title: Pharmacological inhibition of GSK-3 in a guinea pig model of LPS-induced pulmonary inflammation: II. Effects on skeletal muscle atrophy.
abstract: BACKGROUND
  Chronic obstructive pulmonary disease (COPD) is accompanied by pulmonary inflammation and associated with extra-pulmonary manifestations, including skeletal muscle atrophy. Glycogen synthase kinase-3 (GSK-3) has been implicated in the regulation of muscle protein- and myonuclear turnover; two crucial processes that determine muscle mass. In the present study we investigated the effect of the selective GSK-3 inhibitor SB216763 on muscle mass in a guinea pig model of lipopolysaccharide (LPS)-induced pulmonary inflammation-associated muscle atrophy.
  
  
  METHODS
  Guinea pigs were pretreated with either intranasally instilled SB216763 or corresponding vehicle prior to each LPS/saline challenge twice weekly. Pulmonary inflammation was confirmed and indices of muscle mass were determined after 12 weeks. Additionally, cultured skeletal muscle cells were incubated with tumor necrosis factor α (TNF-α) or glucocorticoids (GCs) to model the systemic effects of pulmonary inflammation on myogenesis, in the presence or absence of GSK-3 inhibitors.
  
  
  RESULTS
  Repeated LPS instillation induced muscle atrophy based on muscle weight and muscle fiber cross sectional area. Intriguingly, GSK-3 inhibition using SB216763 prevented the LPS-induced muscle mass decreases and myofiber atrophy. Indices of protein turnover signaling were unaltered in guinea pig muscle. Interestingly, inhibition of myogenesis of cultured muscle cells by TNF-α or synthetic GCs was prevented by GSK-3 inhibitors.
  
  
  CONCLUSIONS
  In a guinea pig model of LPS-induced pulmonary inflammation, GSK-3 inhibition prevents skeletal muscle atrophy without affecting pulmonary inflammation. Resistance to inflammation- or GC-induced impairment of myogenic differentiation, imposed by GSK-3 inhibition, suggests that sustained myogenesis may contribute to muscle mass maintenance despite persistent pulmonary inflammation. Collectively, these results warrant further exploration of GSK-3 as a potential novel drug target to prevent or reverse muscle wasting in COPD.
authors.affiliation: Department of Respiratory Medicine, School for Nutrition, Toxicology and Metabolism (NUTRIM), Maastricht University Medical Centre + (MUMC+), PO box 5800, 6202, AZ Maastricht, The Netherlands. r.langen@maastrichtuniversity.nl.
authors.forename: Koen J P
authors.initials: KJ
authors.lastname: Verhees
authors.forename: Nicholas A M
authors.initials: NA
authors.lastname: Pansters
authors.forename: Hoeke A
authors.initials: HA
authors.lastname: Baarsma
authors.forename: Alexander H V
authors.initials: AH
authors.lastname: Remels
authors.forename: Astrid
authors.initials: A
authors.lastname: Haegens
authors.forename: Chiel C
authors.initials: CC
authors.lastname: de Theije
authors.forename: Annemie M W J
authors.initials: AM
authors.lastname: Schols
authors.forename: Reinoud
authors.initials: R
authors.lastname: Gosens
authors.forename: Ramon C J
authors.initials: RC
authors.lastname: Langen
mesh_terms: D000818:Animals; D002454:Cell Differentiation / Q000187:drug effects; D002478:Cells, Cultured; D004195:Disease Models, Animal; D004791:Enzyme Inhibitors / Q000494:pharmacology / Q000627:therapeutic use*; D005938:Glucocorticoids / Q000494:pharmacology; D038362:Glycogen Synthase Kinase 3 / Q000037:antagonists & inhibitors* / Q000187:drug effects; D006168:Guinea Pigs; D007211:Indoles / Q000494:pharmacology / Q000627:therapeutic use*; D008070:Lipopolysaccharides / Q000009:adverse effects; D008297:Male; D008301:Maleimides / Q000494:pharmacology / Q000627:therapeutic use*; D024510:Muscle Development / Q000187:drug effects; D018482:Muscle, Skeletal / Q000187:drug effects / Q000473:pathology*; D009133:Muscular Atrophy / Q000473:pathology* / Q000517:prevention & control*; D029424:Pulmonary Disease, Chronic Obstructive / Q000139:chemically induced / Q000473:pathology / Q000517:prevention & control*; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology
chemical_list: D004791:Enzyme Inhibitors; D005938:Glucocorticoids; D007211:Indoles; D008070:Lipopolysaccharides; D008301:Maleimides; C417521:SB 216763; D014409:Tumor Necrosis Factor-alpha; D038362:Glycogen Synthase Kinase 3