title: Inducible overexpression of wild-type prion protein in the muscles leads to a primary myopathy in transgenic mice.
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.
authors.affiliation: Department of Pathology, Case Western Reserve University, Cleveland, OH 44106, USA.
authors.forename: Shenghai
authors.initials: S
authors.lastname: Huang
authors.forename: Jingjing
authors.initials: J
authors.lastname: Liang
authors.forename: Mengjie
authors.initials: M
authors.lastname: Zheng
authors.forename: Xinyi
authors.initials: X
authors.lastname: Li
authors.forename: Meiling
authors.initials: M
authors.lastname: Wang
authors.forename: Ping
authors.initials: P
authors.lastname: Wang
authors.forename: Difernando
authors.initials: D
authors.lastname: Vanegas
authors.forename: Di
authors.initials: D
authors.lastname: Wu
authors.forename: Bikram
authors.initials: B
authors.lastname: Chakraborty
authors.forename: Arthur P
authors.initials: AP
authors.lastname: Hays
authors.forename: Ken
authors.initials: K
authors.lastname: Chen
authors.forename: Shu G
authors.initials: SG
authors.lastname: Chen
authors.forename: Stephanie
authors.initials: S
authors.lastname: Booth
authors.forename: Mark
authors.initials: M
authors.lastname: Cohen
authors.forename: Pierluigi
authors.initials: P
authors.lastname: Gambetti
authors.forename: Qingzhong
authors.initials: Q
authors.lastname: Kong
mesh_terms: D000818:Animals; D004318:Doxycycline / Q000494:pharmacology; D005786:Gene Expression Regulation / Q000187:drug effects; D006801:Humans; D051379:Mice; D008822:Mice, Transgenic; D018482:Muscle, Skeletal / Q000187:drug effects / Q000378:metabolism*; D009135:Muscular Diseases / Q000139:chemically induced / Q000235:genetics* / Q000378:metabolism*; D018621:PrPC Proteins / Q000096:biosynthesis* / Q000235:genetics*
chemical_list: D018621:PrPC Proteins; D004318:Doxycycline