Human Molecular Genetics Advance Access published online on February 28, 2007
Human Molecular Genetics, doi:10.1093/hmg/ddm037
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Transgenic expression of inclusion body myopathy associated mutant p97/VCP causes weakness and ubiquitinated protein inclusions in mice
1 Department of Neurology, Washington University School of Medicine, 660 S. Euclid Avenue, Saint Louis, MO 63110 2 Department of Cell Biology and Physiology, Washington University School of Medicine, 660 S. Euclid Avenue, Saint Louis, MO 63110
* Corresponding Author: Conrad C. Weihl, MD/PhD Department of Neurology, Box 8111, Washington University School of Medicine, 660 S. Euclid Avenue, Saint Louis, MO 63110 Office: 314-362-6981 Fax: 314-362-3752 Email: weihlc{at}neuro.wustl.edu
Received December 18, 2006; Revised February 19, 2007; Accepted February 19, 2007
Mutations in p97/VCP cause the autosomal dominantly inherited syndrome inclusion body myopathy (IBM) associated with Paget's disease of the bone and frontotemporal dementia (FTD) (IBMPFD) (1). p97/VCP is a multi-functional protein with a role in the ubiquitin-proteasome system (UPS) (2). To understand how mutations in this protein lead to a myopathy, we generated several lines of transgenic mice expressing p97/VCP-WT (TgVCP-WT) or the most common IBMPFD mutant, p97/VCP R155H (TgVCP-RH), under a muscle specific promoter. TgVCP-RH animals, but not controls, became progressively weaker in a dose dependent manner starting at 6 months of age. Abnormal muscle pathology, which included coarse internal architecture, vacuolation and disorganized membrane morphology with reduced caveolin-3 expression at the sarcolemma developed coincident with the onset of weakness. These changes were not associated with alterations in sarcolemmal integrity as measured by muscle fiber uptake of Evan's blue dye. Even before animals displayed measurable weakness there was an increase in ubiquitin containing protein inclusions and high molecular weight ubiquitinated proteins, markers of UPS dysfunction. We suggest that this early and persistent increase in ubiquitinated proteins induced by IBMPFD mutations in p97/VCP may ultimately lead to animal weakness and the observed muscle pathology. TgVCP-RH animals will be a valuable tool for understanding the pathogenesis of IBM and the role of the UPS in skeletal muscle.
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