Anabolic Effects of Salbutamol Are Lost Upon Immobilization

Background: Periods of muscle disuse occur during hospitalization, illness or the recovery from (sports) injury and lead to a rapid loss of muscle mass and the development of insulin resistance. Salbutamol is a fast-acting β2-adrenoreceptor agonist that may improve muscle protein synthesis and insulin sensitivity during experimental muscle disuse and thereby attenuate or preserve muscle mass; however, this has not yet been tested as a standalone intervention. Methods: Effects of salbutamol treatment on muscle metabolism were studied in a randomized controlled trial using a human forearm immobilization model (n = 20). Before and after immobilization for 2 days, we measured whole-body glucose disposal, forearm glucose uptake and amino acid kinetics during fasting and hyperinsulinaemic-hyperaminoacidaemic-euglycemic clamp conditions using forearm balance and L-[ring-2H5]-phenylalanine infusion. Underlying mechanistic effects were studied as well using a complementary murine hindleg immobilization model (2 weeks) using tracer approaches (i.e., deuterated water and 14C-labelled phenylalanine) and molecular analyses (e.g., RNA-seq and western blot). Results: In humans, salbutamol enhanced insulin-stimulated glucose disposal on the whole-body level (+21%, p = 0.010) but was unable to ameliorate the immobilization-induced decrease in forearm glucose uptake. Salbutamol decreased the efflux of amino acids from the immobilized forearm, indicating increased muscle protein synthesis and/or inhibition of breakdown. However, this did not affect the immobilization-induced impairment of amino acid net balance in both postabsorptive (-250%) and clamp conditions (-261%, both p = 0.031). In agreement, in mice, salbutamol increased cumulative muscle protein synthesis (+0.87%, p < 0.001) but did not result in a net gain of muscle mass upon immobilization due to an accompanying increase in muscle protein turnover (+13%, p < 0.001). Molecular analyses revealed immobilization inhibited salbutamol's effects on the muscle transcriptome, specifically the muscle contraction pathway (-2.1 normalized enrichment score, p < 0.001). Conclusions: Salbutamol increases muscle mass and glucose uptake, although these effects are limited to active but not inactive muscles. This demonstrates that the mechanism of action and efficacy of β2-adrenoreceptor signalling are hampered upon immobilization, which offers potential for a combined treatment intervention of reintroducing muscle contraction and salbutamol administration to improve muscle mass and clinical outcomes during episodes of physical inactivity.