title: Disruption of MEF2C signaling and loss of sarcomeric and mitochondrial integrity in cancer-induced skeletal muscle wasting.
abstract: Cancer cachexia is a highly debilitating paraneoplastic disease observed in more than 50% of patients with advanced cancers and directly contributes to 20% of cancer deaths. Loss of skeletal muscle is a defining characteristic of patients with cancer cachexia and is associated with poor survival. The present study reveals the involvement of a myogenic transcription factor Myocyte Enhancer Factor (MEF) 2C in cancer-induced skeletal muscle wasting. Increased skeletal muscle mRNA expression of Suppressor of Cytokine Signaling (Socs) 3 and the IL-6 receptor indicative of active IL-6 signaling was seen in skeletal muscle of mice bearing the Colon 26 (C26) carcinoma. Loss of skeletal muscle structural integrity and distorted mitochondria were also observed using electron microscopy. Gene and protein expression of MEF2C was significantly downregulated in skeletal muscle from C26-bearing mice. MEF2C gene targets myozenin and myoglobin as well as myokinase were also altered during cachexia, suggesting dysregulated oxygen transport capacity and ATP regeneration in addition to distorted structural integrity. In addition, reduced expression of calcineurin was observed which suggested a potential pathway of MEF2C dysregulation. Together, these effects may limit sarcomeric contractile ability and also predispose skeletal muscle to structural instability; associated with muscle wasting and fatigue in cachexia.
authors.affiliation: Inflammation and Infection Research Centre, School of Medical Sciences, Faculty of Medicine, University of New South Wales, Sydney, NSW, 2052, Australia.
authors.forename: Angie M Y
authors.initials: AM
authors.lastname: Shum
authors.forename: Theodore
authors.initials: T
authors.lastname: Mahendradatta
authors.forename: Ryland J
authors.initials: RJ
authors.lastname: Taylor
authors.forename: Arran B
authors.initials: AB
authors.lastname: Painter
authors.forename: Melissa M
authors.initials: MM
authors.lastname: Moore
authors.forename: Maria
authors.initials: M
authors.lastname: Tsoli
authors.forename: Timothy C
authors.initials: TC
authors.lastname: Tan
authors.forename: Stephen J
authors.initials: SJ
authors.lastname: Clarke
authors.forename: Graham R
authors.initials: GR
authors.lastname: Robertson
authors.forename: Patsie
authors.initials: P
authors.lastname: Polly
mesh_terms: D000818:Animals; D002100:Cachexia / Q000209:etiology* / Q000378:metabolism* / Q000473:pathology; D019703:Calcineurin / Q000378:metabolism; D045744:Cell Line, Tumor; D015536:Down-Regulation; D015850:Interleukin-6 / Q000378:metabolism; D064326:MEF2 Transcription Factors; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008811:Mice, Inbred DBA; D046529:Microscopy, Electron, Transmission; D008931:Mitochondria, Muscle / Q000473:pathology; D008959:Models, Neurological; D018482:Muscle, Skeletal / Q000378:metabolism* / Q000473:pathology; D018006:Myogenic Regulatory Factors / Q000235:genetics / Q000378:metabolism*; D009374:Neoplasms, Experimental / Q000150:complications; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D012518:Sarcomeres / Q000473:pathology; D015398:Signal Transduction
chemical_list: D015850:Interleukin-6; D064326:MEF2 Transcription Factors; C578041:Mef2c protein, mouse; D018006:Myogenic Regulatory Factors; D012333:RNA, Messenger; D019703:Calcineurin