Nuclear transcription factor κ B activation and protein turnover adaptations in skeletal muscle of patients with progressive stages of lung cancer cachexia.

C.M.H. Op den Kamp, R.C.J. Langen, F.J. Snepvangers, C.C. de Theije, J.M. Schellekens, F. Laugs, A.M. Dingemans, A.M.W.J. Schols

Research output: Contribution to journalArticleAcademicpeer-review

Abstract

BACKGROUND: Experimental models of cancer cachexia have indicated that inflammation induces muscle-protein breakdown and wasting via muscular transcription factor kappaB (NF-kappaB) activation. This process may efficacy of nutritional intervention. OBJECTIVES: We assessed muscle NF- activity and protein turnover signaling in progressive stages of cancer cachexia and assessed whether circulating factors can induce NF-kappaB activity. DESIGN: Patients with lung cancer precachexia (n = cachexia (n = 16) were cross-sectionally compared with 22 healthy subjects. mRNA transcripts of muscle proteolytic (ubiquitin proteasome autophagy lysosomal pathway) and myogenic markers, and protein PI3K/Akt, myostatin, and autophagy signaling were measured. A multiplex showed the systemic inflammatory status, whereas plasma exposure to NF-kappaB-luciferase-reporter muscle cells revealed NF-kappaB RESULTS: Compared with healthy control subjects, cachectic patients had (appendicular) muscle mass (-10%), muscle fiber atrophy (-27%), and quadriceps strength (-31%). Subtle alterations in the muscle morphology detectable in precachectic patients, without changes in body increased Akt phosphorylation, downstream phosphosubstrates glycogen kinase 3beta, mammalian target of rapamycin, and Forkhead box protein unaltered. The expression of autophagy effectors B cell lymphoma 19-kDa protein-interacting protein 3 and microtubule-associated proteins light chain 3B gradually increased from precachectic to cachectic without differences in E3 ubiquitin ligases. Systemic and local evident in cachexia and intermediate in precachexia, but the plasma of patients groups caused ex vivo muscle NF-kappaB activation. CONCLUSIONS: cancer, muscular NF-kappaB activity is induced by factors contained circulation. Autophagy may contribute to increased muscle proteolysis in cancer cachexia, whereas the absence of downstream changes in despite increased Akt phosphorylation suggests impaired anabolic may require targeted nutritional intervention.
Original languageEnglish
Pages (from-to)738-748
Number of pages11
JournalAmerican Journal of Clinical Nutrition
Volume98
Issue number3
DOIs
Publication statusPublished - Sep 2013

Keywords

  • PROTEASOME PROTEOLYTIC PATHWAY
  • OBSTRUCTIVE PULMONARY-DISEASE
  • UBIQUITIN MESSENGER-RNA
  • SIGNALING PATHWAYS
  • SURGICAL RESECTION
  • ENERGY-BALANCE
  • MASS
  • EXPRESSION
  • ATROPHY
  • PROGNOSIS

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