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Human Molecular Genetics Advance Access published online on May 11, 2005
Human Molecular Genetics, doi:10.1093/hmg/ddi192
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© The Author 2005. Published by Oxford University Press. All rights reserved
Received March 29, 2005
Revised April 29, 2005
Accepted May 6, 2005

Article

Gene expression in Huntington's disease skeletal muscle: a potential biomarker

Andrew D. Strand 1*, Aaron K. Aragaki 2, Dennis Shaw 3, Thomas Bird 3, Janice Holton 4, Christopher Turner 5, Stephen J. Tapscott 6, Sarah J. Tabrizi 7, Anthony Schapira 8, Charles L. Kooperberg 2, and James M. Olson 1

1 Clinical Research, Fred Hutchinson Cancer Research Center, Seattle, WA 98109, USA
2 Public Health Sciences, Fred Hutchinson Cancer Research Center, Seattle, WA 98109, USA
3 University of Washington, Seattle, WA 98195, USA
4 Department of Molecular Neuroscience, Institute of Neurology, University College London, Queen Square, London WC1N 3BG
5 University Department of Clinical Neurosciences, Royal Free and University College Medical School, UCL, London NW3 2PF
6 Human Biology Division, Fred Hutchinson Cancer Research Center, Seattle, WA 98109, USA
7 Department of Neurodegenerative Disease/MRC Prion Unit Institute of Neurology, National Hospital for Neurology and Neurosurgery, Queen Square, London WC1N 3BG, UK
8 Department of Molecular Neuroscience, Institute of Neurology, University College London, Queen Square, London WC1N 3BG; University Department of Clinical Neurosciences, Royal Free and University College Medical School, UCL, London NW3 2PF

* To whom correspondence should be addressed.
Andrew D. Strand, E-mail: astrand{at}fhcrc.org


  Abstract

Huntington's disease (HD) is an incurable and fatal neurodegenerative disorder. Improvements in the objective measurement of HD will lead to more efficient clinical trials and earlier therapeutic intervention. We hypothesized that abnormalities seen in the R6/2 mouse, a greatly accelerated HD model, might highlight subtle phenotypes in other mouse models and human HD. In this paper we identify common gene expression changes in skeletal muscle from R6/2 mice, HdhCAG(150) homozygous knockin mice, and HD patients. This HD-triggered gene expression phenotype is consistent with the beginnings of a transition from fast-twitch to slow-twitch muscle fiber types. Metabolic adaptations similar to those induced by diabetes or fasting are also present but neither metabolic disorder can explain the full phenotype of HD muscle. The HD-induced gene expression changes reflect disease progression. This raises the possibility that muscle gene expression may be used as an objective biomarker to complement clinical HD-rating systems. Furthermore, an understanding of the molecular basis of muscle dysfunction in HD should provide insight into mechanisms involved in neuronal abnormalities and neurodegeneration.


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