Prion protein expression and functional importance in skeletal muscle

Background: Skeletal muscle expresses prion protein (PrP) which buffers oxidant activity in neurons. Similarly, we hypothesized that PrP deficiency would increase oxidant activity in skeletal muscle and alter redox-sensitive functions, including contraction and glucose uptake. We used real-time polymerase chain reaction and Western blot to measure PrP mRNA and protein in human diaphragm, five murine muscles, and muscle-derived C2C12 cells. Effects of PrP deficiency were tested by comparing PrP-deficient mice versus wild-type mice and morpholino-knockdown versus vehicle-treated myotubes. Oxidant activity (dichlorofluorescin oxidation) and specific force were measured in murine diaprhagm fiber bundles. Results: PrP content differs among mouse muscles (gastrocnemius > extensor digitorum longus, EDL > tibialis anterior, TA; soleus > diaphragm) as does glycosylation (di-, mono-, non-glycosylated; gastrocnemius, EDL, TA = 60%, 30%, 10%; soleus, 30%, 40%, 30%; diaphragm, 30%, 30%, 40%). PrP is predominantly di-glycosylated in human diaphragm. PrP deficiency decreases body weight (15%) and EDL mass (9%); increases cytosolic oxidant activity (fiber bundles, 36%; C2C12 myotubes, 7%); and depresses specific force (12%) in adult (8-12 mos) but not adolescent (2 mos) mice. Conclusions: PrP content varies among murine skeletal muscles and is essential for maintaining normal redox homeostasis, muscle size, and contractile function in adult animals.