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 moderatelytrained men. Here, we investigated whether inhaled formote rol, 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 (VO_2max): (mean±SD) 62±6/52±5 mLO₂/min/kg) inhaled formoterol (n=26, 24 µg) or placebo (n=25) twice-daily for 6 weeks. At baseline and follow-up, we assessed VO_2max and incremental exercise performance during a bike-ergometer ramp-test, body composition by DualEnergy-X-ray-absorptiometry, muscle oxidative capacity by high-resolution mitochondrialrespirometry, enzymatic activity assays and immunoblotting, intravascular volumes by carbonmonoxide rebreathing, and cardiac left ventricle mass and function by echocardiography.
Compared to placebo, formotero increased lean body mass by 0.7 kg (95%Cl: 0.2 to 1.2, treatmentxtrial p=0.022), but decreased VO_2max 5% (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 sexindependent.
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.