title: Deletion of Nlrp3 protects from inflammation-induced skeletal muscle atrophy.
abstract: BACKGROUND
  Critically ill patients develop atrophic muscle failure, which increases morbidity and mortality. Interleukin-1β (IL-1β) is activated early in sepsis. Whether IL-1β acts directly on muscle cells and whether its inhibition prevents atrophy is unknown. We aimed to investigate if IL-1β activation via the Nlrp3 inflammasome is involved in inflammation-induced atrophy.
  
  
  METHODS
  We performed an experimental study and prospective animal trial. The effect of IL-1β on differentiated C2C12 muscle cells was investigated by analyzing gene-and-protein expression, and atrophy response. Polymicrobial sepsis was induced by cecum ligation and puncture surgery in Nlrp3 knockout and wild type mice. Skeletal muscle morphology, gene and protein expression, and atrophy markers were used to analyze the atrophy response. Immunostaining and reporter-gene assays showed that IL-1β signaling is contained and active in myocytes.
  
  
  RESULTS
  Immunostaining and reporter gene assays showed that IL-1β signaling is contained and active in myocytes. IL-1β increased Il6 and atrogene gene expression resulting in myocyte atrophy. Nlrp3 knockout mice showed reduced IL-1β serum levels in sepsis. As determined by muscle morphology, organ weights, gene expression, and protein content, muscle atrophy was attenuated in septic Nlrp3 knockout mice, compared to septic wild-type mice 96 h after surgery.
  
  
  CONCLUSIONS
  IL-1β directly acts on myocytes to cause atrophy in sepsis. Inhibition of IL-1β activation by targeting Nlrp3 could be useful to prevent inflammation-induced muscle failure in critically ill patients.
authors.affiliation: Experimental and Clinical Research Center (ECRC), Charité-Universitätsmedizin Berlin, Max Delbrück Center (MDC) for Molecular Medicine in the Helmholtz Association, Berlin, Germany.|Department of Cardiology, Heart Center Brandenburg and Medical University Brandenburg (MHB), Bernau, Germany.
authors.forename: Nora
authors.initials: N
authors.lastname: Huang
authors.affiliation: Experimental and Clinical Research Center (ECRC), Charité-Universitätsmedizin Berlin, Max Delbrück Center (MDC) for Molecular Medicine in the Helmholtz Association, Berlin, Germany.
authors.forename: Melanie
authors.initials: M
authors.lastname: Kny
authors.affiliation: Experimental and Clinical Research Center (ECRC), Charité-Universitätsmedizin Berlin, Max Delbrück Center (MDC) for Molecular Medicine in the Helmholtz Association, Berlin, Germany.|Department of Cardiology and Pneumology, Medical University Brandenburg (MHB), Brandenburg, Germany.
authors.forename: Fabian
authors.initials: F
authors.lastname: Riediger
authors.affiliation: Experimental and Clinical Research Center (ECRC), Charité-Universitätsmedizin Berlin, Max Delbrück Center (MDC) for Molecular Medicine in the Helmholtz Association, Berlin, Germany.
authors.forename: Katharina
authors.initials: K
authors.lastname: Busch
authors.affiliation: Experimental and Clinical Research Center (ECRC), Charité-Universitätsmedizin Berlin, Max Delbrück Center (MDC) for Molecular Medicine in the Helmholtz Association, Berlin, Germany.
authors.forename: Sibylle
authors.initials: S
authors.lastname: Schmidt
authors.affiliation: Experimental and Clinical Research Center (ECRC), Charité-Universitätsmedizin Berlin, Max Delbrück Center (MDC) for Molecular Medicine in the Helmholtz Association, Berlin, Germany.|Berlin Institute of Health (BIH), Kapelle-Ufer 2, 10117, Berlin, Germany.
authors.forename: Friedrich C
authors.initials: FC
authors.lastname: Luft
authors.affiliation: ZIK Septomics, Host Septomics, Jena, Germany.|Integrated Research and Treatment Center-Center for Sepsis Control and Care (CSCC), Jena University Hospital, Jena, Germany.
authors.forename: Hortense
authors.initials: H
authors.lastname: Slevogt
authors.affiliation: Experimental and Clinical Research Center (ECRC), Charité-Universitätsmedizin Berlin, Max Delbrück Center (MDC) for Molecular Medicine in the Helmholtz Association, Berlin, Germany. jens.fielitz@charite.de.|Department of Cardiology, Heart Center Brandenburg and Medical University Brandenburg (MHB), Bernau, Germany. jens.fielitz@charite.de.|Berlin Institute of Health (BIH), Kapelle-Ufer 2, 10117, Berlin, Germany. jens.fielitz@charite.de.
authors.forename: Jens
authors.initials: J
authors.lastname: Fielitz
keywords: ICUAW; IL-1β; Muscle weakness; Sepsis