title: Induction of MuRF1 is essential for TNF-alpha-induced loss of muscle function in mice.
abstract: BACKGROUND
  Humoral circulating inflammatory cytokines such as tumor necrosis factor alpha (TNF-alpha) can impair skeletal muscle contractility. Furthermore, TNF-alpha expression correlates with elevated levels of atrogin-like muscle-specific ubiquitin E3 ligases, which are presumed to mediate muscle protein breakdown and atrophy. However, the casual relationships between MuRF1 and TNF-alpha and their relative contributions to muscle function impairment are not known.
  
  
  METHODS
  TNF-alpha or saline was injected into either C57Bl6 or MuRF1(-/-) mice. After 16-24 h, the expression of MuRF1 in skeletal muscle was quantified by quantitative reverse transcription-PCR and Western blot analysis. Muscle function was measured in an organ bath. To obtain a broader overview on potential alterations, two-dimensional gel electrophoresis was performed.
  
  
  RESULTS
  Wild-type animals injected with TNF-alpha had higher MuRF1 mRNA expression (saline versus TNF-alpha: 56.6+/-12.1 versus 133.6+/-30.3 arbitrary units; p<0.05) and protein expression (saline versus TNF-alpha: 0.38+/-0.11 versus 1.07+/-0.25 arbitrary units; p<0.05) as compared to saline-injected littermates. Furthermore, TNF-alpha reduced force development at 150 Hz by 25% in C57Bl6 animals (saline versus TNF-alpha: 2412+/-120 versus 1799+/-114 g/cm(2); p<0.05), but not in MuRF1(-/-) mice (saline versus TNF-alpha: 2424+/-198 versus 2431+/-180 g/cm(2); p=NS). Proteome analysis revealed a significant down-regulation of fast skeletal muscle troponin T in wild-type animals treated with TNF-alpha as compared to MuRF1(-/-) mice that received TNF-alpha.
  
  
  CONCLUSIONS
  The results of this study demonstrate for the first time that TNF-alpha-induced reduction in skeletal muscle force development depends on the induction of the atrophy-related E3 ubiquitin ligase MuRF1. A link for the reduction in muscle force may be the TNF-alpha/MuRF1-mediated down-regulation of fast skeletal muscle troponin T.
authors.affiliation: Heart Center Leipzig, University Leipzig, Strümpellstrasse 39, D-04289 Leipzig, Germany. adav@medizin.uni-leipzig.de
authors.forename: Volker
authors.initials: V
authors.lastname: Adams
authors.forename: Norman
authors.initials: N
authors.lastname: Mangner
authors.forename: Alexander
authors.initials: A
authors.lastname: Gasch
authors.forename: Christian
authors.initials: C
authors.lastname: Krohne
authors.forename: Stephan
authors.initials: S
authors.lastname: Gielen
authors.forename: Stephanie
authors.initials: S
authors.lastname: Hirner
authors.forename: Hermann-Josef
authors.initials: HJ
authors.lastname: Thierse
authors.forename: Christian C
authors.initials: CC
authors.lastname: Witt
authors.forename: Axel
authors.initials: A
authors.lastname: Linke
authors.forename: Gerhard
authors.initials: G
authors.lastname: Schuler
authors.forename: Siegfried
authors.initials: S
authors.lastname: Labeit
mesh_terms: D000818:Animals; D002460:Cell Line; D015536:Down-Regulation / Q000187:drug effects; D039561:Eukaryotic Initiation Factor-4E / Q000378:metabolism; D047468:Immunoprecipitation; D066298:In Vitro Techniques; D051379:Mice; D008954:Models, Biological; D009119:Muscle Contraction / Q000187:drug effects; D018485:Muscle Fibers, Skeletal / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D009124:Muscle Proteins / Q000235:genetics* / Q000378:metabolism*; D018482:Muscle, Skeletal / Q000166:cytology / Q000187:drug effects* / Q000502:physiology*; D020648:Peptide Elongation Factor 1 / Q000378:metabolism; D000070584:Tripartite Motif Proteins; D020107:Troponin T / Q000378:metabolism; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology*; D025801:Ubiquitin / Q000378:metabolism; D044767:Ubiquitin-Protein Ligases / Q000235:genetics* / Q000378:metabolism*
chemical_list: D039561:Eukaryotic Initiation Factor-4E; D009124:Muscle Proteins; D020648:Peptide Elongation Factor 1; D000070584:Tripartite Motif Proteins; D020107:Troponin T; D014409:Tumor Necrosis Factor-alpha; D025801:Ubiquitin; C499084:Trim63 protein, mouse; D044767:Ubiquitin-Protein Ligases