Authors: Magnusson-Lind, Anna | Davidsson, Marcus | Silajdžić, Edina | Hansen, Christian | McCourt, Andrew C. | Tabrizi, Sarah J. | Björkqvist, Maria
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: Muscle atrophy, gene expression, NFκB pathway, Acta1, Troponin, myosin, p65/RelA, Traf5, Tradd
Citation: Journal of Huntington's Disease,
vol. 3, no. 1, pp. 13-24, 2014
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