Anabolic effects of salbutamol are lost upon removal of muscle contraction

Highlights: - Muscle disuse causes atrophy and insulin resistance; salbutamol counteracts both. - However, salbutamol’s effects are inhibited in immobilized human and mouse limbs. - RNA-seq reveals blunted signaling effects by salbutamol during immobilization. Abstract: Salbutamol’s efficacy depends on muscle contraction.Muscle disuse leads to rapid loss of muscle mass and development of insulin resistance, which may be ameliorated by beta2-agonist administration. Here, we tested the impact of the fast-acting beta2-agonist salbutamol during immobilization. In humans, salbutamol enhanced insulin-stimulated glucose disposal on the whole-body level, but not in immobilized muscle. Salbutamol decreased the efflux of amino acids from the immobilized forearm, indicating increased muscle protein synthesis and/or inhibition of breakdown, but did not affect amino acid net balance. In agreement, in mice salbutamol increased cumulative muscle protein synthesis, but did not result in a net gain of muscle mass upon immobilization, due to an accompanying increase in muscle protein turnover. Molecular analyses revealed immobilization inhibited salbutamol’s effects on muscle-transcriptome. In conclusion, salbutamol can increase muscle mass and glucose uptake, but not effectively in inactive muscle, demonstrating that the mechanism of action and efficacy of beta2-adrenoreceptor signaling is hampered without muscle contraction. RNAseq expression of mouse (16wk old) leg quadriceps muscle, after 2wk of various treatments (15 mice per treatment group): Healthy reference group receiving ad libitum Chow food (Right leg muscle: H.R); Caloric Restriction control group receiving 60% of their normal Chow food intake and an osmotic pump releasing PBS (Left leg muscle: CR.0.L); Caloric Restriction & Salbutamol group receiving 60% of their normal Chow food intake and an osmotic pump releasing 1 mg salbutamol (dissolved in PBS) per kg body weight per day (Left leg muscle: CR.S.L); Caloric Restriction & Immobilisation control group receiving 60% of their normal Chow food intake, unilateral (Right) immobilization and an osmotic pump releasing PBS (Right leg muscle: CRI.0.R); Caloric Restriction & Immobilisation & Salbutamol group receiving 60% of their normal Chow food intake, unilateral (Right) immobilization and an osmotic pump releasing 1 mg salbutamol (dissolved in PBS) per kg body weight per day (Right leg muscle: CR I.S.R). 0 = no immobilisation or no salbutamol.