Skeletal muscle proteolysis is associated with sympathetic activation and TNF-α-ubiquitin-proteasome pathway in liver cirrhotic rats.

ABSTRACT

BACKGROUND AND AIM: 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/ß, 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.