title: Satellite cells derived from obese humans with type 2 diabetes and differentiated into myocytes in vitro exhibit abnormal response to IL-6.
abstract: Obesity and type 2 diabetes are associated with chronically elevated systemic levels of IL-6, a pro-inflammatory cytokine with a role in skeletal muscle metabolism that signals through the IL-6 receptor (IL-6Rα). We hypothesized that skeletal muscle in obesity-associated type 2 diabetes develops a resistance to IL-6. By utilizing western blot analysis, we demonstrate that IL-6Rα protein was down regulated in skeletal muscle biopsies from obese persons with and without type 2 diabetes. To further investigate the status of IL-6 signaling in skeletal muscle in obesity-associated type 2 diabetes, we isolated satellite cells from skeletal muscle of people that were healthy (He), obese (Ob) or were obese and had type 2 diabetes (DM), and differentiated them in vitro into myocytes. Down-regulation of IL-6Rα was conserved in Ob myocytes. In addition, acute IL-6 administration for 30, 60 and 120 minutes, resulted in a down-regulation of IL-6Rα protein in Ob myocytes compared to both He myocytes (P<0.05) and DM myocytes (P<0.05). Interestingly, there was a strong time-dependent regulation of IL-6Rα protein in response to IL-6 (P<0.001) in He myocytes, not present in the other groups. Assessing downstream signaling, DM, but not Ob myocytes demonstrated a trend towards an increased protein phosphorylation of STAT3 in DM myocytes (P = 0.067) accompanied by a reduced SOCS3 protein induction (P<0.05), in response to IL-6 administration. Despite this loss of negative control, IL-6 failed to increase AMPKα2 activity and IL-6 mRNA expression in DM myocytes. There was no difference in fusion capacity of myocytes between cell groups. Our data suggest that negative control of IL-6 signaling is increased in myocytes in obesity, whereas a dysfunctional IL-6 signaling is established further downstream of IL-6Rα in DM myocytes, possibly representing a novel mechanism by which skeletal muscle function is compromised in type 2 diabetes.
authors: The Centre of Inflammation and Metabolism at Department of Infectious Diseases and Copenhagen Muscle Research Centre, Rigshospitalet, The Faculty of Health Sciences, University of Copenhagen, Copenhagen, Denmark.
authors: Camilla
authors: C
authors: Scheele
authors: Søren
authors: S
authors: Nielsen
authors: Meghan
authors: M
authors: Kelly
authors: Christa
authors: C
authors: Broholm
authors: Anders Rinnov
authors: AR
authors: Nielsen
authors: Sarah
authors: S
authors: Taudorf
authors: Maria
authors: M
authors: Pedersen
authors: Christian P
authors: CP
authors: Fischer
authors: Bente Klarlund
authors: BK
authors: Pedersen
mesh_terms: D002454:Cell Differentiation; D003924:Diabetes Mellitus, Type 2 / Q000473:pathology*; D015536:Down-Regulation; D005260:Female; D006801:Humans; D066298:In Vitro Techniques; D015850:Interleukin-6 / Q000378:metabolism*; D008297:Male; D008875:Middle Aged; D032342:Muscle Cells / Q000473:pathology*; D009765:Obesity / Q000473:pathology*; D032496:Satellite Cells, Skeletal Muscle / Q000473:pathology*; D015398:Signal Transduction
chemical_list: D015850:Interleukin-6