Inducible overexpression of wild-type prion protein in the muscles leads to a primary myopathy in transgenic mice

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

Research output: Contribution to journalArticle

22 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)6800-6805
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume104
Issue number16
DOIs
StatePublished - Apr 17 2007

Keywords

  • Doxycycline
  • Inducible transgenic mice
  • Muscle disease

ASJC Scopus subject areas

  • General

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    Huang, S., Liang, J., Zheng, M., Li, X., Wang, M., Wang, P., Vanegas, D., Wu, D., Chakraborty, B., Hays, A. P., Chen, K., Chen, S. G., Booth, S., Cohen, M., Gambetti, P., & Kong, Q. (2007). Inducible overexpression of wild-type prion protein in the muscles leads to a primary myopathy in transgenic mice. Proceedings of the National Academy of Sciences of the United States of America, 104(16), 6800-6805. https://doi.org/10.1073/pnas.0608885104