Inhaled formoterol impairs aerobic exercise capacity in endurance-trained individuals: a randomised controlled trial

Abstract

The 2022 asthma guidelines emphasise inhaled long-acting beta2-agonist formoterol as part of first treatment step, and therefore formoterol use among athletes will likely increase. However, prolonged supratherapeutic use of inhaled beta2-agonist impairs training outcomes in moderately-trained men. Here, we investigated whether inhaled formoterol, at therapeutic doses, imposes detrimental effects in endurance-trained individuals of both sexes.Fifty-one endurance-trained participants (31/20 male/female; maximal oxygen consumption(V′O2max): (mean±sd) 62±6/52±5 mLO2/min·kg−1) inhaled formoterol (n=26, 24 µg) or placebo (n=25) twice-daily for 6 weeks. At baseline and follow-up, we assessed V′O2maxand 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.Compared to placebo, formoterol increased lean body mass by 0.7 kg (95%CI: 0.2 to 1.2, treatment×trial p=0.022), but decreased V′O2max5% (treatment×trial p=0.013) and incremental exercise performance 3% (treatment×trial p<0.001). Formoterol also lowered muscle citrate synthase activity 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 complex-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.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.

Inhaled salbutamol induces leanness in well-trained healthy females but not males during a period of endurance training: a randomised controlled trial

“…Another notable effect was that the salbutamol-treated participants temporarily had a lower increase in V ′ O 2max than placebo-treated participants during the first 4 weeks of the training intervention after which the salbutamol-treated participants approximated the change in V ′ O 2max observed in the placebo-treated participants at week 6. Although it could be expected that mitochondrial content would also be compromised, as has been shown for prolonged treatment with formoterol [ 28 ], our data did not support such an effect. In fact, salbutamol seemed to increase mitochondrial content as determined by electron transport complex protein expression, where there was an overall increase with salbutamol treatment.…”

“…[ 27 ] did observe a greater effect of β 2 -agonist on protein synthesis in females than males. And although we, and others, have previously found β 2 -agonists to induce leanness in males [ 15 , 28 , 33 , 36 – 38 ], concomitant endurance training was shown to blunt this effect [ 23 , 33 ]. This collectively suggests that β 2 -agonists exert sex-specific effects on body composition and that such effects depend on habitual training patterns.…”

“…Such studies will not only help guide anti-doping regulations but also practices if treatment is associated with detrimental effects. Indeed, recent studies highlight that chronic use of inhaled β 2 -agonists may impose detrimental effects on aerobic exercise outcomes, including in V ′ O 2max and incremental exercise capacity [ 23 , 28 ].…”

Beyond bronchodilation: Illuminating the performance benefits of inhaled beta2‐agonists in sports

“…In addition, a recent study demonstrated that formoterol at 48 μg/day for 6 weeks increased muscle mass by 0.7 kg in highly trained males and females, 110 which confirms that formoterol is a potent anabolic beta 2 ‐agonist, as also shown in rodents 111 . However, in line with findings for inhaled terbutaline, 72 daily formoterol inhalation can impair aerobic exercise capacity 110 . In the aforementioned study, trained males and females experienced a 5% decline in VO 2max during formoterol treatment 110 .…”

Asthma and exercise‐induced bronchoconstriction in athletes: Diagnosis, treatment, and anti‐doping challenges

“…While some of the commonly used drugs in the management of asthma and EIB are permitted, special rules apply to beta 2 -agonists and glucocorticoids to protect athletes' health and prevent misuse for performanceenhancing purposes. Use of beta 2 -agonists at high inhaled doses or via systemic routes can induce muscle hypertrophy and leanness, 62,63,[83][84][85][86][87][88][89] as well as enhance muscle strength and sprint performance. 84,88,[90][91][92][93][94][95][96][97][98][99][100][101][102][103][104][105] For example, oral dosing with salbutamol (16 mg/day) led to greater gains in cross-sectional area of fast-twitch muscle fibers and was associated with better sprint performance than placebo in trained young males undergoing 11 weeks of resistance training.…”