title: Negative regulation of glucose metabolism in human myotubes by supraphysiological doses of 17β-estradiol or testosterone.
abstract: OBJECTIVE
  Exposure of skeletal muscle to high levels of testosterone or estrogen induces insulin resistance, but evidence regarding the direct role of either sex hormone on metabolism is limited. Therefore, the aim of this study was to investigate the direct effect of acute sex hormone exposure on glucose metabolism in skeletal muscle.
  
  
  METHODS
  Differentiated human skeletal myotubes were exposed to either 17β-estradiol or testosterone and metabolic characteristics were assessed. Glucose incorporation into glycogen, glucose oxidation, palmitate oxidation, and phosphorylation of key signaling proteins were determined.
  
  
  RESULTS
  Treatment of myotubes with either 17β-estradiol or testosterone decreased glucose incorporation into glycogen. Exposure of myotubes to 17β-estradiol reduced glucose oxidation under basal and insulin-stimulated conditions. However, testosterone treatment enhanced basal palmitate oxidation and prevented insulin action on glucose and palmitate oxidation. Acute stimulation of myotubes with testosterone reduced phosphorylation of S6K1 and p38 MAPK. Exposure of myotubes to either 17β-estradiol or testosterone augmented phosphorylation GSK3β(Ser9) and PKCδ(Thr505), two negative regulators of glycogen synthesis. Treatment of myotubes with a PKC specific inhibitor (GFX) restored the effect of either sex hormone on glycogen synthesis. PKCδ silencing restored glucose incorporation into glycogen to baseline in response to 17β-estradiol, but not testosterone treatment.
  
  
  CONCLUSIONS
  An acute exposure to supraphysiological doses of either 17β-estradiol or testosterone regulates glucose metabolism, possibly via PKC signaling pathways. Furthermore, testosterone treatment elicits additional alterations in serine/threonine kinase signaling, including the ribosomal protein S6K1 and p38 MAPK.
authors.affiliation: Department of Molecular Medicine and Surgery, Karolinska Institutet, 171 77 Stockholm, Sweden; Department of Functional Biology, Physiology Area, University of Oviedo, Oviedo, Spain.
authors.forename: Pablo
authors.initials: P
authors.lastname: Garrido
authors.affiliation: Department of Molecular Medicine and Surgery, Karolinska Institutet, 171 77 Stockholm, Sweden.
authors.forename: Firoozeh
authors.initials: F
authors.lastname: Salehzadeh
authors.affiliation: Department of Molecular Medicine and Surgery, Karolinska Institutet, 171 77 Stockholm, Sweden.
authors.forename: Daniella E
authors.initials: DE
authors.lastname: Duque-Guimaraes
authors.affiliation: Department of Molecular Medicine and Surgery, Karolinska Institutet, 171 77 Stockholm, Sweden. Electronic address: Lubna.al-Khalili@biotech.kth.se.
authors.forename: Lubna
authors.initials: L
authors.lastname: Al-Khalili
mesh_terms: D000328:Adult; D000728:Androgens / Q000737:chemistry / Q000494:pharmacology*; D001692:Biological Transport / Q000187:drug effects; D002478:Cells, Cultured; D015331:Cohort Studies; D004958:Estradiol / Q000737:chemistry / Q000494:pharmacology*; D004967:Estrogens / Q000737:chemistry / Q000494:pharmacology*; D005260:Female; D020868:Gene Silencing; D005947:Glucose / Q000378:metabolism*; D006003:Glycogen / Q000378:metabolism; D006801:Humans; D007329:Insulin Antagonists / Q000737:chemistry / Q000494:pharmacology*; D020935:MAP Kinase Signaling System / Q000187:drug effects; D008297:Male; D008875:Middle Aged; D018485:Muscle Fibers, Skeletal / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D010084:Oxidation-Reduction / Q000187:drug effects; D019308:Palmitic Acid / Q000378:metabolism; D011493:Protein Kinase C / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D013739:Testosterone / Q000037:antagonists & inhibitors / Q000494:pharmacology*
chemical_list: D000728:Androgens; D004967:Estrogens; D007329:Insulin Antagonists; D047428:Protein Kinase Inhibitors; D019308:Palmitic Acid; D013739:Testosterone; D004958:Estradiol; D006003:Glycogen; C087857:protein kinase C gamma; D011493:Protein Kinase C; D005947:Glucose
keywords: Glucose oxidation; Insulin signaling; Sex hormones