Skeletal muscle atrophy in R6/2 mice - altered circulating skeletal muscle markers and gene expression profile changes

J Huntingtons Dis. 2014;3(1):13-24. doi: 10.3233/JHD-130075.


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.

Keywords: Acta1; Muscle atrophy; NFκB pathway; Tradd; Traf5; Troponin; gene expression; myosin; p65/RelA.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Biomarkers / metabolism
  • Caspase 3 / genetics
  • Caspase 3 / metabolism
  • Caspase 8 / genetics
  • Caspase 8 / metabolism
  • Disease Models, Animal
  • Down-Regulation
  • Fatty Acid Binding Protein 3
  • Fatty Acid-Binding Proteins / genetics
  • Fatty Acid-Binding Proteins / metabolism
  • Huntington Disease / complications
  • Huntington Disease / genetics*
  • Huntington Disease / metabolism
  • Mice
  • Mice, Transgenic
  • Muscle Contraction / genetics
  • Muscle, Skeletal / metabolism*
  • Muscular Atrophy / etiology
  • Muscular Atrophy / genetics*
  • Muscular Atrophy / metabolism
  • Myosin Heavy Chains / genetics
  • Myosin Heavy Chains / metabolism
  • Myosin Light Chains / genetics
  • Myosin Light Chains / metabolism
  • NF-kappa B / genetics
  • NF-kappa B / metabolism
  • Signal Transduction
  • TNF Receptor-Associated Death Domain Protein / genetics
  • TNF Receptor-Associated Death Domain Protein / metabolism
  • TNF Receptor-Associated Factor 5 / genetics
  • TNF Receptor-Associated Factor 5 / metabolism
  • Transcription Factor RelA / genetics
  • Transcription Factor RelA / metabolism
  • Transcriptome
  • Troponin I / genetics
  • Troponin I / metabolism


  • Biomarkers
  • Fabp3 protein, mouse
  • Fatty Acid Binding Protein 3
  • Fatty Acid-Binding Proteins
  • Myosin Light Chains
  • NF-kappa B
  • TNF Receptor-Associated Death Domain Protein
  • TNF Receptor-Associated Factor 5
  • Tradd protein, mouse
  • Transcription Factor RelA
  • Troponin I
  • Casp3 protein, mouse
  • Casp8 protein, mouse
  • Caspase 3
  • Caspase 8
  • Myosin Heavy Chains