Prions in skeletal muscle

Abstract

Here we report that mouse skeletal muscle can propagate prions and accumulate substantial titers of these pathogens. We found both high prion titers and the disease-causing isoform of the prion protein (PrP Sc ) in the skeletal muscle of wild-type mice inoculated with either the Me7 or Rocky Mountain Laboratory strain of murine prions. Particular muscles accumulated distinct levels of PrP Sc , with the highest levels observed in muscle from the hind limb. To determine whether prions are produced or merely accumulate intramuscularly, we established transgenic mice expressing either mouse or Syrian hamster PrP exclusively in muscle. Inoculating these mice intramuscularly with prions resulted in the formation of high titers of nascent prions in muscle. In contrast, inoculating mice in which PrP expression was targeted to hepatocytes resulted in low prion titers. Our data demonstrate that factors in addition to the amount of PrP expressed determine the tropism of prions for certain tissues. That some muscles are intrinsically capable of accumulating substantial titers of prions is of particular concern. Because significant dietary exposure to prions might occur through the consumption of meat, even if it is largely free of neural and lymphatic tissue, a comprehensive effort to map the distribution of prions in the muscle of infected livestock is needed. Furthermore, muscle may provide a readily biopsied tissue from which to diagnose prion disease in asymptomatic animals and even humans.

PrPTSE in muscle-associated lymphatic tissue during the preclinical stage of mice infected orally with bovine spongiform encephalopathy

“…The presence and distribution of infectivity or PrP TSE accumulation in muscles of 'natural' TSE infections differ in different host-strain combinations (Andréoletti et al, 2004;Angers et al, 2006;Beekes & McBride, 2007;Bosque et al, 2002;Casalone et al, 2005;Glatzel et al, 2003;Herzog et al, 2005;Peden et al, 2006;Thomzig et al, 2004Thomzig et al, , 2006. This heterogeneity has also been observed in experimental models of TSEs.…”

Transmission of prions

“…If a sufficiently high dose of prions is administered i.p., neuroinvasion can occur without participation of the LRS (60). Although prions have not been detected in muscle of scrapie or BSE-infected animals, infectivity has been found in some, but not all skeletal muscles of mice experimentally infected with ME7 or RML prions (61).…”

Recent Developments in Prion Disease Research: Diagnostic Tools and In Vitro Cell Culture Models

“…Most of the diagnostic methods for prion infections depend on PrP Sc detection, while susceptibility of cells to prions, at least in part, depends on cell-type. Since PrP Sc tends to accumulate in the brains of prion-infected animals with neurons serving as the target, it is only natural that PrP Sc accumulations are selectively located in the neurons of both the central nervous system (CNS) and peripheral nervous system (PNS) [10,32,34,62,137]. However, certain combinations of prion strain and host species show PrP Sc accumulations in not only the CNS and PNS but also other tissues such as the tonsils, spleen, lymphnode, retina, proximal nerves, and gut-associ-ated lymphoid tissues [2,12,37,39,47,89].…”

“…only the CNS but also the placenta, lymphoreticular systems (see above), and muscles [10,127]. As the use of prion-susceptible cell line N2a is virtually simple for culture, this cell line is the most extensively employed for prion infection studies, although its low post-infection titers and rapid attenuation of titers require improvement [15,85].…”