β₂‐Adrenergic stimulation enhances Ca²⁺ release and contractile properties of skeletal muscles, and counteracts exercise‐induced reductions in Na⁺–K⁺‐ATPase V_max in trained men

Abstract

Key pointsr From animal models, it is well established that β 2 -adrenergic stimulation increases contractile force, rates of Ca 2+ release and uptake from the sarcoplasmic reticulum, and Na + -K + -ATPase activity of skeletal muscles. However, these effects are unexplored in humans.r Here we report that β 2 -adrenergic stimulation with the high dose selective β 2 -adrenoceptor agonist terbutaline elicits positive inotropic and lusitropic effects on non-fatigued m. quadriceps that are associated with enhanced rates of Ca 2+ release and uptake from the sarcoplasmic reticulum in trained men.r However, we also observed that the positive inotropic and lusitropic effects of β 2 -adrenergic stimulation on m. quadriceps were blunted when muscle fatigue developed.r Furthermore, we show that β 2 -adrenergic stimulation counteracts exercise-induced reductions in Na + -K + -ATPase V max (maximum rate of activity) and elevates glycolytic activity during high intensity exercise.r These findings are important for our understanding of the role of β 2 -adreceptor activation in regulation of ion handling and contractile properties of non-fatigued and fatigued skeletal muscles in humans.Abstract The aim of the present study was to examine the effect of β 2 -adrenergic stimulation on skeletal muscle contractile properties, sarcoplasmic reticulum (SR) rates of Ca 2+ release and uptake, and Na + -K + -ATPase activity before and after fatiguing exercise in trained men. The study consisted of two experiments (EXP1, n = 10 males, EXP2, n = 20 males), where β 2 -adrenoceptor agonist (terbutaline) or placebo was randomly administered in double-blinded crossover designs. In EXP1, maximal voluntary isometric contraction (MVC) of m. quadriceps was measured, followed by exercise to fatigue at 120% of maximal oxygen uptake (V O 2 ,max ). A muscle biopsy was taken after MVC (non-fatigue) and at time of fatigue. In EXP2, contractile properties of m. quadriceps were measured with electrical stimulations before (non-fatigue) and after two fatiguing 45 s sprints. Non-fatigued MVCs were 6 ± 3 and 6 ± 2% higher (P < 0.05) with terbutaline than placebo in EXP1 and EXP2, respectively. Furthermore, peak twitch force was 11 ± 7% higher (P < 0.01) with terbutaline than placebo at non-fatigue. After sprints, MVC declined (P < 0.05) to the same levels with terbutaline as placebo, whereas peak twitch force was lower (P < 0.05) and half-relaxation time was prolonged (P < 0.05) with terbutaline. Rates of SR Ca 2+ release and uptake at 400 nM [Ca 2+ ] were 15 ± 5 and 14 ± 5% (P < 0.05) higher, respectively, with terbutaline than placebo at non-fatigue, but declined (P < 0.05) to similar levels at time of fatigue. Na + -K + -ATPase activity was unaffected by terbutaline compared with placebo at non-fatigue, but terbutaline counteracted exercise-induced reductions in maximum rate of activity (V max ) at time of fatigue. In conclusion, increased contractile force induced by β 2 -adrenergic stimulation is associated with enhanced rate of Ca 2+ release in humans....

Influence of exercise in normal and hot ambient conditions on the pharmacokinetics of inhaled terbutaline in trained men

“…However, given that oral ingestion of beta 2 ‐agonists may enhance performance when administered acutely and for a longer duration (Collomp et al., ; van Baak et al., ; Hostrup et al., ; Hostrup et al. , ) and that acute high‐dose inhalation of terbutaline has been shown enhance sprint ability and muscle force (Hostrup et al., ,b; Kalsen et al., ), it is essential to establish a urinary threshold and decision limit for terbutaline. Although it is difficult to discriminate oral ingestion of terbutaline from inhalation in doping control analysis of urine samples (Elers et al., ), any potential urinary threshold for terbutaline should be based on urine concentrations observed after inhalation of a dose that equivalents the therapeutic threshold of 8 × 0.2 mg daily for salbutamol.…”

“…In 2014, terbutaline accounted for 76% (93 urine samples) of the adverse analytical findings (AAF) of beta 2 ‐agonists in doping control urine samples reported by WADA laboratories (WADA Laboratory Report). Although therapeutic inhalation of beta 2 ‐agonists (Kindermann, ; Dickinson et al., ; Koch et al., ), along with high‐dose inhalation (Elers et al., ; Hostrup et al., ; Kalsen et al., ), has been shown not to enhance endurance performance, recent studies have shown that supratherapeutic inhalation of terbutaline enhances muscle force and sprint performance of well‐trained subjects (Hostrup et al., ; Kalsen et al., ). Data on urine concentrations of terbutaline after inhaled use are, thus, essential for WADA to distinguish therapeutic use from supratherapeutic misuse.…”

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

“…Skeletal muscle, the largest tissue of the human body in non‐obese individuals, has a high density of beta‐adrenoceptors of which the beta 2 ‐subtype accounts for approximately 90% . Stimulation of muscle beta 2 ‐adrenoceptors with selective agonists modulates myocellular excitation‐contraction coupling and metabolism, which appear mediated by cAMP/protein kinase A (PKA)‐dependent signaling . Furthermore, beta 2 ‐agonists stimulate muscle protein turnover and growth .…”

The influence of exercise and dehydration on the urine concentrations of salbutamol after inhaled administration of 1600 µg salbutamol as a single dose in relation to doping analysis

“…Although the World Anti‐Doping Agency (WADA) 2015 list of prohibited substances restricts use of all beta 2 ‐agonists in competitive sports, salbutamol, salmeterol and formoterol are allowed by inhalation within defined therapeutic thresholds . For salbutamol, the therapeutic threshold is 1600 µg a day by inhalation with a corresponding urinary threshold and decision limit of 1000 and 1200 ng/mL, respectively, to discriminate therapeutic inhaled use from supratherapeutic misuse, which may enhance exercise performance . Urine samples of salbutamol containing more than 1200 ng/mL are considered as adverse analytical findings (AAFs) unless the athlete proves the urine concentration was due to therapeutic use through a pharmacokinetic study.…”