title: Skeletal muscle atrophy in R6/2 mice - altered circulating skeletal muscle markers and gene expression profile changes.
abstract: BACKGROUND
  In addition to classical neurological symptoms, Huntington's disease (HD) is complicated by peripheral pathology, including progressive skeletal muscle wasting, and common skeletal muscle gene expression changes have been shown in HD mice and human HD.
  
  
  OBJECTIVE
  To highlight possible mechanisms underlying muscle wasting in HD, we examined gene expression in pathways governing skeletal muscle contractility, skeletal myogenesis, skeletal muscle wasting, apoptosis and the NFκB signaling pathway in two HD mouse models (the transgenic R6/2 and full-length knock-in Q175). In addition, we assessed circulating markers that increase in response to skeletal muscle injury, skeletal Troponin I (sTnI), fatty acid binding protein 3 (FABP3), and Myosin light chain 3 (Myl3).
  
  
  METHODS
  We measured gene expression in muscle tissue as well as in cultured primary myocytes using qPCR. Concentrations of cytokines and muscle proteins were obtained using multiplex ELISA.
  
  
  RESULTS
  Circulating markers of muscle injury (sTnI, FABP3, and Myl3) were significantly increased in mouse serum. In skeletal muscle, we observed reduced gene expression of components involved in muscle contractility, with pronounced downregulation of Acta1, Myh2 and Tnni2, among others. Alongside, we found increased expression of caspases (3 and 8) and key elements of the NFκB signaling pathway, p65/RelA, Tradd, and TRAF5. We also found similar gene expression alterations in cultured primary myocytes from R6/2 mice stimulated with TNF-α.
  
  
  CONCLUSIONS
  Our results indicate that activation of apoptotic and NFκB pathways occur alongside down-regulation of key compartments of the muscle contractility unit in skeletal muscle of HD mice, and muscle atrophy could possibly be a source of circulating disease progression markers.
authors: Brain Disease Biomarker Unit, Department of Experimental Medical Science, Lund University, Lund, Sweden.
authors: Anna
authors: A
authors: Magnusson-Lind
authors: Molecular Neuromodulation, Department of Experimental Medical Science, Lund University, Lund, Sweden.
authors: Marcus
authors: M
authors: Davidsson
authors: Brain Disease Biomarker Unit, Department of Experimental Medical Science, Lund University, Lund, Sweden.
authors: Edina
authors: E
authors: Silajdžić
authors: Neural Plasticity and Repair, Department of Experimental Medical Science, Lund University, Lund, Sweden.
authors: Christian
authors: C
authors: Hansen
authors: Brain Disease Biomarker Unit, Department of Experimental Medical Science, Lund University, Lund, Sweden.
authors: Andrew C
authors: AC
authors: McCourt
authors: Institute of Neurology, Department of Neurodegenerative Disease, UCL, London, UK.
authors: Sarah J
authors: SJ
authors: Tabrizi
authors: Brain Disease Biomarker Unit, Department of Experimental Medical Science, Lund University, Lund, Sweden.
authors: Maria
authors: M
authors: Björkqvist
mesh_terms: D000818:Animals; D015415:Biomarkers / Q000378:metabolism; D053148:Caspase 3 / Q000235:genetics / Q000378:metabolism; D053181:Caspase 8 / Q000235:genetics / Q000378:metabolism; D004195:Disease Models, Animal; D015536:Down-Regulation; D000074026:Fatty Acid Binding Protein 3; D050556:Fatty Acid-Binding Proteins / Q000235:genetics / Q000378:metabolism; D006816:Huntington Disease / Q000150:complications / Q000235:genetics* / Q000378:metabolism; D051379:Mice; D008822:Mice, Transgenic; D009119:Muscle Contraction / Q000235:genetics; D018482:Muscle, Skeletal / Q000378:metabolism*; D009133:Muscular Atrophy / Q000209:etiology / Q000235:genetics* / Q000378:metabolism; D018995:Myosin Heavy Chains / Q000235:genetics / Q000378:metabolism; D018994:Myosin Light Chains / Q000235:genetics / Q000378:metabolism; D016328:NF-kappa B / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction; D053199:TNF Receptor-Associated Death Domain Protein / Q000235:genetics / Q000378:metabolism; D048015:TNF Receptor-Associated Factor 5 / Q000235:genetics / Q000378:metabolism; D051996:Transcription Factor RelA / Q000235:genetics / Q000378:metabolism; D059467:Transcriptome; D019210:Troponin I / Q000235:genetics / Q000378:metabolism
chemical_list: D015415:Biomarkers; C493409:Fabp3 protein, mouse; D000074026:Fatty Acid Binding Protein 3; D050556:Fatty Acid-Binding Proteins; D018994:Myosin Light Chains; D016328:NF-kappa B; D053199:TNF Receptor-Associated Death Domain Protein; D048015:TNF Receptor-Associated Factor 5; C481226:Tradd protein, mouse; D051996:Transcription Factor RelA; D019210:Troponin I; C505409:Casp3 protein, mouse; C505526:Casp8 protein, mouse; D053148:Caspase 3; D053181:Caspase 8; D018995:Myosin Heavy Chains
keywords: Acta1; Muscle atrophy; NFκB pathway; Tradd; Traf5; Troponin; gene expression; myosin; p65/RelA