title: Cisplatin triggers atrophy of skeletal C2C12 myotubes via impairment of Akt signalling pathway and subsequent increment activity of proteasome and autophagy systems.
abstract: Cisplatin (cisPt) is an antineoplastic drug which causes an array of adverse effects on different organs and tissues, including skeletal muscle. In this work we show that cisPt behaves as a potent trigger to activate protein hypercatabolism in skeletal C2C12 myotubes. Within 24h of 50 μM cisPt administration, C2C12 myotubes displayed unchanged cell viability but showed a subset of hallmark signs typically recognized during atrophy, including severe reduction in body size, repression of Akt phosphorylation, transcriptional up-regulation of atrophy-related genes, such as atrogin-1, gabarap, beclin-1 and bnip-3, and loss of myogenic markers. As a consequence, proteasomal activity and formation of autophagosomes were remarkably increased in cisPt-treated myotubes, but forced stimulation of Akt pathway, as obtained through insulin administration or delivery of a constitutively activated Akt form, was sufficient to counter the cisPt-induced protein breakdown, leading to rescue of atrophic size. Overall, these results indicate that cisPt induces atrophy of C2C12 myotubes via activation of proteasome and autophagy systems, suggesting that the Akt pathway represents one sensitive target of cisPt molecular action in skeletal muscle.
authors.affiliation: Department of Biomedical Sciences and Biotechnologies, Unit of Biochemistry, Faculty of Medicine, University of Brescia, viale Europa 11, 25123 Brescia, Italy. fanzani@med.unibs.it
authors.forename: Alessandro
authors.initials: A
authors.lastname: Fanzani
authors.forename: Alessandra
authors.initials: A
authors.lastname: Zanola
authors.forename: Francesca
authors.initials: F
authors.lastname: Rovetta
authors.forename: Stefania
authors.initials: S
authors.lastname: Rossi
authors.forename: Maria Francesca
authors.initials: MF
authors.lastname: Aleo
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000633:toxicity*; D017209:Apoptosis / Q000187:drug effects; D001284:Atrophy; D001343:Autophagy / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D002478:Cells, Cultured; D002945:Cisplatin / Q000008:administration & dosage / Q000633:toxicity*; D004305:Dose-Response Relationship, Drug; D051379:Mice; D018485:Muscle Fibers, Skeletal / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D032446:Myoblasts / Q000187:drug effects / Q000378:metabolism; D009336:Necrosis; D010766:Phosphorylation; D046988:Proteasome Endopeptidase Complex / Q000378:metabolism*; D051057:Proto-Oncogene Proteins c-akt / Q000502:physiology*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction; D014158:Transcription, Genetic
chemical_list: D000970:Antineoplastic Agents; D051057:Proto-Oncogene Proteins c-akt; D046988:Proteasome Endopeptidase Complex; D002945:Cisplatin