Chronic β₂‐adrenoceptor agonist treatment alters muscle proteome and functional adaptations induced by high intensity training in young men

Abstract

Although the effects of training have been studied for decades, data on muscle proteome signature remodelling induced by high intensity training in relation to functional changes in humans remains incomplete. Likewise, β -agonists are frequently used to counteract exercise-induced bronchoconstriction, but the effects β -agonist treatment on muscle remodelling and adaptations to training are unknown. In a placebo-controlled parallel study, we randomly assigned 21 trained men to 4 weeks of high intensity training with (HIT+β A) or without (HIT) daily inhalation of β -agonist (terbutaline, 4 mg dose ). Of 486 proteins identified by mass-spectrometry proteomics of muscle biopsies sampled before and after the intervention, 32 and 85 were changing (false discovery rate (FDR) ≤5%) with the intervention in HIT and HIT+β A, respectively. Proteome signature changes were different in HIT and HIT+β A (P = 0.005), wherein β -agonist caused a repression of 25 proteins in HIT+β A compared to HIT, and an upregulation of 7 proteins compared to HIT. β -Agonist repressed or even downregulated training-induced enrichment of pathways related to oxidative phosphorylation and glycogen metabolism, but upregulated pathways related to histone trimethylation and the nucleosome. Muscle contractile phenotype changed differently in HIT and HIT+β A (P ≤ 0.001), with a fast-to-slow twitch transition in HIT and a slow-to-fast twitch transition in HIT+β A. β -Agonist attenuated training-induced enhancements in maximal oxygen consumption (P ≤ 0.01) and exercise performance (6.1 vs. 11.6%, P ≤ 0.05) in HIT+β A compared to HIT. These findings indicate that daily β -agonist treatment attenuates the beneficial effects of high intensity training on exercise performance and oxidative capacity, and causes remodelling of muscle proteome signature towards a fast-twitch phenotype.

Effect of beta2‐adrenergic agonist and resistance training on maximal oxygen uptake and muscle oxidative enzymes in men

“…Because basal metabolic rate is related to total mass of predominantly lean tissues (eg, skeletal muscle), O 2 ‐reserve and O 2max relative to body mass are more sensitive to changes in aerobic capacity than absolute O 2max . Partly consistent with the present findings, we previously observed that 4 weeks of endurance training, with daily terbutaline treatment in a similar dose, abolished training‐induced improvements in O 2max and iPPO compared with placebo . In contrast, Dickinson et al observed no effect of daily treatment of beta 2 ‐adrenergic agonist salbutamol (1.6 mg daily) on O 2max in recreationally active individuals following a 6‐week period with concurrent resistance and endurance training.…”

“…In the present study, terbutaline treatment caused a non‐significant decline in the content of IDH, the rate‐limiting enzyme in the Krebs cycle . This indicates similar detrimental effects on oxidative enzymes as observed in a similar population . In contrast, the content of HAD, an important enzyme in the process of mitochondrial beta‐oxidation, did not change which is in accordance with Hostrup et al who showed that 4 weeks of supratherapeutic terbutaline administration did not affect content of HAD.…”

“…In the present study, we observed that mean content of electron transport chain complex I‐V of the vastus lateralis muscle declined in response to terbutaline treatment. This observation coincides with the apparent oxidative‐to‐glycolytic muscle phenotypic shift observed after long‐term beta 2 ‐adrenergic agonist treatment in a variety of mammalian species . In addition, long‐term beta 2 ‐adrenergic agonist treatment can cause a transition of myosin heavy chain (MHC) isoform from I to IIa, which may contribute to a reduced oxidative capacity of the skeletal muscle .…”

“…However, while muscle mass can increase in response to beta 2 ‐adrenergic agonist treatment, animal studies also indicate that chronic treatment, for several weeks, reduces content of oxidative enzymes in skeletal muscle and compromises endurance performance . In line with this, we recently observed that selective beta 2 ‐adrenergic agonist terbutaline abolished the beneficial effect of endurance training on incremental exercise performance, maximal oxygen uptake (O 2max ), and content of mitochondrial enzymes in skeletal muscle of trained young men . In contrast, Dickinson et al observed no confounding effect of treatment with selective beta 2 ‐adrenergic agonist salbutamol on O 2max and performance during a concurrent endurance and resistance training program.…”

“…The study was designed as a block randomized controlled parallel trial and is part of a larger project investigating adaptations in skeletal muscle in response to beta 2 ‐adrenergic agonist treatment . A part pertaining the effect of terbutaline treatment on whole‐body composition have been described elsewhere .…”