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

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 ( V ˙ 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 V ˙ 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 V ˙ O2max and incremental peak power output (iPPO). Treatment main effects were observed for V ˙ O2 -reserve (P < .05), V ˙ O2max relative to body mass (P < .05), V ˙ 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 V ˙ O2max and iPPO in relative terms, but not in absolute.

Beta2 -adrenergic ligand racemic formoterol exhibits enantioselective disposition in blood and skeletal muscle of humans, and elicits myocellular PKA signaling at therapeutic inhaled doses.

While studies have demonstrated substantial differences in beta2 -adrenergic agonist enantiomer pharmacology, enantioselective disposition of long-acting beta2 -adrenergic ligand racemic (rac)-formoterol in blood is inadequately explored after inhaled therapy given analytical challenges. Furthermore, information on enantioselective disposition and partitioning of beta2 -adrenergic agonist in skeletal muscle is absent despite its promising data on muscle anabolism in humans. Using a sensitive ultra-high performance liquid chromatography-mass spectrometry (UPLC-MS/MS) assay, we determined disposition of (R,R)-formoterol and (S,S)-formoterol in plasma and skeletal muscle samples from 11 non-asthmatic men who had inhaled rac-formoterol at therapeutic doses (2 × 27 µg). Mean (SD) concentrations of (R,R)- and (S,S)-formoterol in plasma and in muscle biopsies of the vastus lateralis 1 hour after inhalation of formoterol were 31 (15) and 45 (18) pg × mL-1 for (R,R)-formoterol and (S,S)-formoterol, respectively, in plasma, and 0.56 (0.32) and 0.51 (0.29) pg × mgwet wt -1 , respectively, in muscle. Formoterol exhibited different enantioselective disposition in plasma and muscle (p < 0.0001). In plasma, mean log (R,R):(S,S)-formoterol ratio was lower than 0 [-0.17(0.07), p < 0.0001], whereas in muscle, mean log (R,R):(S,S)-formoterol ratio was slightly higher than 0 [0.04(0.07), p < 0.05]. Log (R,R):(S,S)-formoterol ratio in muscle was related to muscle fiber-type composition. Furthermore, formoterol induced an approximately two-fold increase in muscle p-PKASer/thr phosphorylation (p < 0.01), indicating a substantial beta2 -adrenergic response. Collectively, these findings suggest that formoterol exhibits modest enantioselective disposition in plasma after inhaled therapy in humans, which appear related to a greater (R,R)-enantiomer disposition in skeletal muscle that may be dependent on fiber-type composition.

Mechanisms underlying enhancements in muscle force and power output during maximal cycle ergometer exercise induced by chronic ß2-adrenergic stimulation in men.

The study was a randomized placebo-controlled trial investigating mechanisms by which chronic ß2-adrenergic stimulation enhances muscle force and power output during maximal cycle ergometer exercise in young men. Eighteen trained men were assigned to an experimental group [oral terbutaline 5 mg/30 kg body weight (bw) twice daily (TER); n = 9] or a control group [placebo (PLA); n = 9] for a 4-wk intervention. No changes were observed with the intervention in PLA. Isometric muscle force of the quadriceps increased (P ≤ 0.01) by 97 ± 29 N (means ± SE) with the intervention in TER compared with PLA. Peak and mean power output during 30 s of maximal cycling increased (P ≤ 0.01) by 32 ± 8 and 25 ± 9 W, respectively, with the intervention in TER compared with PLA. Maximal oxygen consumption (V̇o2max) and time to fatigue during incremental cycling did not change with the intervention. Lean body mass increased by 1.95 ± 0.8 kg (P ≤ 0.05) with the intervention in TER compared with PLA. Change in single fiber cross-sectional area of myosin heavy chain (MHC) I (1,205 ± 558 µm(2); P ≤ 0.01) and MHC II fibers (1,277 ± 595 µm(2); P ≤ 0.05) of the vastus lateralis muscle was higher for TER than PLA with the intervention, whereas no changes were observed in MHC isoform distribution. Expression of muscle proteins involved in growth, ion handling, lactate production, and clearance increased (P ≤ 0.05) with the intervention in TER compared with PLA, with no change in oxidative enzymes. Our observations suggest that muscle hypertrophy is the primary mechanism underlying enhancements in muscle force and peak power during maximal cycling induced by chronic ß2-adrenergic stimulation in humans.