Abstract
Skeletal muscle myopathy is universal in cirrhotic patients, however, little is known about the main mechanisms involved. The study aims to investigate skeletal muscle morphological, histological, and functional modifications in experimental models of cirrhosis and the principal molecular pathways responsible for skeletal muscle myopathy. Cirrhosis was induced by bile duct ligation (BDL) and carbon tetrachloride (CCl4) administration in mice. Control animals (CTR) underwent bile duct exposure or vehicle administration only. At sacrifice, peripheral muscles were dissected and weighed. Contractile properties of extensor digitorum longus (EDL) were studied in vitro. Muscle samples were used for histological and molecular analysis. Quadriceps muscle histology revealed a significant reduction in cross‐sectional area of muscle and muscle fibers in cirrhotic mice with respect to CTR. Kinetic properties of EDL in both BDL and CCl4 were reduced with respect to CTR; BDL mice also showed a reduction in muscle force and a decrease in the resistance to fatigue. Increase in myostatin expression associated with a decrease in AKT‐mTOR expressions was observed in BDL mice, together with an increase in LC3 protein levels. Upregulation of the proinflammatory citochines TNF‐a and IL6 and an increased expression of NF‐kB and MuRF‐1 were observed in CCl4 mice. In conclusion, skeletal muscle myopenia was present in experimental models of BDL and CCl4‐induced cirrhosis. Moreover, reduction in protein synthesis and activation of protein degradation were the main mechanisms responsible for myopenia in BDL mice, while activation of ubiquitin‐pathway through inflammatory cytokines seems to be the main potential mechanism involved in CCl4 mice.
Highlights
Muscle wasting is a characteristic feature of liver cirrhosis (O’Brien and Williams 2008)
Common bile duct ligation (BDL) is a model of secondary biliary cirrhosis, and it has been mainly employed in rats (Alvaro et al 2000; Mancinelli et al 2010), it has been developed in mice (Chang et al 2005)
As demonstrated by histological analysis performed on liver sections, marked cholangiolar proliferation and expansive portal fibrosis was observed 5 weeks after BDL in all the mice included in the study
Summary
Muscle wasting is a characteristic feature of liver cirrhosis (O’Brien and Williams 2008). Elevated plasma concentrations of myostatin, a negative regulator of muscle mass, were reported in patients with cirrhosis (Garcıa et al 2010), while contradictory results have been published on the expression of myostatin in muscle biopsy obtained from cirrhotic patients Physiological Reports published by Wiley Periodicals, Inc. on behalf of The Physiological Society and the American Physiological Society. The expression of ubiquitin-proteasome pathway was reported to be unaltered, while the expression of autophagy markers was found to be enhanced with respect to control animals (Dasarathy et al 2004, 2011, 2007; Qiu et al 2012)
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