title: Skeletal muscle proteolysis is associated with sympathetic activation and TNF-α-ubiquitin-proteasome pathway in liver cirrhotic rats.
abstract: OBJECTIVE
  This study examined the effects of adrenergic blockade on muscle wasting and expression of the ubiquitin-proteasome system, tumor necrosis factor-α (TNF-α) and its signaling pathways in skeletal muscles of cirrhotic rats.
  
  
  METHODS
  Cirrhosis was induced by bile duct ligation in adult male Sprague-Dawley rats for 5 weeks. Oral administration of propranolol (75 mg/kg per day) and intraperitoneal administration of TNF-α receptor antagonist (100 µg/kg per day) were delivered for the last 7 and 14 days experimental periods, respectively.
  
  
  RESULTS
  Bile duct ligation caused a reduction of myosin heavy chain protein and muscle wasting. The release of free tyrosine and 3-methylhistidine, MAFbx and MuRF-1 ubiquitin ligase expression, myosin heavy chain protein ubiquitination, and 20S proteasome activity were higher in skeletal muscles of cirrhotic rats than in sham controls. In addition, circulating norepinephrine, protein levels of muscle TNF-α, TNF-α receptor-1, and TNF receptor-associated factor-2, phosphorylation of IKK-α/β, IκB-α, and p65, and NF-κB activity were also increased. Administration of propranolol and TNF-α receptor antagonist led to reduction of post-receptor actions of TNF-α and ubiquitin-proteasome activity in cirrhotic rats.
  
  
  CONCLUSIONS
  Our findings suggest a potential role of the sympathetic system, in association with pro-inflammatory responses, in the pathogenesis of muscle wasting in liver cirrhosis.
authors.affiliation: Division of Endocrinology and Metabolism.|Institute of Biomedical Sciences, National Chung Hsing University, Taichung, Taiwan.
authors.forename: Shih-Yi
authors.initials: SY
authors.lastname: Lin
authors.affiliation: Institute of Clinical Medicine, School of Medicine, National Yang Ming University, Taipei, Taiwan.|Institute of Biomedical Sciences, National Chung Hsing University, Taichung, Taiwan.
authors.forename: Ya-Yu
authors.initials: YY
authors.lastname: Wang
authors.affiliation: Division of Endocrinology and Metabolism.
authors.forename: Yu-Han
authors.initials: YH
authors.lastname: Chuang
authors.affiliation: Division of Family Medicine, Taichung Veterans General Hospital, Taichung, Taiwan.|Department of Medical Research, Taichung Veterans General Hospital.
authors.forename: Chun-Jung
authors.initials: CJ
authors.lastname: Chen
mesh_terms: D000818:Animals; D004195:Disease Models, Animal; D008103:Liver Cirrhosis / Q000378:metabolism* / Q000503:physiopathology; D008297:Male; D018482:Muscle, Skeletal / Q000378:metabolism*; D018995:Myosin Heavy Chains / Q000378:metabolism; D046988:Proteasome Endopeptidase Complex / Q000378:metabolism*; D059748:Proteolysis; D017207:Rats, Sprague-Dawley; D015398:Signal Transduction / Q000502:physiology*; D013564:Sympathetic Nervous System / Q000502:physiology*; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism*; D025801:Ubiquitin / Q000378:metabolism*
chemical_list: D014409:Tumor Necrosis Factor-alpha; D025801:Ubiquitin; D046988:Proteasome Endopeptidase Complex; D018995:Myosin Heavy Chains
keywords: cirrhosis; muscle wasting; proteolysis