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Anabolic effects of salbutamol are lost upon removal of muscle contraction

ABSTRACT: 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.

ORGANISM(S): Mus musculus

PROVIDER: GSE278016 | GEO | 2025/09/25

REPOSITORIES: GEO

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Project description:Abstract Background: The prevalence of sarcopenia is increasing and effective interventions are required to prevent or reverse age-related muscle loss. However it is often challenging expensive and time-consuming to develop and test the effectiveness of such interventions. Furthermore translational animal models that adequately mimic underlying physiological pathways are scarce. Strong predictors for the incidence of sarcopenia include a sedentary life-style and malnutrition. Therefore our objective was to investigate the translational value of three potential mouse models for sarcopenia namely partial immobilized caloric restricted (CR) and a combination (immobilized & CR) model. Methods: C57BL/6J mice were calorically restricted (-40%) and/or one hindleg was immobilized for two weeks to induce loss of muscle mass and function. Muscle mass function and diameter and distribution of slow (type 1) and fast ( type 2) myofibers were compared to those of young control (4 months) and old reference mice (21 months). Transcriptome analysis of quadriceps muscle was performed to identify underlying pathways and were compared with those being expressed in aged human vastus lateralis muscle-biopsies using a meta-analysis of five different human studies. Results: Caloric restriction induced overall loss of lean body mass (-15% p<0.001) whereas immobilization decreased muscle strength (-28% p<0.001) and muscle mass of hindleg muscles specifically (on average -25% p<0.001). The proportion of slow myofibers increased with aging in mice (+5% p<0.05) and this was not recapitulated by the CR and/or immobilization models. The diameter of fast myofibers decreased with aging (-7% p<0.05) and this was mimicked by all models. Transcriptome analysis revealed that the combination of CR and immobilization recapitulated more pathways characteristic for human muscle-aging (73%) than naturally aged (21 months old) mice (45%). These pathways included critical pathways relevant for protein synthesis/ breakdown (mitochondrial) metabolism neurology and the vascular system. Conclusions: The combination model exhibits loss of both muscle mass (due to CR) and function (due to immobilization) and has a remarkable similarity with pathways underlying human sarcopenia. Our results demonstrate that naturally aging up to 21 months in mice only partially recapitulates the human pathology with fewer overlapping pathways than the combination model. These findings underline that external factors such as sedentary behavior and malnutrition are key elements of a translational mouse model and favor the combination model as a rapid model for testing the treatments against sarcopenia.

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Anabolic effects of salbutamol are lost upon removal of muscle contraction

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