Due to a high prevalence of asthma and exercise-induced bronchoconstriction in elite athletes, there is a high use of beta 2 -adrenoceptor agonists (beta 2 -agonists) in the athletic population. While anabolic in rodents, no study has been able to detect hypertrophy in humans after chronic beta 2 -agonist inhalation. We investigated whether inhaled beta 2 -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. K E Y W O R D S adrenergic, athletes, beta-agonist, doping, physical activity How to cite this article: Jessen S, Onslev J, Lemminger A, Backer V, Bangsbo J, Hostrup M. Hypertrophic effect of inhaled beta 2 -agonist with and without concurrent exercise training: A randomized controlled trial. Scand J Med Sci Sports. 2018;28:2114-2122.

Inhaled beta 2 -adrenoceptor agonists (beta 2 -agonists) are among the most used substances in competitive sports. The 2020 Prohibited List issued by the World Anti-Doping Agency restricts use of all selective and non-selective beta 2 -agonists in-and out-of competition with few exemptions. Formoterol, salbutamol, and salmeterol are allowed by inhalation within defined dosing limits. These restrictions are in place because supratherapeutic use of beta 2 -agonist has the potential to be anabolic and to enhance performance, as well as due to potential side effects. Despite substantial documentation that beta 2 -agonists exert anabolic and lipolytic actions, these actions are not widely recognized. Furthermore, a common misconception is that the inhaled route does not exert these effects. However, given the high relative systemic bioavailability via the inhaled route, inhalation at high doses can also exert anabolic and lipolytic actions. In this review, we highlight the anabolic and lipolytic actions beta 2agonists can exert, regardless of the type of beta 2 -agonist and the route of administration. The doses needed to provide such effects are also associated with adverse effects and would in most cases be detected in routine doping control. Notwithstanding, the beta 2 -agonist regulations are associated with some challenges and given their ability to induce muscle growth and to enhance performance, it is important to continue developing effective detection strategies to prevent potential misuse of beta 2 -agonists while allowing treatment of asthmatic subjects without causing adverse side effects or ergogenic actions. K E Y W O R D Sanabolic, beta agonists, doping, hypertrophy, muscle growth

The purpose of the present study was to investigate whether exercise training‐induced adaptations in human skeletal muscle mitochondrial bioenergetics are magnified under thermal conditions resembling sustained intense contractile activity and whether training‐induced changes in mitochondrial oxidative phosphorylation (OXPHOS) efficiency influence exercise efficiency. Twenty healthy men performed 6 wk of high‐intensity exercise training [i.e., speed endurance training (SET; n = 10)], or maintained their usual lifestyle (n = 10). Before and after the intervention, mitochondrial respiratory function was determined ex vivo in permeabilized muscle fibers under experimentally‐induced normothermia (35°C) and hyperthermia (40°C) mimicking in vivo muscle temperature at rest and during intense exercise, respectively. In addition, activity and content of muscle mitochondrial enzymes and proteins were quantified. Exercising muscle efficiency was determined in vivo by measurements of leg hemodynamics and blood parameters during one‐legged knee‐extensor exercise. SET enhanced maximal OXPHOS capacity and OXPHOS efficiency at 40°C, but not at 35°C, and attenuated hyperthermia‐induced decline in OXPHOS efficiency. Furthermore, SET increased expression of markers of mitochondrial content and up‐regulated content of MFN2, DRP1, and ANT1. Also, SET improved exercise efficiency and capacity. These findings indicate that muscle mitochondrial bioenergetics adapts to high‐intensity exercise training in a temperature‐dependent manner and that enhancements in mitochondrial OXPHOS efficiency may contribute to improving exercise performance.—Fiorenza, M., Lemminger, A. K., Marker, M., Eibye, K., Iaia, F. M., Bangsbo, J., Hostrup, M. High‐intensity exercise training enhances mitochondrial oxidative phosphorylation efficiency in a temperature‐dependent manner in human skeletal muscle: implications for exercise performance. FASEB J. 33, 8976–8989 (2019). http://www.fasebj.org

Exercise is an effective strategy in the prevention and treatment of metabolic diseases. Alterations in the skeletal muscle proteome, including post-translational modifications, regulate its metabolic adaptations to exercise. Here, we examined the effect of high-intensity interval training (HIIT) on the proteome and acetylome of human skeletal muscle, revealing the response of 3168 proteins and 1263 lysine acetyl-sites on 464 acetylated proteins. We identified global protein adaptations to exercise training involved in metabolism, excitation-contraction coupling, and myofibrillar calcium sensitivity. Furthermore, HIIT increased the acetylation of mitochondrial proteins, particularly those of complex V. We also highlight the regulation of exercise-responsive histone acetyl-sites. These data demonstrate the plasticity of the skeletal muscle proteome and acetylome, providing insight into the regulation of contractile, metabolic and transcriptional processes within skeletal muscle. Herein, we provide a substantial hypothesis-generating resource to stimulate further mechanistic research investigating how exercise improves metabolic health.

While beta2‐adrenoceptor stimulation has been shown to increase lean mass and to alter metabolic properties of skeletal muscle, adaptations in muscle oxidative enzymes and maximal oxygen uptake (trueV˙O2max) in response to beta2‐adrenergic agonist treatment are inadequately explored in humans, particularly in association with resistance training. Herein, we investigated beta2‐adrenergic‐induced changes in trueV˙O2max, leg and arm composition, and muscle content of oxidative enzymes in response to treatment with the selective beta2‐adrenergic agonist terbutaline with and without concurrent resistance training in young men. Forty‐six subjects were randomized to 4 weeks of lifestyle maintenance (n = 23) or resistance training (n = 23). Within the lifestyle maintenance and resistance training group, subjects received daily terbutaline (8 × 0.5 mg) (n = 13) or placebo (n = 10) treatment. No apparent treatment by training interactions was observed during the study period. Terbutaline increased leg and arm lean mass with the intervention, whereas no treatment differences were observed in absolute trueV˙O2max and incremental peak power output (iPPO). Treatment main effects were observed for trueV˙O2‐reserve (P < .05), trueV˙O2max relative to body mass (P < .05), trueV˙O2max relative to leg lean mass (P < .01), and iPPO relative to leg lean mass, in which terbutaline had a negative effect compared with placebo. Furthermore, content of electron transport chain complex I‐V decreased by 11% (P < .05) for terbutaline compared with placebo. Accordingly, chronic treatment with the selective beta2‐adrenergic agonist terbutaline may negatively affect trueV˙O2max and iPPO in relative terms, but not in absolute.