title: Nuclear transcription factor κ B activation and protein turnover adaptations in skeletal muscle of patients with progressive stages of lung cancer cachexia.
abstract: BACKGROUND
  Experimental models of cancer cachexia have indicated that systemic inflammation induces muscle-protein breakdown and wasting via muscular nuclear transcription factor κB (NF-κB) activation. This process may limit the efficacy of nutritional intervention.
  
  
  OBJECTIVE
  We assessed muscle NF-κB activity and protein turnover signaling in progressive stages of clinical lung cancer cachexia and assessed whether circulating factors can induce muscular NF-κB activity.
  
  
  METHODS
  Patients with lung cancer precachexia (n = 10) and cachexia (n = 16) were cross-sectionally compared with 22 healthy control subjects. mRNA transcripts of muscle proteolytic (ubiquitin proteasome system and autophagy lysosomal pathway) and myogenic markers and protein expression of PI3K/Akt, myostatin, and autophagy signaling were measured. A multiplex analysis showed the systemic inflammatory status, whereas plasma exposure to stable NF-κB-luciferase-reporter muscle cells revealed NF-κB inducibility.
  
  
  RESULTS
  Compared with healthy control subjects, cachectic patients had reduced (appendicular) muscle mass (-10%), muscle fiber atrophy (-27%), and decreased quadriceps strength (-31%). Subtle alterations in the muscle morphology were also detectable in precachectic patients, without changes in body composition. Despite increased Akt phosphorylation, downstream phosphosubstrates glycogen synthase kinase 3β, mammalian target of rapamycin, and Forkhead box protein were unaltered. The expression of autophagy effectors B cell lymphoma 2/adenovirus E1B 19-kDa protein-interacting protein 3 and microtubule-associated proteins 1A/1B light chain 3B gradually increased from precachectic to cachectic patients, without differences in E3 ubiquitin ligases. Systemic and local inflammation was evident in cachexia and intermediate in precachexia, but the plasma of both patients groups caused ex vivo muscle NF-κB activation.
  
  
  CONCLUSIONS
  In lung cancer, muscular NF-κB activity is induced by factors contained within the circulation. Autophagy may contribute to increased muscle proteolysis in lung cancer cachexia, whereas the absence of downstream changes in phosphosubstrates despite increased Akt phosphorylation suggests impaired anabolic signaling that may require targeted nutritional intervention.
authors.affiliation: Department of Respiratory Medicine, NUTRIM School for Nutrition, Toxicology and Metabolism, Maastricht University Medical Centre, Maastricht, Netherlands. c.opdenkamp@maastrichtuniversity.nl
authors.forename: Céline M
authors.initials: CM
authors.lastname: Op den Kamp
authors.forename: Ramon C
authors.initials: RC
authors.lastname: Langen
authors.forename: Frank J
authors.initials: FJ
authors.lastname: Snepvangers
authors.forename: Chiel C
authors.initials: CC
authors.lastname: de Theije
authors.forename: Johanna M
authors.initials: JM
authors.lastname: Schellekens
authors.forename: Fabian
authors.initials: F
authors.lastname: Laugs
authors.forename: Anne-Marie C
authors.initials: AM
authors.lastname: Dingemans
authors.forename: Annemie M
authors.initials: AM
authors.lastname: Schols
mesh_terms: D000368:Aged; D001343:Autophagy; D002100:Cachexia / Q000209:etiology / Q000378:metabolism* / Q000473:pathology; D016022:Case-Control Studies; D003430:Cross-Sectional Studies; D005260:Female; D006801:Humans; D007249:Inflammation / Q000097:blood / Q000378:metabolism*; D008175:Lung Neoplasms / Q000150:complications / Q000378:metabolism* / Q000473:pathology; D008247:Lysosomes / Q000378:metabolism; D008297:Male; D008875:Middle Aged; D009124:Muscle Proteins / Q000378:metabolism*; D053580:Muscle Strength; D016328:NF-kappa B / Q000097:blood / Q000378:metabolism*; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D046988:Proteasome Endopeptidase Complex / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D052097:Quadriceps Muscle / Q000378:metabolism* / Q000473:pathology; D012333:RNA, Messenger / Q000378:metabolism
chemical_list: D009124:Muscle Proteins; D016328:NF-kappa B; D012333:RNA, Messenger; D019869:Phosphatidylinositol 3-Kinases; D051057:Proto-Oncogene Proteins c-akt; D046988:Proteasome Endopeptidase Complex