title: Myriocin prevents muscle ceramide accumulation but not muscle fiber atrophy during short-term mechanical unloading.
abstract: Bedridden patients in intensive care unit or after surgery intervention commonly develop skeletal muscle weakness. The latter is promoted by a variety of prolonged hospitalization-associated conditions. Muscle disuse is the most ubiquitous and contributes to rapid skeletal muscle atrophy and progressive functional strength reduction. Disuse causes a reduction in fatty acid oxidation, leading to its accumulation in skeletal muscle. We hypothesized that muscle fatty acid accumulation could stimulate ceramide synthesis and promote skeletal muscle weakness. Therefore, the present study was designed to determine the effects of sphingolipid metabolism on skeletal muscle atrophy induced by 7 days of disuse. For this purpose, male Wistar rats were treated with myriocin, an inhibitor of de novo synthesis of ceramides, and subjected to hindlimb unloading (HU) for 7 days. Soleus muscles were assayed for fiber diameter, ceramide levels, protein degradation, and apoptosis signaling. Serum and liver were removed to evaluate the potential hepatoxicity of myriocin treatment. We found that HU increases content of saturated C16:0 and C18:0 ceramides and decreases soleus muscle weight and fiber diameter. HU increased the level of polyubiquitinated proteins and induced apoptosis in skeletal muscle. Despite a prevention of C16:0 and C18:0 muscle accumulation, myriocin treatment did not prevent skeletal muscle atrophy and concomitant induction of apoptosis and proteolysis. Moreover, myriocin treatment increased serum transaminases and induced hepatocyte necrosis. These data highlight that inhibition of de novo synthesis of ceramides during immobilization is not an efficient strategy to prevent skeletal muscle atrophy and exerts adverse effects like hepatotoxicity.
authors.affiliation: Laboratory "Movement Sport and Health Sciences," University Rennes 2-ENS Rennes, Bruz, France;
authors.forename: Erwann
authors.initials: E
authors.lastname: Salaun
authors.affiliation: Laboratory "Movement Sport and Health Sciences," University Rennes 2-ENS Rennes, Bruz, France;
authors.forename: Luz
authors.initials: L
authors.lastname: Lefeuvre-Orfila
authors.affiliation: INSERM UMR 991, Iron and the Liver Team Rennes, Faculty of Medicine, University of Rennes 1, Rennes, France; Laboratory of Biochemistry, University Hospital Pontchaillou, Rennes, France;
authors.forename: Thibault
authors.initials: T
authors.lastname: Cavey
authors.affiliation: Laboratory "Movement Sport and Health Sciences," University Rennes 2-ENS Rennes, Bruz, France;
authors.forename: Brice
authors.initials: B
authors.lastname: Martin
authors.affiliation: INSERM UMR 991, Iron and the Liver Team Rennes, Faculty of Medicine, University of Rennes 1, Rennes, France; Department of Pathology, University Hospital Pontchaillou, Rennes, France.
authors.forename: Bruno
authors.initials: B
authors.lastname: Turlin
authors.affiliation: INSERM UMR 991, Iron and the Liver Team Rennes, Faculty of Medicine, University of Rennes 1, Rennes, France; Laboratory of Biochemistry, University Hospital Pontchaillou, Rennes, France;
authors.forename: Martine
authors.initials: M
authors.lastname: Ropert
authors.affiliation: INSERM UMR 991, Iron and the Liver Team Rennes, Faculty of Medicine, University of Rennes 1, Rennes, France;
authors.forename: Olivier
authors.initials: O
authors.lastname: Loreal
authors.affiliation: Laboratory "Movement Sport and Health Sciences," University Rennes 2-ENS Rennes, Bruz, France; frederic.derbre@univ-rennes2.fr.
authors.forename: Frédéric
authors.initials: F
authors.lastname: Derbré
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D002518:Ceramides / Q000378:metabolism*; D005227:Fatty Acids / Q000378:metabolism; D005229:Fatty Acids, Monounsaturated / Q000494:pharmacology*; D022781:Hepatocytes / Q000187:drug effects / Q000378:metabolism; D019417:Hindlimb Suspension / Q000379:methods; D008297:Male; D018485:Muscle Fibers, Skeletal / Q000187:drug effects* / Q000378:metabolism; D009133:Muscular Atrophy / Q000097:blood / Q000188:drug therapy* / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar; D000637:Transaminases / Q000097:blood
chemical_list: D002518:Ceramides; D005227:Fatty Acids; D005229:Fatty Acids, Monounsaturated; D000637:Transaminases; C001996:thermozymocidin
keywords: NF-κB; apoptosis; myriocin; ubiquitination; unloading