Chronic treatment with terbutaline increases glucose and oleic acid oxidation and protein synthesis in cultured human myotubes

Christine Skagen; Tuula A Nyman; Xiao-Rong Peng; Gavin O'Mahony; Eili Tranheim Kase; Arild Chr Rustan; G Hege Thoresen

doi:10.1016/j.crphar.2021.100039

Chronic treatment with terbutaline increases glucose and oleic acid oxidation and protein synthesis in cultured human myotubes

Curr Res Pharmacol Drug Discov. 2021 Jun 11:2:100039. doi: 10.1016/j.crphar.2021.100039. eCollection 2021.

Authors

Christine Skagen¹, Tuula A Nyman², Xiao-Rong Peng³, Gavin O'Mahony⁴, Eili Tranheim Kase¹, Arild Chr Rustan¹, G Hege Thoresen^{1

5}

Affiliations

¹ Section for Pharmacology and Pharmaceutical Biosciences, Department of Pharmacy, University of Oslo, Norway.
² Department of Immunology, Institute of Clinical Medicine, University of Oslo and Oslo University Hospital, Norway.
³ Bioscience Metabolism, Research and Early Development Cardiovascular, Renal and Metabolism, BioPharmaceuticals R&D, AstraZeneca, Gothenburg, Sweden.
⁴ Medicinal Chemsitry, Research and Early Development Cardiovascular, Renal and Metabolism, BioPharmaceuticals R&D, AstraZeneca, Gothenburg, Sweden.
⁵ Department of Pharmacology, Institute of Clinical Medicine, University of Oslo, Norway.

Abstract

Objective: In vivo studies have reported several beneficial metabolic effects of β-adrenergic receptor agonist administration in skeletal muscle, including increased glucose uptake, fatty acid metabolism, lipolysis and mitochondrial biogenesis. Although these effects have been widely studied in vivo, the in vitro data are limited to mouse and rat cell lines. Therefore, we sought to discover the effects of the β₂-adrenergic receptor agonist terbutaline on metabolism and protein synthesis in human primary skeletal muscle cells.

Methods: Human cultured myotubes were exposed to terbutaline in various concentrations (0.01-30 μM) for 4 or 96 h. Thereafter uptake of [¹⁴C]deoxy-D-glucose, oxydation of [¹⁴C]glucose and [¹⁴C]oleic acid were measured. Incorporation of [¹⁴C]leucine, gene expression by qPCR and proteomics analyses by mass spectrometry by the STAGE-TIP method were performed after 96 h exposure to 1 and 10 μM of terbutaline.

Results: The results showed that 4 h treatment with terbutaline in concentrations up to 1 μM increased glucose uptake in human myotubes, but also decreased both glucose and oleic acid oxidation along with oleic acid uptake in concentrations of 10-30 μM. Moreover, administration of terbutaline for 96 h increased glucose uptake (in terbutaline concentrations up to 1 μM) and oxidation (1 μM), as well as oleic acid oxidation (0.1-30 μM), leucine incorporation into cellular protein (1-10 μM) and upregulated several pathways related to mitochondrial metabolism (1 μM). Data are available via ProteomeXchange with identifier PXD024063.

Conclusion: These results suggest that β₂-adrenergic receptor have direct effects in human skeletal muscle affecting fuel metabolism and net protein synthesis, effects that might be favourable for both type 2 diabetes and muscle wasting disorders.

Keywords: Adrenergic receptor (AR), Cyclic AMP (cAMP); Beta adrenergic receptor; Deoxyglucose (DOG), protein-coupled receptor (GPCR); Energy metabolism; Mammalian target of Rapamycin (mTOR), Oleic acid (OA); Mitochondrial metabolism; Myotubes; Oxidation; Protein Kinase A (PKA), Scintillation Proximity Assay (SPA); Type 2 diabetes (T2D), Trichloroacetic acid (TCA).