title: Plasma from septic shock patients induces loss of muscle protein.
abstract: BACKGROUND
  ICU-acquired muscle weakness commonly occurs in patients with septic shock and is associated with poor outcome. Although atrophy is known to be involved, it is unclear whether ligands in plasma from these patients are responsible for initiating degradation of muscle proteins. The aim of the present study was to investigate if plasma from septic shock patients induces skeletal muscle atrophy and to examine the time course of plasma-induced muscle atrophy during ICU stay.
  
  
  METHODS
  Plasma was derived from septic shock patients within 24 hours after hospital admission (n = 21) and healthy controls (n = 12). From nine patients with septic shock plasma was additionally derived at two, five and seven days after ICU admission. These plasma samples were added to skeletal myotubes, cultured from murine myoblasts. After incubation for 24 hours, myotubes were harvested and analyzed on myosin content, mRNA expression of E3-ligase and Nuclear Factor Kappa B (NFκB) activity. Plasma samples were analyzed on cytokine concentrations.
  
  
  RESULTS
  Myosin content was approximately 25% lower in myotubes exposed to plasma from septic shock patients than in myotubes exposed to plasma from controls (P < 0.01). Furthermore, patient plasma increased expression of E3-ligases Muscle RING Finger protein-1 (MuRF-1) and Muscle Atrophy F-box protein (MAFbx) (P < 0.01), enhanced NFκB activity (P < 0.05) and elevated levels of ubiquitinated myosin in myotubes. Myosin loss was significantly associated with elevated plasma levels of interleukin (IL)-6 in septic shock patients (P < 0.001). Addition of antiIL-6 to septic shock plasma diminished the loss of myosin in exposed myotubes by approximately 25% (P < 0.05). Patient plasma obtained later during ICU stay did not significantly reduce myosin content compared to controls.
  
  
  CONCLUSIONS
  Plasma from patients with septic shock induces loss of myosin and activates key regulators of proteolysis in skeletal myotubes. IL-6 is an important player in sepsis-induced muscle atrophy in this model. The potential to induce atrophy is strongest in plasma obtained during the early phase of human sepsis.
authors.affiliation: Department of Pulmonary Diseases, Radboud University Nijmegen Medical Centre, Geert Grooteplein-Zuid 10, 6525 GA, Nijmegen, The Netherlands.
authors.forename: Hieronymus W H
authors.initials: HW
authors.lastname: van Hees
authors.forename: Willem-Jan M
authors.initials: WJ
authors.lastname: Schellekens
authors.forename: Marianne
authors.initials: M
authors.lastname: Linkels
authors.forename: Floris
authors.initials: F
authors.lastname: Leenders
authors.forename: Jan
authors.initials: J
authors.lastname: Zoll
authors.forename: Rogier
authors.initials: R
authors.lastname: Donders
authors.forename: P N Richard
authors.initials: PN
authors.lastname: Dekhuijzen
authors.forename: Johannes G
authors.initials: JG
authors.lastname: van der Hoeven
authors.forename: Leo M A
authors.initials: LM
authors.lastname: Heunks
mesh_terms: D000368:Aged; D000818:Animals; D016022:Case-Control Studies; D005260:Female; D006801:Humans; D007362:Intensive Care Units; D008297:Male; D051379:Mice; D008875:Middle Aged; D009124:Muscle Proteins / Q000378:metabolism*; D018482:Muscle, Skeletal / Q000473:pathology*; D009133:Muscular Atrophy / Q000209:etiology*; D012772:Shock, Septic / Q000097:blood*; D013997:Time Factors
chemical_list: D009124:Muscle Proteins