Abstract |
The prion protein (PrP) level in muscle has been reported to be elevated in patients with inclusion-body myositis, polymyositis, dermatomyositis, and neurogenic muscle atrophy, but it is not clear whether the elevated PrP accumulation in the muscles is sufficient to cause muscle diseases. We have generated transgenic mice with muscle-specific expression of PrP under extremely tight regulation by doxycycline, and we have demonstrated that doxycycline-induced overexpression of PrP strictly limited to muscles leads to a myopathy characterized by increased variation of myofiber size, centrally located nuclei, and endomysial fibrosis, in the absence of intracytoplasmic inclusions, rimmed vacuoles, or any evidence of a neurogenic disorder. The PrP-induced myopathy correlates with accumulation of an N-terminal truncated PrP fragment in the muscle, and the muscular PrP displayed consistent mild resistance to protease digestion. Our findings indicate that overexpression of wild-type PrP in skeletal muscles is sufficient to cause a primary myopathy with no signs of peripheral neuropathy, possibly due to accumulation of a cytotoxic truncated form of PrP and/or PrP aggregation.
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Authors | Shenghai Huang, Jingjing Liang, Mengjie Zheng, Xinyi Li, Meiling Wang, Ping Wang, Difernando Vanegas, Di Wu, Bikram Chakraborty, Arthur P Hays, Ken Chen, Shu G Chen, Stephanie Booth, Mark Cohen, Pierluigi Gambetti, Qingzhong Kong |
Journal | Proceedings of the National Academy of Sciences of the United States of America
(Proc Natl Acad Sci U S A)
Vol. 104
Issue 16
Pg. 6800-5
(Apr 17 2007)
ISSN: 0027-8424 [Print] United States |
PMID | 17420473
(Publication Type: Journal Article, Research Support, N.I.H., Extramural)
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Chemical References |
- PrPC Proteins
- Doxycycline
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Topics |
- Animals
- Doxycycline
(pharmacology)
- Gene Expression Regulation
(drug effects)
- Humans
- Mice
- Mice, Transgenic
- Muscle, Skeletal
(drug effects, metabolism)
- Muscular Diseases
(chemically induced, genetics, metabolism)
- PrPC Proteins
(biosynthesis, genetics)
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