title: The proteasome inhibitor MG132 reduces immobilization-induced skeletal muscle atrophy in mice.
abstract: BACKGROUND
  Skeletal muscle atrophy is a serious concern for the rehabilitation of patients afflicted by prolonged limb restriction. This debilitating condition is associated with a marked activation of NFκB activity. The ubiquitin-proteasome pathway degrades the NFκB inhibitor IκBα, enabling NFκB to translocate to the nucleus and bind to the target genes that promote muscle atrophy. Although several studies showed that proteasome inhibitors are efficient to reduce atrophy, no studies have demonstrated the ability of these inhibitors to preserve muscle function under catabolic condition.
  
  
  METHODS
  We recently developed a new hindlimb immobilization procedure that induces significant skeletal muscle atrophy and used it to show that an inflammatory process characterized by the up-regulation of TNFα, a known activator of the canonical NFκB pathway, is associated with the atrophy. Here, we used this model to investigate the effect of in vivo proteasome inhibition on the muscle integrity by histological approach. TNFα, IL-1, IL-6, MuRF-1 and Atrogin/MAFbx mRNA level were determined by qPCR. Also, a functional measurement of locomotors activity was performed to determine if the treatment can shorten the rehabilitation period following immobilization.
  
  
  RESULTS
  In the present study, we showed that the proteasome inhibitor MG132 significantly inhibited IκBα degradation thus preventing NFκB activation in vitro. MG132 preserved muscle and myofiber cross-sectional area by downregulating the muscle-specific ubiquitin ligases atrogin-1/MAFbx and MuRF-1 mRNA in vivo. This effect resulted in a diminished rehabilitation period.
  
  
  CONCLUSIONS
  These finding demonstrate that proteasome inhibitors show potential for the development of pharmacological therapies to prevent muscle atrophy and thus favor muscle rehabilitation.
authors.affiliation: Centre de Recherche Clinique Étienne-Lebel, 3001-12th Avenue North, Sherbrooke, QC J1H5N4, Canada.
authors.forename: Annabelle Z
authors.initials: AZ
authors.lastname: Caron
authors.forename: Sonia
authors.initials: S
authors.lastname: Haroun
authors.forename: Elisabeth
authors.initials: E
authors.lastname: Leblanc
authors.forename: Frédéric
authors.initials: F
authors.lastname: Trensz
authors.forename: Chantal
authors.initials: C
authors.lastname: Guindi
authors.forename: Aziz
authors.initials: A
authors.lastname: Amrani
authors.forename: Guillaume
authors.initials: G
authors.lastname: Grenier
mesh_terms: D000818:Animals; D002460:Cell Line; D015853:Cysteine Proteinase Inhibitors / Q000494:pharmacology*; D004195:Disease Models, Animal; D019417:Hindlimb Suspension / Q000009:adverse effects*; D007976:Leupeptins / Q000494:pharmacology*; D008297:Male; D051379:Mice; D008815:Mice, Inbred Strains; D018482:Muscle, Skeletal / Q000187:drug effects / Q000201:enzymology / Q000473:pathology; D009133:Muscular Atrophy / Q000188:drug therapy* / Q000473:pathology / Q000534:rehabilitation; D046988:Proteasome Endopeptidase Complex / Q000502:physiology; D061988:Proteasome Inhibitors
chemical_list: D015853:Cysteine Proteinase Inhibitors; D007976:Leupeptins; D061988:Proteasome Inhibitors; D046988:Proteasome Endopeptidase Complex; C072553:benzyloxycarbonylleucyl-leucyl-leucine aldehyde