biopac Systems). Torque and EMG data were digitized online (sampling frequency = 2 kHz) with a 16-bit A/D converter (MP150; Biopac Systems) and stored for later analysis.

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Electrical stimulation procedures.

A modified constant-current high-voltage stimulator (model DS7AH; Digitimer, Hertfordshire, UK) was used to deliver square-wave pulses (duration = 1 ms, maximal voltage = 400 V) either over the femoral nerve (single and paired stimuli) or over the quadriceps muscle (trains of stimuli).

Over-the-nerve stimulation was delivered using a self-adhesive cathode electrode (diameter = 5.1 cm; Dermatrode, American Imex, CA, USA) placed into the femoral triangle, 3–5 cm below the inguinal ligament, with constant compression supplied by a strap. The self-adhesive anode electrode (5.1 × 10.2 cm; Compex, Ecublens, Switzerland) was placed over the gluteal fold. The stimulation site providing the greatest twitch response was located by a handheld cathode-ball electrode (diameter = 0.5 cm; Compex). Before BSL, the current intensity of a single pulse was progressively increased by 10-mA increments (interpulse interval = 10 s) until the maximal twitch torque and vastus lateralis M-wave amplitude were reached. This intensity of stimulation was further increased by 10% to ensure full motor unit recruitment (mean intensity = 173 ± 62 mA) and subsequently maintained throughout the experimental session to deliver single and paired (interpulse interval = 10 ms) stimulations.

Over-the-muscle stimulation was delivered using two large self-adhesive electrodes (10.1 × 17.8 cm, dispersive electrode; Uni-Patch, Wabasha, MN), trimmed to fit over the muscle bellies of each participant. The cathode was placed distally over the superficial aspect of the vastus medialis and vastus lateralis muscles. The anode was proximally placed ∼4–5 cm below the femoral triangle. Before BSL, the current intensity of a 1-s tetanus at 100 Hz was increased until knee extensor torque reached ∼50% of the individual MVC torque measured on the familiarization session (mean intensity = 78 ± 12 mA). This stimulation intensity was subsequently used throughout the experimental session to deliver 1-s pulse trains at 10, 20, 50, and 100 Hz. The locations of EMG and stimulation electrodes were marked on the skin so that they could be correctly relocated during the second experimental session.

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Experimental Procedures
Neuromuscular tests.

The testing procedure began with single stimulations to evoke maximal M-wave and twitch responses (Fig. 1B). Afterward, participants performed two knee extensor MVC (separated by 1 min), during which they were instructed to reach maximal torque in 1 s and then to maintain it for 4 s while receiving strong verbal encouragements. Paired stimuli were delivered over the isometric MVC plateau (to evoke a superimposed doublet) and 2 s after the contraction (to evoke a potentiated doublet) to assess the level of voluntary activation (VA) according to the twitch interpolation technique (34). Subsequently, 1-s pulse trains at four different frequencies (10, 20, 50, and 100 Hz, randomly presented and separated by 10 s) were delivered to evoke submaximal tetanic responses. Participants were asked to complete 5-s submaximal (∼50% MVC) voluntary contractions of their knee extensors and to interrupt them 2 s before single and trains of stimuli were delivered. This was performed to equalize the postactivation potentiation effect on all the evoked responses (30).

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Data Analysis

Torque signals were low-pass filtered using a Blackman window-based filter (−61 dB). The highest torque achieved over the two MVC at respective time points was taken as MVC torque. The following contractile properties were measured from single twitch traces: peak torque (PT) and maximal rate of torque relaxation (−dT/dt), as the lowest peak from the first derivative of the torque signal. The peak torque of evoked tetanic responses were quantified and termed P10, P20, P50, and P100 for 10, 20, 50, and 100 Hz tetanus, respectively. In addition, the P10/P100 ratio was calculated to assess whether terbutaline affected unfused and fused tetanus differently. The level of VA during MVC was estimated according to the following formula: VA = [1 − (superimposed doublet peak torque / potentiated doublet peak torque)] × 100. When the superimposed doublet was evoked at a torque level that was slightly below the MVC torque, VA was corrected as suggested by Strojnik and Komi (43).

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EMG activity.

The root mean square EMG activity of the vastus lateralis muscle was calculated for a 500-ms period around MVC torque (EMGmax), that is, 250 ms before and after MVC torque, and for a 2-s window for all submaximal voluntary contractions of the fatigue protocol (EMGsubmax). EMGsubmax was examined as a surrogate of central motor drive. The 2-s epochs were positioned 2 s after the onset of each submaximal contraction. A computer algorithm identified the onset of the contraction where the torque signal deviated by more than 40 N·m above the baseline for 1.5 s. For each condition, EMGsubmax was the average of six contractions per minute of the fatigue protocol. EMGsubmax was then normalized to EMGmax obtained at BSL for each condition. Vastus lateralis M-wave peak-to-peak amplitude and area were also calculated to assess membrane excitability.

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Statistical Analysis

Statistical analyses were accomplished using SigmaStat (version 2.03; Jandel, San Jose, CA) and SPSS (version PASW statistic 18; IBM, Armonk, NY). The effects of terbutaline and placebo administration on neuromuscular function before the fatigue protocol (i.e., BSL vs PRE [as a percentage]; see Fig. 2) were compared using paired t-tests. The effects of the fatigue protocol on all neuromuscular parameters were analyzed using a two-way ANOVA with repeated measures in which the main factors were treatment (terbutaline vs placebo) and time (PRE vs POST vs REC). To evaluate changes in central motor drive throughout the fatigue protocol, we conducted a two-way ANOVA with repeated measures on EMGsubmax, with treatment and time as main factors. When significant main effects or interactions were identified in the ANOVAs, Tukey’s post hoc tests were conducted. The level of significance was set at P < 0.05. Results are expressed as the mean ± SD in the text and table and as mean ± SEM in the figures.

Figure 2
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Effects of Terbutaline and Placebo on Neuromuscular Function before Fatigue

BSL to PRE changes for twitch PT, M-wave amplitude and area, P10/P100 ratio, MVC torque, VA, and EMGmax did not differ between treatments (Fig. 2). In contrast, the increase in −dT/dt (P < 0.005; Fig. 2A) and the decline in P100 (P < 0.01) were greater for terbutaline compared with placebo, with a similar tendency for P10 (P = 0.06; Fig. 2B). P20 and P50 data confirmed the result observed for P100 (data not shown).

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Effects of Terbutaline and Placebo on Twitch Contractile Properties after Fatigue

For twitch PT (Fig. 3A), there was a significant main effect of time (P < 0.001), no main effect of treatment, and no significant interaction between treatment and time. Compared with PRE, twitch PT was reduced at POST (−37% ± 12%, P < 0.001) and REC (−39% ± 9%, P < 0.001) regardless of the treatment. For both conditions, twitch PT was unaltered from POST to REC. Twitch −dT/dt showed a significant treatment-by-time interaction (P < 0.05). As represented in Figure 3B, PRE twitch −dT/dt was 22% ± 13% higher in terbutaline compared with placebo (P < 0.005). Twitch −dT/dt decreased from PRE to POST in both placebo and terbutaline conditions, respectively, by −19% ± 26% and −35% ± 24% (P < 0.05). POST twitch −dT/dt was not different between treatments. Twitch −dT/dt did not change from POST to REC in both conditions. However, REC twitch −dT/dt was 14% ± 24% higher in terbutaline compared with placebo (P < 0.05). A significant main effect of time was observed for vastus lateralis M-wave amplitude and area (P < 0.05), as they declined from PRE to REC (−14% ± 19% and −14% ± 11%, respectively, P < 0.05) regardless of the treatment (Figs. 3C–3D). For both conditions, M-wave amplitude and area remained unchanged from PRE to POST and from POST to REC. There was no effect of treatment and no interaction on M-wave properties.

Figure 3
Figure 3
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Effects Terbutaline and Placebo on Unfused and Fused Tetanic Contractions after Fatigue

P10 and P100 responses showed a significant main effect of treatment (P < 0.05) and time (P < 0.001), but no treatment-by-time interaction. As represented in Figure 4A and 4B, P10 and P100 were lower in terbutaline compared with placebo (−15% ± 7% and −17% ± 4%, respectively, P < 0.05) regardless of time. Compared with PRE, both P10 and P100 were reduced at POST (−70% ± 8% and −43% ± 18%, respectively, P < 0.001) and REC (−62% ± 11% and −34% ± 19%, respectively, P < 0.001) regardless of the treatment. For both conditions, P10 and P100 were unchanged from POST to REC. P20 and P50 data confirmed the results observed for P10 and P100 (Supplementary Figs. 1A and 1B, Supplemental Digital Content 1, peak torque associated to P20 and P50). For P10/P100 ratio, there was a significant main effect of time (P < 0.001). Compared with PRE, P10/P100 ratio was reduced at POST (−43% ± 18%, P < 0.001) and REC (−34% ± 19%, P < 0.001) regardless of the treatment (Fig. 4C). The P10/P100 ratio did not change from POST to REC in both conditions. There was no significant main effect of treatment and no interaction for P10/P100 ratio.

Figure 4
Figure 4
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Effects of Terbutaline and Placebo on Voluntary Contractions after Fatigue

As summarized in Table 1, MVC torque and VA showed a significant main effect of time (P < 0.001), and no treatment effect and treatment-by-time interaction were observed. Compared with PRE, MVC torque was reduced at POST (−25% ± 5%, P < 0.001) and REC (−19% ± 4%, P < 0.001) regardless of the treatment. Moreover, MVC torque increased by 7% ± 6% from POST to REC (P < 0.05). Compared with PRE, VA was lower at POST (−7% ± 3%, P < 0.001) and REC (−5% ± 3%, P < 0.001) regardless of the treatment. VA did not change from POST to REC in both conditions. EMGmax was not significantly affected by treatment and time. For EMGsubmax, there was no treatment main effect, nor was there a significant treatment-by-time interaction. Starting from the eighth minute of the fatigue protocol and regardless of the treatment, EMGsubmax increased significantly as compared with the first minute (P < 0.05; Fig. 5).

Table 1
Table 1
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Figure 5
Figure 5
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The present study examined central and peripheral neuromuscular adjustments induced by an acute oral administration of the β2-agonist terbutaline (8 mg) both before and after voluntary fatiguing contractions of the knee extensor muscles. The main findings of this study were that, compared with placebo treatment, terbutaline reduced tetanic torque regardless of fatigue state and increased muscle relaxation rate in the nonfatigued state. Nevertheless, these alterations in muscle contractility observed during electrically evoked contractions did not impair the maximal voluntary force generation capacity of the knee extensor muscles and did not result in any compensatory adjustments of the central motor drive (as estimated from surface EMG) during the voluntary exercise.

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Effects of Terbutaline on Neuromuscular Function before Fatigue

Several in vitro animal studies have provided evidence that β2-adrenergic agonists potentiated twitch force by directly increasing Ca2+ release from the sarcoplasmic reticulum (7,26). Such inotropic action was elicited using muscle stimulation and high doses of β2-agonists delivered directly to the muscle fibers. Despite changes in free myoplasmic Ca2+ concentration could not be excluded, our present findings confirm the contention that acute ingestion of β2-agonists does not potentiate the twitch response evoked with nerve stimulation of the nonfatigued human muscles (16,17). We suppose that these discrepancies in twitch potentiation results may stem from the different methods used to investigate the effects of β2-agonists in human versus animal models. Furthermore, the unchanged M-wave characteristics suggest that terbutaline did not affect sarcolemmal excitability and/or the action potential propagation. Consistent with previous studies (16,17), the increased twitch −dT/dt we observed in the terbutaline condition indicates an accelerated rate of force relaxation, which would result from the augmentation of sarcoplasmic reticulum Ca2+ uptake (8,26).

The unfused tetanic torque (P10) was slightly, although not significantly, diminished in the terbutaline condition compared with placebo. Several animal and human studies reported a marked decrease in unfused tetanic force in response to acute β-agonists administration, as a consequence of the lusitropic effect occurring in slow muscle fibers (5,6,16,33). This lowers the degree of twitch fusion and summation, which inevitably reduces average tension during unfused tetanus. The terbutaline-induced reduction of unfused tetanic torque observed in the present study (−15%) is undoubtedly less pronounced than that reported in a recent investigation completed on the human soleus muscle (−40%) (16), likely because of differences in fiber type distribution between the quadriceps and the soleus muscles (28). Furthermore, as the results of this and our previous study (16) clearly demonstrate, an acute administration of terbutaline also reduced the force-generating capacity during fused tetanic contractions. The magnitude of the decline in tetanic torque responses induced by terbutaline ingestion does not seem compatible with the unaltered MVC torque. It must, however, be acknowledged that the pattern of motor unit recruitment is considerably different between electrically evoked and voluntary contractions (3), so the possibility exists that the quadriceps femoris subpopulation of muscle fibers activated by submaximal tetanic stimulation were not reflective of the quasi-entire pool activated during MVC trials. In addition, we cannot exclude the possibility that some aspects of peripheral nerve activation and/or neuromuscular transmission during fused tetanic contractions were impaired by terbutaline administration, although M-waves evoked by single stimulation of the femoral nerve were unaffected. Given that the human central nervous system hardly drives skeletal muscles at 100 Hz but instead involves lower frequencies of activation (21), we hypothesized that the neural drive to the knee extensor muscles was able to maintain force during MVC because it does not work at a high enough rates to be affected by terbutaline.

The action of β2-agonists on voluntary strength has been investigated in several studies using a variety of protocols (16,17,44). Most of them have used isometric contractions to assess MVC force, and in accord with the present findings, no significant effect of β2-agonists was reported (16,17). β2-Agonists may also improve the voluntary force-generating capacity through a stimulatory effect on the central nervous system (14,36). Indeed, β2-agonists have an antidepressant action probably due to enhanced brain serotonin turnover (23,42). However, consistent with previous studies (16,17), the degree of voluntary activation of the knee extensor muscles during MVC is not increased by terbutaline, thus excluding any “excitatory” effect on the central nervous system.

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Effects of Terbutaline on Neuromuscular Function after Fatigue

β2-Adrenergic agonists have been shown to improve fatigue resistance and force recovery in isolated animal skeletal muscles and fibers bundles (9,27,29,35). The force potentiation of fatigued muscles is related to the repolarization of the membrane potential through enhanced Na+-K+ pump activity and/or increased sarcoplasmic reticulum Ca2+ release (9,29,35). Conversely, as demonstrated by the present results obtained in a human muscle, terbutaline ingestion did not potentiate twitch torque neither in fatigue condition nor after recovery. In animal models, however, the above-mentioned effects were observed in severely fatigued muscles (i.e., >50% loss of tetanic force) because of high-frequency electrical stimulation (9,29) or in muscle fibers previously immersed in an hyperkalemic medium (27), therefore raising doubts about the physiological relevance of these findings. It is well known that high-frequency electrical stimulation mainly impairs sarcolemma excitability (10), which is not a prerequisite of skeletal muscle fatigue in humans. The unaltered postfatigue M-wave amplitude and area we found exclude a loss of sarcolemma excitability and/or action potential propagation failure.

After fatigue, twitch −dT/dt declined for both treatments, largely because of diminished Ca2+ uptake by the sarcoplasmic reticulum and/or slowed cross-bridge detachment (25). Under fatigue conditions, metabolic perturbations (including increased intracellular concentrations of H+, ADP, and Pi and decreased muscle ATP availability) could slow Ca2+ uptake rates and cross-bridge cycling (19,20). Postfatigue twitch −dT/dt did not differ between treatments, suggesting that, during severe exercise, changes in metabolic factors may have blunted the positive lusitropic effect elicited by terbutaline. Furthermore, the fatigue protocol would have raised the sympathetic activation in both conditions (45), which mainly acts through β2-adrenergic receptors (37,39), thus matching the positive lusitropic action of terbutaline. After the recovery period, however, −dT/dt was higher in terbutaline condition compared with placebo. It is unlikely that terbutaline resolved the metabolic perturbations because no effect on the recovery of twitch torque was shown compared with placebo. Instead, it is more likely that sympathetic outflow would have reached the basal level after 30 min of recovery for both treatments (40), thus reducing its action on the β2-adrenergic receptors and, consequently, unmasking the effect of terbutaline on relaxation rate.

The postexercise decline in P10/P100 ratio in both terbutaline and placebo conditions is indicative of low-frequency fatigue. Low-frequency fatigue has previously been related to disturbance of excitation–contraction coupling, which results in a reduction in the amount of Ca2+ released from sarcoplasmic reticulum (2). By virtue of the sigmoidal shape of the [Ca2+]i–tension relationship, this effect is more pronounced at low stimulation frequencies. Although postfatigue −dT/dt was identical for the two treatments, the torque of both unfused and fused tetanic responses was lower in terbutaline condition. This finding is in contrast with a recent report from our laboratory, where an acute administration of salbutamol prevented tetanic (20 Hz) force decline after intermittent high-frequency electrical stimulation of the quadriceps muscle (17). Such result suggested that during fatigue, when Ca2+ release is thought to be impaired, salbutamol could preserve tetanic force by maintaining Ca2+ handling (17). Bearing in mind the different experimental procedures used in our previous study and in the present investigation, the current findings support the contention that acute terbutaline administration exerts a weakening action on the submaximal contractions evoked by electrical muscle stimulation. This weakening action, nevertheless, did not impair the maximal voluntary force generation capacity of the knee extensors in the fatigued state.

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Vastus lateralis.

The EMG activity recorded during the submaximal intermittent voluntary contractions increased linearly through the entire fatigue protocol in each of the two conditions. This suggests that the central motor drive to the fatigued vastus lateralis muscle was progressively augmented to maintain the target torque, essentially because of additional recruitment and/or increased discharge rate of motor units (1). Despite terbutaline administration affected tension-generating capacity of both unfused and fused tetanus, mainly as a consequence of the increased rate of torque relaxation, central motor drive to the muscle was similar in both treatments. This indicates that the weakening action induced by terbutaline on the contractile machinery during submaximal stimulated contractions did not apparently require any compensatory adjustment of the central nervous system to maintain a constant torque during a submaximal voluntary contraction. Nevertheless, the progressive increase of quadriceps muscle force more than 30% MVC levels relies, beside the progressive increase of the motor unit recruitment, even on a higher discharge rate of the active motor units (15). It is therefore likely that, at 50% MVC, motor unit discharge rate would be sufficiently elevated to compensate for the weakening effect of terbutaline. Consequently, terbutaline administration did not augment in any way the degree of muscle fatigue compared with placebo, as also confirmed by similar postexercise reductions in both MVC torque and voluntary activation in the two conditions.

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Technical Considerations

We used surface EMG to estimate central motor drive to the quadriceps femoris muscle during the fatigue protocol. It is important to acknowledge that many physiological but also nonphysiological factors can influence the amplitude of the interference EMG signal, thus compromising its validity (22,24). For example, in this study, participants completed the two experimental sessions on different days. The surface EMG signal is variable, and replacing the EMG electrodes on separate occasions could introduce a significant bias. For this reason, we took some precautions to minimize day-to-day fluctuations in EMG recordings. First, the position of the EMG electrodes was marked on the skin to ensure that sensors were placed in the same locations during the two experimental sessions. Second, submaximal EMG activity was normalized to the maximal EMG activity obtained in the same conditions, thus minimizing the influence of factors that contribute to signal variation between measurements performed over different days (32).

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Functional Implications

The present results do not provide evidence of an ergogenic action induced by β2-agonists on the skeletal muscle contractility, neither before nor after fatiguing exercise. Conversely, our data support the hypothesis of a weakening effect on the contractile function of the human quadriceps muscle during submaximal contractions evoked by electrical stimulation, as recently demonstrated for the soleus muscle (16). Although the expression of a positive lusitropic effect, which results in muscle weakening, hardly complies with the numerous studies reporting increased physical performance after an administration of β2-agonists (12,14,31,44), there are potential explanations. First, during exercise entailing moderate- to high-intensity contractions, motor unit discharge rate would be sufficiently elevated to compensate for the weakening effect of terbutaline on the contractile machinery, thus leaving force generation capacity unaffected by the action of β2-agonists. Second, the faster relaxation rate of the muscle induced by terbutaline could improve the switch between agonist–antagonist muscles in rapid alternating movements. However, this would only be effective for short-lasting exercise because physiological changes occurring with severe fatigue, including metabolic perturbations and a greater sympathetic activation, could abolish the lusitropic effect. On this basis, it is not surprising that improvements in physical performance after an administration of β2-agonists were essentially observed for anaerobic and explosive tasks, such as the Wingate test (14,31).

In summary, an acute oral administration of terbutaline (8 mg) altered the contractile function of the knee extensor muscles during electrically evoked contractions, regardless of the fatigue state. The increased muscle relaxation rate induced by terbutaline in the nonfatigued state was blunted by severe fatigue. Furthermore, terbutaline ingestion reduced tetanic torque in both prefatigue and postfatigue conditions. However, these terbutaline-induced alterations in muscle contractility did not impair the maximal voluntary force generation capacity, did not result in any compensatory adjustments of the central nervous system during the voluntary exercise, and did not increase muscle fatigue of the knee extensors.

The authors thank the subjects for their committed participation.

They declare no conflict of interest. No funding was received for this work.

The results of the present study do not constitute endorsement by the American College of Sports Medicine.

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1. Adam A, De Luca CJ. Firing rates of motor units in human vastus lateralis muscle during fatiguing isometric contractions. J Appl Physiol. 2005; 99 (1): 268–80.

2. Allen DG, Westerblad H, Lee JA, Lannergren J. Role of excitation–contraction coupling in muscle fatigue. Sports Med. 1992; 13 (2): 116–26.

3. Bickel CS, Gregory CM, Dean JC. Motor unit recruitment during neuromuscular electrical stimulation: a critical appraisal. Eur J Appl Physiol. 111 (10): 2399–407.

4. Bigland-Ritchie B, Jones DA, Woods JJ. Excitation frequency and muscle fatigue: electrical responses during human voluntary and stimulated contractions. Exp Neurol. 1979; 64 (2): 414–27.

5. Bowman WC. Effects of adrenergic activators and inhibitors on the skeletal muscles. In: Szekeres L, editor. Handbook of Experimental Pharmacology. New York: Springer; 1980. p. 47–128.

6. Bowman WC, Zaimis E. The effects of adrenaline, noradrenaline and isoprenaline on skeletal muscle contractions in the cat. J Physiol. 1958; 144 (1): 92–107.

7. Cairns SP, Dulhunty AF. Beta-adrenergic potentiation of E-C coupling increases force in rat skeletal muscle. Muscle Nerve. 1993; 16 (12): 1317–25.

8. Cairns SP, Dulhunty AF. The effects of beta-adrenoceptor activation on contraction in isolated fast- and slow-twitch skeletal muscle fibres of the rat. Br J Pharmacol. 1993; 110 (3): 1133–41.

9. Cairns SP, Dulhunty AF. Beta-adrenoceptor activation shows high-frequency fatigue in skeletal muscle fibers of the rat. Am J Physiol. 1994; 266 (5 Pt 1): C1204–9.

10. Cairns SP, Taberner AJ, Loiselle DS. Changes of surface and t-tubular membrane excitability during fatigue with repeated tetani in isolated mouse fast- and slow-twitch muscle. J Appl Physiol. 2009; 106 (1): 101–12.

11. Cairns SP, Westerblad H, Allen DG. Changes of tension and [Ca2+]i during beta-adrenoceptor activation of single, intact fibres from mouse skeletal muscle. Pflugers Arch. 1993; 425 (1–2): 150–5.

12. Collomp K, Candau R, Collomp R, et al. Effects of acute ingestion of salbutamol during submaximal exercise. Int J Sports Med. 2000; 21 (7): 480–4.

13. Collomp K, Candau R, Millet G, et al. Effects of salbutamol and caffeine ingestion on exercise metabolism and performance. Int J Sports Med. 2002; 23 (8): 549–54.

14. Collomp K, Le Panse B, Portier H, et al. Effects of acute salbutamol intake during a Wingate test. Int J Sports Med. 2005; 26 (7): 513–7.

15. Conwit RA, Tracy B, Cowl A, et al. Firing rate analysis using decompostion-enhanced spike triggered averaging in the quadriceps femoris. Muscle Nerve. 1998; 21 (10): 1338–40.

16. Crivelli G, Borrani F, Capt R, Gremion G, Maffiuletti NA. Actions of beta2-adrenoceptor agonist drug on human soleus muscle contraction. Med Sci Sports Exerc. 2013; 45 (7): 1252–60.

17. Crivelli G, Millet GP, Gremion G, Borrani F. Effects of salbutamol on the contractile properties of human skeletal muscle before and after fatigue. Acta Physiol (Oxf). 2011; 203 (2): 311–20.

18. Davies DS. Pharmacokinetics of terbutaline after oral administration. Eur J Respir Dis Suppl. 1984; 134: 111–7.

19. Dawson MJ, Gadian DG, Wilkie DR. Mechanical relaxation rate and metabolism studied in fatiguing muscle by phosphorus nuclear magnetic resonance. J Physiol. 1980; 299: 465–84.

20. Edwards RH, Hill DK, Jones DA. Metabolic changes associated with the slowing of relaxation in fatigued mouse muscle. J Physiol. 1975; 251 (2): 287–301.

21. Enoka RM, Fuglevand AJ. Motor unit physiology: some unresolved issues. Muscle Nerve. 2001; 24 (1): 4–17.

22. Enoka RM, Stuart DG. Neurobiology of muscle fatigue. J Appl Physiol. 1992; 72 (5): 1631–48.

23. Erdo SL, Kiss B, Rosdy B. Effect of salbutamol on the cerebral levels, uptake and turnover of serotonin. Eur J Pharmacol. 1982; 78 (3): 357–61.

24. Farina D, Merletti R, Enoka RM. The extraction of neural strategies from the surface EMG. J Appl Physiol. 2004; 96 (4): 1486–95.

25. Gollnick PD, Korge P, Karpakka J, Saltin B. Elongation of skeletal muscle relaxation during exercise is linked to reduced calcium uptake by the sarcoplasmic reticulum in man. Acta Physiol Scand. 1991; 142 (1): 135–6.

26. Ha TN, Posterino GS, Fryer MW. Effects of terbutaline on force and intracellular calcium in slow-twitch skeletal muscle fibres of the rat. Br J Pharmacol. 1999; 126 (8): 1717–24.

27. Hansen AK, Clausen T, Nielsen OB. Effects of lactic acid and catecholamines on contractility in fast-twitch muscles exposed to hyperkalemia. Am J Physiol Cell Physiol. 2005; 289 (1): C104–12.

28. Johnson MA, Polgar J, Weightman D, Appleton D. Data on the distribution of fibre types in thirty-six human muscles. An autopsy study. J Neurol Sci. 1973; 18 (1): 111–29.

29. Juel C. The effect of beta 2-adrenoceptor activation on ion-shifts and fatigue in mouse soleus muscles stimulated in vitro. Acta Physiol Scand. 1988; 134 (2): 209–16.

30. Kufel TJ, Pineda LA, Mador MJ. Comparison of potentiated and unpotentiated twitches as an index of muscle fatigue. Muscle Nerve. 2002; 25 (3): 438–44.

31. Le Panse B, Arlettaz A, Portier H, Lecoq AM, De Ceaurriz J, Collomp K. Effects of acute salbutamol intake during supramaximal exercise in women. Br J Sports Med. 2007; 41 (7): 430–4.

32. Lehman GJ, McGill SM. The importance of normalization in the interpretation of surface electromyography: a proof of principle. J Manipulative Physiol Ther. 1999; 22 (7): 444–6.

33. Marsden CD, Meadows JC. The effect of adrenaline on the contraction of human muscle. J Physiol. 1970; 207 (2): 429–48.

34. Merton PA. Voluntary strength and fatigue. J Physiol. 1954; 123 (3): 553–64.

35. Mikkelsen UR, Gissel H, Fredsted A, Clausen T. Excitation-induced cell damage and beta2-adrenoceptor agonist stimulated force recovery in rat skeletal muscle. Am J Physiol Regul Integr Comp Physiol. 2006; 290 (2): R265–72.

36. Price AH, Clissold SP. Salbutamol in the 1980s. A reappraisal of its clinical efficacy. Drugs. 1989; 38 (1): 77–122.

37. Roatta S, Arendt-Nielsen L, Farina D. Sympathetic-induced changes in discharge rate and spike-triggered average twitch torque of low-threshold motor units in humans. J Physiol. 2008; 586 (Pt 22): 5561–74.

38. Roatta S, Farina D. Sympathetic actions on the skeletal muscle. Exerc Sport Sci Rev. 2010; 38 (1): 31–5.

39. Roatta S, Farina D. Sympathetic activation by the cold pressor test does not increase the muscle force generation capacity. J Appl Physiol. 2011; 110 (6): 1526–33.

40. Rostrup M, Westheim A, Refsum HE, Holme I, Eide I. Arterial and venous plasma catecholamines during submaximal steady-state exercise. Clin Physiol. 1998; 18 (2): 109–15.

41. Sedliak M, Finni T, Cheng S, Haikarainen T, Hakkinen K. Diurnal variation in maximal and submaximal strength, power and neural activation of leg extensors in men: multiple sampling across two consecutive days. Int J Sports Med. 2008; 29 (3): 217–24.

42. Simon P, Lecrubier Y, Jouvent R, Puech A, Widlocher D. Beta-receptor stimulation in the treatment of depression. Adv Biochem Psychopharmacol. 1984; 39: 293–9.

43. Strojnik V, Komi PV. Neuromuscular fatigue after maximal stretch-shortening cycle exercise. J Appl Physiol. 1998; 84 (1): 344–50.

44. van Baak MA, Mayer LH, Kempinski RE, Hartgens F. Effect of salbutamol on muscle strength and endurance performance in nonasthmatic men. Med Sci Sports Exerc. 2000; 32 (7): 1300–6.

45. Zouhal H, Jacob C, Delamarche P, Gratas-Delamarche A. Catecholamines and the effects of exercise, training and gender. Sports Med. 2008; 38 (5): 401–23.



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