@article {Jessen00643-2022, author = {S{\o}ren Jessen and Anders Lemminger and Vibeke Backer and Mads Fischer and Andrea Di Credico and Andreas Breenfeldt Andersen and Jens Bangsbo and Morten Hostrup}, title = {Inhaled formoterol impairs aerobic exercise capacity in endurance-trained individuals: a randomised controlled trial}, volume = {9}, number = {2}, elocation-id = {00643-2022}, year = {2023}, doi = {10.1183/23120541.00643-2022}, publisher = {European Respiratory Society}, abstract = {Background The 2022 Global Initiative for Asthma guidelines emphasise the inhaled long-acting β2-agonist formoterol as part of the first treatment step, and therefore formoterol use among athletes will probably increase. However, prolonged supratherapeutic use of inhaled β2-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{\textpm}sd maximal oxygen consumption (V̇O2max) 62{\textpm}6 mL{\textperiodcentered}min-1{\textperiodcentered}kg bw-1 and 52{\textpm}5 mL{\textperiodcentered}min-1{\textperiodcentered}kg bw-1, respectively) inhaled formoterol (24 {\textmu}g; n=26) or placebo (n=25) twice daily for 6 weeks. At baseline and follow-up, we assessed V̇O2max 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{\textendash}1.2 kg; treatment{\texttimes}trial p=0.022), but decreased V̇O2max by 5\% (treatment{\texttimes}trial p=0.013) and incremental exercise performance by 3\% (treatment{\texttimes}trial p\<0.001). In addition, formoterol lowered muscle citrate synthase activity by 15\% (treatment{\texttimes}trial p=0.063), mitochondrial complex II and III content (treatment{\texttimes}trial p=0.028 and p=0.007, respectively), and maximal mitochondrial respiration through complexes I and I+II by 14\% and 16\% (treatment{\texttimes}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.Prolonged treatment with inhaled formoterol impairs aerobic exercise capacity in endurance-trained individuals. Physicians may consider alternative treatment options if low-dose formoterol fails to control airway symptoms in asthmatic athletes. https://bit.ly/3vLsjHM}, URL = {https://openres.ersjournals.com/content/9/2/00643-2022}, eprint = {https://openres.ersjournals.com/content/9/2/00643-2022.full.pdf}, journal = {ERJ Open Research} }