title: The role of TRAIL in mediating autophagy in myositis skeletal muscle: a potential nonimmune mechanism of muscle damage.
abstract: OBJECTIVE
  Multinucleated cells are relatively resistant to classic apoptosis, and the factors initiating cell death and damage in myositis are not well defined. We hypothesized that nonimmune autophagic cell death may play a role in muscle fiber damage. Recent reports indicate that TRAIL may induce both NF-κB activation and autophagic cell death in other systems. We undertook this study to investigate the role of TRAIL in cell death and pathogenesis in vitro and in vivo, using myositis muscle tissues from humans and mice.
  
  
  METHODS
  Gene expression profiling was performed in myositis patient and control muscle specimens. Immunohistochemistry analysis was performed to confirm the gene array findings. We also analyzed TRAIL-induced cell death (apoptosis and autophagy) and NF-κB activation in vitro in cultured cells.
  
  
  RESULTS
  TRAIL was expressed predominantly in myositis muscle fibers, but not in biopsy specimens from normal or other dystrophic-diseased muscle. Autophagy markers were up-regulated in humans with myositis and in mouse models of myositis. TRAIL expression was restricted to regenerating/atrophic areas of muscle fascicles, blood vessels, and infiltrating lymphocytes. TRAIL induced NF-κB activation and IκB degradation in cultured cells that are resistant to TRAIL-induced apoptosis but that undergo autophagic cell death.
  
  
  CONCLUSIONS
  Our data demonstrate that TRAIL is expressed in myositis muscle and may mediate both activation of NF-κB and autophagic cell death in myositis. Thus, this nonimmune pathway may be an attractive target for therapeutic intervention in myositis.
authors.affiliation: Children's National Medical Center and George Washington University Medical Center, Washington, DC, USA.
authors.forename: Heather M
authors.initials: HM
authors.lastname: Alger
authors.forename: Nina
authors.initials: N
authors.lastname: Raben
authors.forename: Emidio
authors.initials: E
authors.lastname: Pistilli
authors.forename: Dwight L
authors.initials: DL
authors.lastname: Francia
authors.forename: Rashmi
authors.initials: R
authors.lastname: Rawat
authors.forename: Derese
authors.initials: D
authors.lastname: Getnet
authors.forename: Svetlana
authors.initials: S
authors.lastname: Ghimbovschi
authors.forename: Yi-Wen
authors.initials: YW
authors.lastname: Chen
authors.forename: Ingrid E
authors.initials: IE
authors.lastname: Lundberg
authors.forename: Kanneboyina
authors.initials: K
authors.lastname: Nagaraju
mesh_terms: D000818:Animals; D001343:Autophagy / Q000502:physiology*; D020869:Gene Expression Profiling; D006801:Humans; D051379:Mice; D008822:Mice, Transgenic; D018482:Muscle, Skeletal / Q000378:metabolism*; D009220:Myositis / Q000235:genetics / Q000378:metabolism*; D016328:NF-kappa B / Q000235:genetics / Q000378:metabolism; D053221:TNF-Related Apoptosis-Inducing Ligand / Q000235:genetics / Q000378:metabolism*
chemical_list: D016328:NF-kappa B; D053221:TNF-Related Apoptosis-Inducing Ligand