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Due to a high prevalence of asthma and exercise‐induced bronchoconstriction in elite athletes, there is a high use of beta2‐adrenoceptor agonists (beta2‐agonists) in the athletic population. While anabolic in rodents, no study has been able to detect hypertrophy in humans after chronic beta2‐agonist inhalation. We investigated whether inhaled beta2‐agonist, terbutaline, alters body composition and metabolic rate with and without concurrent exercise training in healthy young men. Sixty‐seven participants completed a 4‐week intervention of daily terbutaline (8 × 0.5 mg) or placebo treatment without concurrent training (habitual; n = 23), with resistance (n = 23) or endurance (n = 21) training 3 times weekly. Before and after the interventions, participant's body composition was determined by dual‐energy X‐ray absorptiometry and resting metabolic rate and substrate oxidation by indirect calorimetry. Terbutaline increased lean body mass by 1.03 kg (95% CI 0.29‐1.76; P < .05) and 1.04 kg (95% CI 0.16‐1.93; P < .05) compared to placebo in the habitual and resistance training group, respectively, but had no effect compared to placebo in the endurance training group [−0.56 kg (95% CI −1.74‐0.62; P > .05)]. Fat mass, bone mineral content, and resting metabolic rate did not change differently between treatments with the intervention. Daily inhalation of terbutaline in near‐therapeutic doses induces skeletal muscle growth. This observation should be a concern for antidoping authorities. [ABSTRACT FROM AUTHOR]

Key points: Low‐volume high‐intensity exercise training promotes muscle mitochondrial adaptations that resemble those associated with high‐volume moderate‐intensity exercise training. These training‐induced mitochondrial adaptations stem from the cumulative effects of transient transcriptional responses to each acute exercise bout. However, whether metabolic stress is a key mediator of the acute molecular responses to high‐intensity exercise is still incompletely understood. Here we show that, by comparing different work‐matched low‐volume high‐intensity exercise protocols, more marked metabolic perturbations were associated with enhanced mitochondrial biogenesis‐related muscle mRNA responses. Furthermore, when compared with high‐volume moderate‐intensity exercise, only the low‐volume high‐intensity exercise eliciting severe metabolic stress compensated for reduced exercise volume in the induction of mitochondrial biogenic mRNA responses. The present results, besides improving our understanding of the mechanisms mediating exercise‐induced mitochondrial biogenesis, may have implications for applied and clinical research that adopts exercise as a means to increase muscle mitochondrial content and function in healthy or diseased individuals. Abstract: The aim of the present study was to examine the impact of exercise‐induced metabolic stress on regulation of the molecular responses promoting skeletal muscle mitochondrial biogenesis. Twelve endurance‐trained men performed three cycling exercise protocols characterized by different metabolic profiles in a randomized, counter‐balanced order. Specifically, two work‐matched low‐volume supramaximal‐intensity intermittent regimes, consisting of repeated‐sprint (RS) and speed endurance (SE) exercise, were employed and compared with a high‐volume continuous moderate‐intensity exercise (CM) protocol. Vastus lateralis muscle samples were obtained before, immediately after, and 3 h after exercise. SE produced the most marked metabolic perturbations as evidenced by the greatest changes in muscle lactate and pH, concomitantly with higher post‐exercise plasma adrenaline levels in comparison with RS and CM. Exercise‐induced phosphorylation of CaMKII and p38 MAPK was greater in SE than in RS and CM. The exercise‐induced PGC‐1α mRNA response was higher in SE and CM than in RS, with no difference between SE and CM. Muscle NRF‐2, TFAM, MFN2, DRP1 and SOD2 mRNA content was elevated to the same extent by SE and CM, while RS had no effect on these mRNAs. The exercise‐induced HSP72 mRNA response was larger in SE than in RS and CM. Thus, the present results suggest that, for a given exercise volume, the initial events associated with mitochondrial biogenesis are modulated by metabolic stress. In addition, high‐intensity exercise seems to compensate for reduced exercise volume in the induction of mitochondrial biogenic molecular responses only when the intense exercise elicits marked metabolic perturbations. [ABSTRACT FROM AUTHOR]

While chronic systemic administration of glucocorticoids increases muscle Na+,K+ ATPase content, such effect is unexplored after therapeutic inhalation. We investigated the effect of therapeutic inhalation of the glucocorticoid budesonide on Na+,K+ ATPase content of skeletal muscle in men. Ten healthy trained subjects, aged 23 ± 4 years (mean ± 95% CI), participated in the study. Before and after 2 weeks of daily inhalation of budesonide (1.6 mg/day), a biopsy was taken from the vastus lateralis muscle for measurement of Na+,K+ ATPase content and blood samples were drawn for determination of plasma budesonide, cortisol, and K+. Subjects' performance during cycling to fatigue at 90% of incremental peak power output ( iPPO) was measured in response to 4 mg inhaled terbutaline to maximally stimulate Na+,K+ ATPase activity. Plasma concentrations of budesonide rose to 5.0 ± 1.6 nM with the intervention, whereas no changes were observed in plasma cortisol. Muscle Na+,K+ ATPase content increased ( P ≤ 0.01) by 46 ± 34 pmol/(g wet wt) (17% increase) with the intervention. Cycling performance at 90% of iPPO did not change ( P = 0.21) with the intervention (203 vs 214 s) in response to terbutaline. The present observations show that therapeutic inhalation of glucocorticoids increases muscle Na+,K+ ATPase content, but does not enhance high-intensity cycling endurance in response to terbutaline. [ABSTRACT FROM AUTHOR]

This study investigated the pharmacokinetics of inhaled terbutaline at rest and after exercise in normal and hot ambient conditions with respect to doping analysis. Thirteen trained young men participated in the study. Urine and blood samples were collected after inhalation of 4 mg terbutaline during three trials: exercise in hot ambient conditions (30-35 °C) ( EXH), exercise in normal ambient conditions (20-25 °C) ( EX), and rest (20-25 °C) (R). Exercise consisted of 130 min at various intensities. Adjustment of urine concentrations of terbutaline to a specific gravity ( USG) of 1.02 g/mL was compared with no adjustment. Area under the serum concentration-time curve within the first 6 h was higher for EX (27 ± 3 ng/mL/h) ( P ≤ 0.01) and EXH (25 ± 4 ng/mL/h) ( P ≤ 0.05) than for R (20 ± 3 ng/mL/h). When unadjusted for USG, urine concentrations of terbutaline after 4 h were different in the order EXH > EX > R ( P ≤ 0.01). When unadjusted for USG, urine concentrations of terbutaline were 299 ± 151 ng/mL higher ( P ≤ 0.001) after 4 h compared with adjusted concentrations in EXH. Excretion rate of terbutaline was higher ( P ≤ 0.001) for EX than for EXH and R within the first 0-1½ h. In conclusion, EXHs results in higher urine concentrations of terbutaline. This should be considered when evaluating doping cases of terbutaline. [ABSTRACT FROM AUTHOR]

Key points From animal models, it is well established that β2-adrenergic stimulation increases contractile force, rates of Ca2+ release and uptake from the sarcoplasmic reticulum, and Na+-K+-ATPase activity of skeletal muscles. However, these effects are unexplored in humans., Here we report that β2-adrenergic stimulation with the high dose selective β2-adrenoceptor agonist terbutaline elicits positive inotropic and lusitropic effects on non-fatigued m. quadriceps that are associated with enhanced rates of Ca2+ release and uptake from the sarcoplasmic reticulum in trained men., However, we also observed that the positive inotropic and lusitropic effects of β2-adrenergic stimulation on m. quadriceps were blunted when muscle fatigue developed., Furthermore, we show that β2-adrenergic stimulation counteracts exercise-induced reductions in Na+-K+-ATPase Vmax (maximum rate of activity) and elevates glycolytic activity during high intensity exercise., These findings are important for our understanding of the role of β2-adreceptor activation in regulation of ion handling and contractile properties of non-fatigued and fatigued skeletal muscles in humans., Abstract The aim of the present study was to examine the effect of β2-adrenergic stimulation on skeletal muscle contractile properties, sarcoplasmic reticulum (SR) rates of Ca2+ release and uptake, and Na+-K+-ATPase activity before and after fatiguing exercise in trained men. The study consisted of two experiments (EXP1, n = 10 males, EXP2, n = 20 males), where β2-adrenoceptor agonist (terbutaline) or placebo was randomly administered in double-blinded crossover designs. In EXP1, maximal voluntary isometric contraction (MVC) of m. quadriceps was measured, followed by exercise to fatigue at 120% of maximal oxygen uptake ( [ABSTRACT FROM AUTHOR]

There is a high prevalence of asthma and airway hyperresponsiveness (AHR) in elite athletes, which leads to a major use of beta2-agonists. In a randomized double-blinded crossover study, we investigated the effects of combined inhalation of beta2-agonists (salbutamol, formoterol, and salmeterol), in permitted doses within the World Anti-Doping Agency 2013 prohibited list, in elite swimmers with (AHR, n = 13) or without (non-AHR, n = 17) AHR. Maximal voluntary isometric contraction of m. quadriceps (MVC), sprint performance on a swim ergometer and performance in an exhaustive swim test at 110% of VO2max were determined. Venous plasma interleukin-6 (IL-6) and interleukin-8 (IL-8) were measured post-exercise. No improvement was observed in the exhaustive swim test, but swim ergometer sprint time was improved (P < 0.05) in both groups from 57 ± 1.7 to 56 ± 1.8 s in AHR and 58.3 ± 1 to 57.4 ± 1 s in non-AHR. MVC and post-exercise plasma IL-6 increased (P < 0.05) with beta2-agonists in both groups, whereas IL-8 only increased in AHR. In summary, inhalation of beta2-agonists, in permitted doses, did not improve swim performance in elite swimmers. However, swim ergometer sprint performance and MVC were increased, which should be considered when making future anti-doping regulations. [ABSTRACT FROM AUTHOR]

Skeletal muscle mass plays a pivotal role in metabolic function, but conditions such as bed rest or injury often render resistance training impractical. The beta 2 -adrenergic receptor has been highlighted as a potential target to promote muscle hypertrophy and treat atrophic conditions. Here, we investigate the proteomic changes associated with beta 2 -adrenergic-mediated muscle hypertrophy, using resistance training as a hypertrophic comparator. We utilize MS-based proteomics to map skeletal muscle proteome remodeling in response to beta 2 -adrenergic stimulation or resistance training as well as cell model validation. We report that beta 2 -adrenergic stimulation mimics multiple features of resistance training in proteome-wide remodeling, comprising systematic upregulation of ribosomal subunits and concomitant downregulation of mitochondrial proteins. Approximately 20% of proteins were regulated in both conditions, comprising proteins involved in steroid metabolism (AKR1C1, AKR1C2, AKRC1C3), protein-folding (SERPINB1), and extracellular matrix organization (COL1A1, COL1A2). Among overall most significantly upregulated proteins were kelch-like family members (KLHL) 40 and 41. In follow-up experiments, we identify KLHL41 as having novel implications for beta 2 -adrenergic-mediated muscle hypertrophy. Treating C2C12 cells with beta 2 -agonist for 96 h increased myotube diameter by 48% (p < 0.001). This anabolic effect was abolished by prior knockdown of KLHL41. Using siRNA, KLHL41 abundance was decreased by 60%, and the anabolic response to beta 2 -agonist was diminished (+ 15%, i.e., greater in the presence of KLHL41, knock-down × treatment: p = 0.004). In conclusion, protein-wide remodeling induced by beta 2 -adrenergic stimulation mimics multiple features of resistance training, and thus the beta 2 -adrenergic receptor may be a target with therapeutic potential in the treatment of muscle wasting conditions without imposing mechanical load., (© 2024 The Author(s). Scandinavian Journal of Medicine & Science In Sports published by John Wiley & Sons Ltd.)

Purpose: We investigated the effects of low- and high-volume speed endurance training (SET), with a reduced training volume, on sprint ability, short- and long-term exercise capacity, muscle mitochondrial properties, ion transport proteins, and maximal enzyme activity in highly trained athletes., Methods: Highly trained male cyclists (maximal oxygen consumption (V̇O 2max ): 68.3 ± 5.0 mL·min -1 ·kg -1 , n = 24) completed 6 wk of either low (SET-L; 6 × 30-s intervals, n = 8) or high (SET-H; 12 × 30-s intervals, n = 8) volume SET twice per week with a 30% reduction in training volume. A control group (CON; n = 8) maintained their training. Exercise performance was evaluated by i) 6-s sprinting, ii) a 4-min time trial, and iii) a 60-min preload at 60% V̇O 2max followed by a 20-min time trial. A biopsy of m. vastus lateralis was collected before and after the training intervention., Results: In SET-L, 4-min time trial performance was improved ( P < 0.05) by 3.8%, with no change in SET-H and CON. Sprint ability, prolonged endurance exercise capacity, V̇O 2max , muscle mitochondrial respiratory capacity, maximal citrate synthase activity, fiber type-specific mitochondrial proteins (complexes I-V), and phosphofructokinase (PFK) content did not change in any of the groups. In SET-H, maximal activity of muscle PFK and abundance of Na + -K + pump-subunit α 1 , α 2 , β 1 , and phospholemman (FXYD1) were 20%, 50%, 19%, 24%, and 42% higher ( P < 0.05), respectively after compared with before the intervention, with no changes in SET-L or CON., Conclusions: Low SET volume combined with a reduced aerobic low- and moderate-intensity training volume does improve short-duration intense exercise performance and maintain sprinting ability, V̇O 2max , endurance exercise performance, and muscle oxidative capacity, whereas, high volume of SET seems necessary to upregulate muscle ion transporter content and maximal PFK activity in highly trained cyclists., (Copyright © 2024 by the American College of Sports Medicine.)

Salbutamol is a common short-acting beta 2 -adrenergic agonist used in treatment of asthma and exercise-induced bronchoconstriction but also possesses anabolic and metabolic actions in skeletal muscle. As a chiral compound, salbutamol is a racemic 1:1 mixture of two enantiomers, (R)-salbutamol and (S)-salbutamol, which exhibit divergent pharmacokinetic and pharmacodynamic actions. Despite salbutamol being available for decades, information on the enantioselective disposition of salbutamol enantiomers in human skeletal muscle is absent. In this study, we determined concentrations of (R)-salbutamol and (S)-salbutamol by UHPLC-MS/MS in arterial plasma and vastus lateralis muscle samples from 12 lean young men 2½ and 7 h following ingestion of 24 mg oral salbutamol. Mean (range) arterial plasma concentrations were 10-fold higher (p < 0.001) for (S)-salbutamol than (R)-salbutamol, being 33(9-62) and 49(30-84) ng·mL -1 for (S)-salbutamol and 4 (1-6) and 4 (2-5) ng·mL -1 for (R)-salbutamol 2½ and 7 h following administration, respectively, reflecting faster elimination of the (R)-enantiomer. Mean (range) muscle concentrations were higher (p < 0.001) for (S)-salbutamol than (R)-salbutamol 2½ h (0.17 [0.1-0.26] vs. 0.04 [0.02-0.06]) and 7 h (0.31 [0.21-0.46] vs. 0.06 [0.04-0.12] ng·mg d.w. -1 ) after administration. However, muscle:plasma partition coefficient was two-fold higher (p < 0.001) for (R)-salbutamol than (S)-salbutamol 7 h following administration. These observations demonstrate that oral salbutamol exhibits enantioselective disposition in systemic circulation and muscle favoring the (S)-enantiomer but with higher relative partitioning of the (R)-enantiomer in skeletal muscle. Furthermore, the concentration-time profiles of salbutamol enantiomers are different in skeletal muscle and systemic circulation following oral ingestion. These findings have implications for the application of chiral switch (R)-salbutamol in doping control., (© 2024 The Author(s). Drug Testing and Analysis published by John Wiley & Sons Ltd.)

While it is well-established that a period of interval training performed at near maximal effort, such as speed endurance training (SET), enhances intense exercise performance in well-trained individuals, less is known about its effect on cardiac morphology and function as well as blood volume. To investigate this, we subjected 12 Under-20 Danish national team ice hockey players (age 18 ± 1 years, mean ± SD) to 4 weeks of SET, consisting of 6-10 × 20 s skating bouts at maximal effort interspersed by 2 min of recovery conducted three times weekly. This was followed by 4 weeks of regular training (follow-up). We assessed resting cardiac function and dimensions using transthoracic echocardiography and quantified total blood volume with the carbon monoxide rebreathing technique at three time points: before SET, after SET and after the follow-up period. After SET, stroke volume had increased by 10 (2-18) mL (mean (95% CI)), left atrial end-diastolic volume by 10 (3-17) mL, and circumferential strain improved by 0.9%-points (1.7-0.1) (all P < 0.05). At follow-up, circumferential strain and left atrial end-diastolic volume were reverted to baseline levels, while stroke volume remained elevated. Blood volume and morphological parameters for the left ventricle, including mass and end-diastolic volume, did not change during the study. In conclusion, our findings demonstrate that a brief period of SET elicits beneficial central cardiac adaptations in elite ice hockey players independent of changes in blood volume., (© 2024 The Author(s). Experimental Physiology published by John Wiley & Sons Ltd on behalf of The Physiological Society. This is an open access article under the terms of the Creative Commons Attribution License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.)

Context: Given the promising effects of prolonged treatment with beta2-agonist on insulin sensitivity in animals and non-diabetic individuals, the beta2-adrenergic receptor has been proposed as a target to counter peripheral insulin resistance. On the other hand, rodent studies also reveal that beta2-agonists acutely impair insulin action, posing a potential caveat for their use in treating insulin resistance., Objective: To assess the impact of beta2-agonist on muscle insulin action and glucose metabolism and identify the underlying mechanism(s) in 10 insulin-resistant subjects., Methods and Participants: In a cross-over design, we assessed the effect of beta2-agonist on insulin-stimulated muscle glucose uptake during a 3-h hyperinsulinemic isoglycemic clamp with and without intralipid infusion in 10 insulin-resistant overweight subjects. Two hours into the clamp, we infused beta2-agonist. We collected muscle biopsies before, two hours into and by the end of the clamp and analyzed them using metabolomic and lipidomic techniques., Results: We establish that beta2-agonist, independently from and additively to intralipid, impairs insulin-stimulated muscle glucose uptake via different mechanisms. In combination, beta2-agonist and intralipid nearly eliminates insulin-dependent muscle glucose uptake. While both beta2-agonist and intralipid elevated muscle glucose-6-phosphate, only intralipid caused accumulation of downstream muscle glycolytic intermediates, whereas beta2-agonist attenuated incorporation of glucose into glycogen., Conclusions: Our findings suggest that beta2-agonist inhibits glycogenesis while intralipid inhibits glycolysis in skeletal muscle of insulin-resistant individuals. These results should be addressed in future treatment of insulin resistance with beta2-agonist., (© The Author(s) 2024. Published by Oxford University Press on behalf of the Endocrine Society. All rights reserved. For commercial re-use, please contact reprints@oup.com for reprints and translation rights for reprints. All other permissions can be obtained through our RightsLink service via the Permissions link on the article page on our site—for further information please contact journals.permissions@oup.com. See the journal About page for additional terms.)

Background: Athletes commonly use creatine, caffeine, and sodium bicarbonate for performance enhancement. While their isolated effects are well-described, less is known about their potential additive effects., Methods: Following a baseline trial, we randomized 12 endurance-trained males (age: 25 ± 5 years, VO 2max : 56.7 ± 4.6 mL kg -1  min -1 ; mean ± SD) and 11 females (age: 25 ± 3 years, VO 2max : 50.2 ± 3.4 mL kg -1  min -1 ) to 5 days of creatine monohydrate (0.3 g kg -1  per day) or placebo loading, followed by a daily maintenance dose (0.04 g kg -1 ) throughout the study. After the loading period, subjects completed four trials in randomized order where they ingested caffeine (3 mg kg -1 ), sodium bicarbonate (0.3 g kg -1 ), placebo, or both caffeine and sodium bicarbonate before a maximal voluntary contraction (MVC), 15-s sprint, and 6-min time trial., Results: Compared to placebo, mean power output during 15-s sprint was higher following loading with creatine than placebo (+34 W, 95% CI: 10 to 58, p = 0.008), but with no additional effect of caffeine (+10 W, 95% CI: -7 to 24, p = 0.156) or sodium bicarbonate (+5 W, 95% CI: -4 to 13, p = 0.397). Mean power output during 6-min time trial was higher with caffeine (+12 W, 95% CI: 5 to 18, p = 0.001) and caffeine + sodium bicarbonate (+8 W, 95% CI: 0 to 15, p = 0.038), whereas sodium bicarbonate (-1 W, 95% CI: -7 to 6, p = 0.851) and creatine (-6 W, 95% CI: -15 to 4, p = 0.250) had no effects., Conclusion: While creatine and caffeine can enhance sprint- and time trial performance, respectively, these effects do not seem additive. Therefore, supplementing with either creatine or caffeine appears sufficient to enhance sprint or short intense exercise performance., (© 2024 The Authors. Scandinavian Journal of Medicine & Science In Sports published by John Wiley & Sons Ltd.)

Given the prevalent use of inhaled beta 2 -agonists in sports, there is an ongoing debate as to whether they enhance athletic performance. Over the last decades, inhaled beta 2 -agonists have been claimed not to enhance performance with little consideration of dose or exercise modality. In contrast, orally administered beta 2 -agonists are perceived as being performance enhancing, predominantly on muscle strength and sprint ability, but can also induce muscle hypertrophy and slow-to-fast fiber phenotypic switching. But because inhaled beta 2 -agonists are more efficient to achieve high systemic concentrations than oral delivery relative to dose, it follows that the inhaled route has the potential to enhance performance too. The question is at which inhaled doses such effects occur. While supratherapeutic doses of inhaled beta 2 -agonists enhance muscle strength and short intense exercise performance, effects at low therapeutic doses are less apparent. However, even high therapeutic inhaled doses of commonly used beta 2 -agonists have been shown to induce muscle hypertrophy and to enhance sprint performance. This is concerning from an anti-doping perspective. In this paper, we raise awareness of the circumstances under which inhaled beta 2 -agonists can constitute a performance-enhancing benefit., (© 2024 The Authors. Scandinavian Journal of Medicine & Science In Sports published by John Wiley & Sons Ltd.)

Purpose: Many athletes use long-acting beta 2 -agonist formoterol in treatment of asthma. However, studies in non-athlete cohorts demonstrate that inhaled formoterol can enhance sprint performance calling into question whether its use in competitive sports should be restricted. We investigated whether formoterol at upper recommended inhaled doses (54 μg) would enhance sprint ability and intense exercise performance in elite cyclists., Methods: Twenty-one male cyclists (V̇O 2max : 70.4 ± 4.3 mL × min -1  × kg -1 , mean ± SD) completed two 6-s all-out sprints followed by 4-min all-out cycling after inhaling either 54 μg formoterol or placebo. We also assessed cyclists' leg muscle mass by dual-energy X-ray absorptiometry and muscle fiber type distribution of vastus lateralis biopsies., Results: Peak and mean power output during the 6-s sprint was 32 W (95% CI, 19-44 W, p < 0.001) and 36 W (95% CI, 24-48 W, p < 0.001) higher with formoterol than placebo, corresponding to an enhancing effect of around 3%. Power output during 4-min all-out cycling was 9 W (95% CI, 2-16 W, p = 0.01) greater with formoterol than placebo, corresponding to an enhancing effect of 2.3%. Performance changes in response to formoterol were unrelated to cyclists' VO 2max and leg lean mass, whereas muscle fiber Type I distribution correlated with change in sprinting peak power in response to formoterol (r 2  = 0.314, p = 0.012)., Conclusion: Our findings demonstrate that an inhaled one-off dose of 54 μg formoterol has a performance-enhancing potential on sprint ability and short intense performance in elite male cyclists, which is irrespective of training status but partly related to muscle fiber type distribution for sprint ability., (© 2023 The Authors. Scandinavian Journal of Medicine & Science In Sports published by John Wiley & Sons Ltd.)

Introduction: Male elite cyclists (average VO 2 -max: 71 mL/min/kg, n = 18) completed 7 weeks of high-intensity interval training (HIT) (3×/week; 4-min and 30-s intervals) during the competitive part of the season. The influence of a maintained or lowered total training volume combined with HIT was evaluated in a two-group design. Weekly moderate-intensity training was lowered by ~33% (~5 h) (LOW, n = 8) or maintained at normal volume (NOR, n = 10). Endurance performance and fatigue resistance were evaluated via 400 kcal time-trials (~20 min) commenced either with or without prior completion of a 120-min preload (including repeated 20-s sprints to simulate physiologic demands during road races)., Results: Time-trial performance without preload was improved after the intervention (p = 0.006) with a 3% increase in LOW (p = 0.04) and a 2% increase in NOR (p = 0.07). Preloaded time-trial was not significantly improved (p = 0.19). In the preload, average power during repeated sprinting increased by 6% in LOW (p < 0.01) and fatigue resistance in sprinting (start vs end of preload) was improved (p < 0.05) in both groups. Blood lactate during the preload was lowered (p < 0.001) solely in NOR. Measures of oxidative enzyme activity remained unchanged, whereas the glycolytic enzyme PFK increased by 22% for LOW (p = 0.02)., Conclusion: The present study demonstrates that elite cyclists can benefit from intensified training during the competitive season both with maintained and lowered training volume at moderate intensity. In addition to benchmarking the effects of such training in ecological elite settings, the results also indicate how some performance and physiological parameters may interact with training volume., (© 2023 The Authors. Scandinavian Journal of Medicine & Science In Sports published by John Wiley & Sons Ltd.)

Athletes often experience lower airway dysfunction, such as asthma and exercise-induced bronchoconstriction (EIB), which affects more than half the athletes in some sports, not least in endurance sports. Symptoms include coughing, wheezing, and breathlessness, alongside airway narrowing, hyperresponsiveness, and inflammation. Early diagnosis and management are essential. Not only because untreated or poorly managed asthma and EIB potentially affects competition performance and training, but also because untreated airway inflammation can result in airway epithelial damage, remodeling, and fibrosis. Asthma and EIB do not hinder performance, as advancements in treatment strategies have made it possible for affected athletes to compete at the highest level. However, practitioners and athletes must ensure that the treatment complies with general guidelines and anti-doping regulations to prevent the risk of a doping sanction because of inadvertently exceeding specified dosing limits. In this review, we describe considerations and challenges in diagnosing and managing athletes with asthma and EIB. We also discuss challenges facing athletes with asthma and EIB, while also being subject to anti-doping regulations., (© 2023 The Authors. Scandinavian Journal of Medicine & Science In Sports published by John Wiley & Sons Ltd.)

Introduction: Many athletes use short-acting inhaled β 2 -agonists multiple times weekly during training sessions to prevent exercise-induced bronchoconstriction, but it is unclear if treatment impairs training outcomes. Herein, we investigated performance adaptations in well-trained females and males training with prior inhalation of salbutamol., Methods: 19 females and 21 males with maximal oxygen uptake ( V ' O 2max ) of 50.5±3.3 and 57.9±4.9 mL·min -1 ·kg -1 , respectively, participated in this double-blinded, placebo-controlled, parallel-group study. We randomised participants to placebo or salbutamol inhalation (800-1600 µg·training day -1 ) for 6 weeks of combined endurance (1× per week) and high-intensity interval training (2× per week). We assessed participants' body composition, V ' O 2max and muscle contractile function, and collected vastus lateralis muscle biopsies., Results: Salbutamol induced a sex-specific loss of whole-body fat mass (sex×treatment: p=0.048) where only salbutamol-treated females had a fat mass reduction compared to placebo (-0.8 kg at 6 weeks; 95% CI: -0.5 to -1.6; p=0.039). Furthermore, salbutamol-treated females exhibited a repartitioning effect, lowering fat mass while gaining lean mass (p=0.011), which was not apparent for males (p=0.303). Salbutamol negatively impacted V ' O 2max in both sexes (treatment main effect: p=0.014) due to a blunted increase in V ' O 2max during the initial 4 weeks of the intervention. Quadriceps contractile strength was impaired in salbutamol-treated females (-39 N·m; 95% CI: -61 to -17; p=0.002) compared to placebo at 6 weeks. Muscle electron transport chain complex I-V abundance increased with salbutamol (treatment main effect: p=0.035), while content of SERCAI, β 2 -adrenoceptor and desmin remained unchanged., Conclusion: Inhaled salbutamol appears to be an effective repartitioning agent in females but may impair aerobic and strength-related training outcomes., Competing Interests: Conflicts of interest: The authors have no conflicting interests., (Copyright ©The authors 2023.)

Objective: To evaluate if high-intensity interval training three times weekly for 12 weeks improves asthma control in overweight, postmenopausal women with uncontrolled, late-onset asthma., Methods: The reported study is a randomized clinical pilot study (www.clinicaltrials.gov; NCT03747211) that compared 12 weeks of high-intensity interval training (spinning) with usual care. The five-question Asthma Control Questionnaire (ACQ-5) was used as primary outcome. Secondary measures included systemic inflammation and inflammation of the airways, body composition, and cardiac function during exercise., Results: We included 12 women with asthma (mean age 65 years (SD 6); mean body mass index 30 kg/m 2 (SD 2)) from whom eight were randomized to exercise and four to control. Baseline ACQ-5 was 1.95 (SD 0.53) in the control group and 2.03 (0.54) in the exercise group. Patients had a mean blood eosinophil level of 0.16 × 10 9 cells/L (SD 0.07) and a mean fraction of exhaled nitric oxide of 23 ppb (SD 25). Mixed models showed that participants in the exercise group reduced their ACQ-5 by 0.55 points (95%CI -1.10 to -0.00; P  = 0.08) compared with the control group. The exercise group significantly reduced their mean body fat percentage (-2.7%; 95%CI -4.5 to -0.8; P  = 0.02), fat mass (-2.8 kg; 95%CI -5.1 to -0.4; P  = 0.044) and android fat mass (-0.33 kg; 95%CI -0.60- -0.06; P  = 0.038). In analyses of cardiac measures, we saw no significant effects on right ventricular function (fractional area change), diastolic function or left ventricular function., Conclusions: Although changes in ACQ-5 were slightly insignificant, these preliminary findings indicate that aerobic exercise training can be used as a means to improve asthma control in overweight, postmenopausal women with asthma., Competing Interests: No potential conflict of interest was reported by the author(s)., (© 2023 The Author(s). Published by Informa UK Limited, trading as Taylor & Francis Group.)

Background: Airway hyperresponsiveness is a hallmark of asthma across asthma phenotypes. Airway hyperresponsiveness to mannitol specifically relates to mast cell infiltration of the airways, suggesting inhaled corticosteroids to be effective in reducing the response to mannitol, despite low levels of type 2 inflammation., Objective: We sought to investigate the relationship between airway hyperresponsiveness and infiltrating mast cells, and the response to inhaled corticosteroid treatment., Methods: In 50 corticosteroid-free patients with airway hyperresponsiveness to mannitol, mucosal cryobiopsies were obtained before and after 6 weeks of daily treatment with 1600 μg of budesonide. Patients were stratified according to baseline fractional exhaled nitric oxide (Feno) with a cutoff of 25 parts per billion., Results: Airway hyperresponsiveness was comparable at baseline and improved equally with treatment in both patients with Feno-high and Feno-low asthma: doubling dose, 3.98 (95% CI, 2.49-6.38; P < .001) and 3.85 (95% CI, 2.51-5.91; P < .001), respectively. However, phenotypes and distribution of mast cells differed between the 2 groups. In patients with Feno-high asthma, airway hyperresponsiveness correlated with the density of chymase-high mast cells infiltrating the epithelial layer (ρ, -0.42; P = .04), and in those with Feno-low asthma, it correlated with the density in the airway smooth muscle (ρ, -0.51; P = .02). The improvement in airway hyperresponsiveness after inhaled corticosteroid treatment correlated with a reduction in mast cells, as well as in airway thymic stromal lymphopoietin and IL-33., Conclusions: Airway hyperresponsiveness to mannitol is related to mast cell infiltration across asthma phenotypes, correlating with epithelial mast cells in patients with Feno-high asthma and with airway smooth muscle mast cells in patients with Feno-low asthma. Treatment with inhaled corticosteroids was effective in reducing airway hyperresponsiveness in both groups., (Copyright © 2023 The Authors. Published by Elsevier Inc. All rights reserved.)

Background: Inhaled corticosteroids (ICS) are the cornerstone of asthma treatment. However, ICS has side effects, and dose reduction is recommended when possible. Physical exercise improves asthma control, but it is unknown whether it reduces the reliance on ICS., Objective: To assess whether supervised high-intensity interval training reduces the need for ICS in untrained asthma patients., Methods: An assessor-blinded single-center randomized controlled trial, Copenhagen, Denmark. One hundred fifty untrained ICS-treated adults with symptomatic asthma were randomly assigned (2:1) to 6 months of supervised exercise 3 times weekly or a lifestyle as usual control group. Every second month, a clinical algorithm based on symptom control was applied in both groups to adjust ICS dose. Primary outcome was the proportion who had their ICS dose reduced by 25% or more after 6 months. Secondary outcomes included actual ICS dosage in micrograms per day., Results: Between October 2017 and December 2019, 102 patients were allocated to exercise intervention (86% completed) and 48 to the control (85% completed). At the 6-month visit, 63% versus 50% met the primary outcome in the exercise and control groups, respectively (adjusted risk difference 9.6% [95% CI -3.8 to 18.8]; P = .15). Daily ICS dose was reduced in favor of the exercise group, with a mean difference of -234 μg (95% CI -391 to -77; P = .0037), corresponding to a 24% reduction from baseline. This effect was sustained at 12 months. The intervention was safe and well tolerated., Conclusions: Six months of regular exercise results in reduction in daily ICS dose without compromising asthma control., (Copyright © 2023 The Authors. Published by Elsevier Inc. All rights reserved.)

A bioanalytical method for detecting the ultra-long-acting beta 2 -agonist (U-LABA) inhaled vilanterol and its metabolites, GSK932009 and GW630200, in urine was developed to potentially monitor permitted therapeutic versus prohibited supratherapeutic use in sport. The World Anti-Doping Agency (WADA) has established urinary concentration thresholds for the beta 2 -agonists salbutamol and formoterol. Therapeutic use of vilanterol (25 μg once daily) was recently permitted by WADA; however, there is no established decision limit for adverse analytical findings due to insufficient urine concentration data. In this study, we validated an assay to detect vilanterol in urine collected from four healthy male and female athletes 0-72 h who received inhaled corticosteroid fluticasone furoate/U-LABA vilanterol (800/100 μg) combination, four times the normal therapeutic dose. After administration, subjects performed 1 h of bike ergometer exercise. The experiment was conducted again after repeat dosing for 1 week. Our method utilised liquid chromatography with tandem mass spectrometry and was validated over urine concentrations of 5-5000 (vilanterol) and 50-50,000 pg/ml (GSK932009 and GW630200). Plasma samples were analysed for vilanterol, using a previously validated assay. The peak concentration values for urine vilanterol, GSK932009 and GW630200 were 9.5, 10.4 and 0.17 ng/ml, for single dosing, and 18.6, 19.5 and 0.20 ng/ml, for repeat dosing. Urine samples from four volunteers using the final validated method are reported, demonstrating this assay has sensitivity to detect vilanterol or GSK932009 in urine for ≥72 h post single or repeat dosing with 800/100 μg fluticasone furoate/vilanterol, whereas GW630200 was quantifiable ≤4 h post dose., (© 2022 GSK. Drug Testing and Analysis published by John Wiley & Sons Ltd.)

The 2023 Prohibited List issued by the World Anti-Doping Agency (WADA) permits athletes to inhale the beta 2 -agonist vilanterol at a standard dose of 25 μg daily. However, given limited data on urine pharmacokinetics, vilanterol has no urinary threshold or decision limit to discriminate therapeutic from supratherapeutic use. We investigated urine concentrations of vilanterol and its main metabolites GSK932009 and GW630200 over 0-72 h following inhalation of therapeutic (25 μg) or supratherapeutic (100 μg) doses and repeat-dose administration for 7 days of 25 or 100 μg·day -1 in 25 trained men and women. Vilanterol administration was followed by 1 h of exercise. GW630200 urine concentrations were low and insufficient for threshold purposes, and while GSK932009 had higher urine concentrations, it could not discriminate between therapeutic and supratherapeutic use. Mean (range) maximum urine concentrations of parent vilanterol were 1.2 (0.2-4.1) and 6.2 (1.4-14.3) ng·ml -1 for single-dose 25 and 100 μg vilanterol, respectively, and 2.0 (0.3-4.8) and 22.4 (6.4-42.1) ng·ml -1 for repeat-dose 25 and 100 μg·day -1 vilanterol. In 333 samples collected 6 h post-administration and considering WADA TD2022DL, a 3.1 ng·ml -1 vilanterol cut-off showed 30% sensitivity in detecting supratherapeutic use at 100 μg versus therapeutic use at 25 μg. Considering inter- and intra-individual variability and guard bands in doping analysis, a 6 ng·ml -1 decision limit, which could be shifted upwards in samples with specific gravity >1.018, appears sufficiently high to minimize risk of samples exceeding the decision limit after therapeutic use of vilanterol, while demonstrating the ability to detect supratherapeutic use at 100 μg., (© 2023 The Authors. Drug Testing and Analysis published by John Wiley & Sons Ltd.)

Context: Oral contraceptives (OCs) manipulate hormonal fluctuations of the menstrual cycle and affect physical performance. Most investigations on the effect of OCs on physical performance did not discriminate between different types of OCs. Thus, the effects of monophasic OCs (MOCs) - the most common type of OCs - on muscle strength and recovery from exercise are largely unknown., Objective: To examine the effect of MOC use on muscle strength and markers of recovery after exercise-induced muscle damage (EIMD) in premenopausal women., Data Sources: Electronic databases Embase, PubMed, SportDiscus, and Web of Science were searched for studies examining the effect of MOCs on acute muscle strength and recovery., Study Selection: Keywords applied for the study selection were oral contraceptive* AND muscle strength or oral contraceptive* AND muscle damage ., Study Design: Systematic review., Level of Evidence: Lowest quality assessed for an included study in this review was serious risk of bias using ROBINS-I tool made from Cochrane for nonrandomized studies., Data Extraction: A total of 104 studies on muscle strength were identified, of which 11 met the inclusion criteria. Concerning recovery, 51 studies were identified, of which 4 met the inclusion criteria., Results: Of the 11 studies included, 10 showed no effect of MOCs on acute muscle strength. Of the 4 studies on recovery, 2 found a greater decrease in muscle strength, and 3 found higher creatine kinase (CK) levels after EIMD in MOC users than in nonusers. The included studies were all rated with moderate-to-serious risk of bias., Conclusion: These findings suggest that MOCs may impair recovery from EIMD as indicated by lowered muscle strength and elevated CK levels. There is insufficient evidence to conclude whether MOCs acutely affect muscle strength. Moderate-to-serious risk of bias in studies makes interpretation challenging.

Background: The 2022 Global Initiative for Asthma guidelines emphasise the inhaled long-acting β 2 -agonist formoterol as part of the first treatment step, and therefore formoterol use among athletes will probably increase. However, prolonged supratherapeutic use of inhaled β 2 -agonists impairs training outcomes in moderately trained men. We investigated whether inhaled formoterol, at therapeutic doses, imposes detrimental effects in endurance-trained individuals of both sexes., Methods: 51 endurance-trained participants (31 male, 20 female; mean±sd maximal oxygen consumption ( V̇ O 2 max ) 62±6 mL·min -1 ·kg bw -1 and 52±5 mL·min -1 ·kg bw -1 , respectively) inhaled formoterol (24 µg; n=26) or placebo (n=25) twice daily for 6 weeks. At baseline and follow-up, we assessed V̇ O 2 max and incremental exercise performance during a bike-ergometer ramp-test; body composition by dual-energy X-ray absorptiometry; muscle oxidative capacity by high-resolution mitochondrial respirometry, enzymatic activity assays and immunoblotting; intravascular volumes by carbon monoxide rebreathing; and cardiac left ventricle mass and function by echocardiography., Results: Compared to placebo, formoterol increased lean body mass by 0.7 kg (95% CI 0.2-1.2 kg; treatment×trial p=0.022), but decreased V̇ O 2 max by 5% (treatment×trial p=0.013) and incremental exercise performance by 3% (treatment×trial p<0.001). In addition, formoterol lowered muscle citrate synthase activity by 15% (treatment×trial p=0.063), mitochondrial complex II and III content (treatment×trial p=0.028 and p=0.007, respectively), and maximal mitochondrial respiration through complexes I and I+II by 14% and 16% (treatment×trial p=0.044 and p=0.017, respectively). No apparent changes were observed in cardiac parameters and intravascular blood volumes. All effects were sex-independent., Conclusion: Our findings demonstrate that inhaled therapeutic doses of formoterol impair aerobic exercise capacity in endurance-trained individuals, which is in part related to impaired muscle mitochondrial oxidative capacity. Thus, if low-dose formoterol fails to control respiratory symptoms in asthmatic athletes, physicians may consider alternative treatment options., Competing Interests: Conflict of interest: All authors have nothing to disclose., (Copyright ©The authors 2023.)