title: Skeletal muscle myopenia in mice model of bile duct ligation and carbon tetrachloride-induced liver cirrhosis.
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.
authors.affiliation: Gastroenterology Department of Clinical Medicine, Sapienza University of Rome, Rome, Italy.
authors.forename: Michela
authors.initials: M
authors.lastname: Giusto
authors.affiliation: Department of Anatomy, Histology, Forensic Medicine and Orthopedics -Unit of Histology and Medical Embryology, Sapienza University of Rome Laboratory affiliated to Istituto Pasteur Italia - Fondazione Cenci Bolognetti Rome, Italy.
authors.forename: Laura
authors.initials: L
authors.lastname: Barberi
authors.affiliation: Gastroenterology Department of Clinical Medicine, Sapienza University of Rome, Rome, Italy.
authors.forename: Francesca
authors.initials: F
authors.lastname: Di Sario
authors.affiliation: Department of Mechanical and Aerospace Engineering, Sapienza University of Rome, Rome, Italy.
authors.forename: Emanuele
authors.initials: E
authors.lastname: Rizzuto
authors.affiliation: Department of Anatomy, Histology, Forensic Medicine and Orthopedics -Unit of Histology and Medical Embryology, Sapienza University of Rome Laboratory affiliated to Istituto Pasteur Italia - Fondazione Cenci Bolognetti Rome, Italy.
authors.forename: Carmine
authors.initials: C
authors.lastname: Nicoletti
authors.affiliation: Department of Anatomy, Histology, Forensic Medicine and Orthopedics -Unit of Histology and Medical Embryology, Sapienza University of Rome Laboratory affiliated to Istituto Pasteur Italia - Fondazione Cenci Bolognetti Rome, Italy.
authors.forename: Francesca
authors.initials: F
authors.lastname: Ascenzi
authors.affiliation: Department of Anatomy, Histology, Forensic Medicine and Orthopedics, Sapienza University of Rome, Rome, Italy.
authors.forename: Anastasia
authors.initials: A
authors.lastname: Renzi
authors.affiliation: Department of Clinical and Experimental Medicine, Federico II University of Naples, Naples, Italy.
authors.forename: Nicola
authors.initials: N
authors.lastname: Caporaso
authors.affiliation: Department of Clinical and Experimental Medicine, Federico II University of Naples, Naples, Italy.
authors.forename: Giuseppe
authors.initials: G
authors.lastname: D'Argenio
authors.affiliation: Department of Anatomy, Histology, Forensic Medicine and Orthopedics, Sapienza University of Rome, Rome, Italy.
authors.forename: Eugenio
authors.initials: E
authors.lastname: Gaudio
authors.affiliation: Department of Anatomy, Histology, Forensic Medicine and Orthopedics -Unit of Histology and Medical Embryology, Sapienza University of Rome Laboratory affiliated to Istituto Pasteur Italia - Fondazione Cenci Bolognetti Rome, Italy.
authors.forename: Antonio
authors.initials: A
authors.lastname: Musarò
authors.affiliation: Gastroenterology Department of Clinical Medicine, Sapienza University of Rome, Rome, Italy manuela.merli@uniroma1.it.
authors.forename: Manuela
authors.initials: M
authors.lastname: Merli
mesh_terms: D000818:Animals; D002251:Carbon Tetrachloride; D004195:Disease Models, Animal; D015850:Interleukin-6 / Q000378:metabolism; D008026:Ligation; D008105:Liver Cirrhosis, Biliary / Q000150:complications* / Q000378:metabolism / Q000473:pathology; D008106:Liver Cirrhosis, Experimental / Q000139:chemically induced / Q000150:complications* / Q000378:metabolism / Q000473:pathology; D051379:Mice; D009119:Muscle Contraction / Q000502:physiology; D009124:Muscle Proteins / Q000378:metabolism; D018482:Muscle, Skeletal / Q000473:pathology; D009135:Muscular Diseases / Q000209:etiology* / Q000378:metabolism / Q000473:pathology; D016328:NF-kappa B / Q000378:metabolism; D000070584:Tripartite Motif Proteins / Q000378:metabolism; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism; D044767:Ubiquitin-Protein Ligases / Q000378:metabolism
chemical_list: D015850:Interleukin-6; D009124:Muscle Proteins; D016328:NF-kappa B; D000070584:Tripartite Motif Proteins; D014409:Tumor Necrosis Factor-alpha; C577686:interleukin-6, mouse; D002251:Carbon Tetrachloride; C499084:Trim63 protein, mouse; D044767:Ubiquitin-Protein Ligases
keywords: Cirrhosis; molecular pathways; muscle; myopathy