Prion protein (PrP) is a glycoprotein constitutively expressed on the neuronal cell surface. A protease-resistant isoform of prion protein is implicated in the pathogenesis of a series of transmissible spongiform encephalopathies. We have developed a line of mice homozygous for a disrupted PrP gene in which the whole PrP-coding sequence is replaced by a drug-resistant gene. In keeping with previous results, we find that homozygous loss of the PrP gene has no deleterious effect on the development of these mice and renders them resistant to prion. The PrP-null mice grew normally after birth, but at about 70 weeks of age all began to show progressive symptoms of ataxia. Impaired motor coordination in these ataxic mice was evident in a rotorod test. Pathological examination revealed an extensive loss of Purkinje cells in the vast majority of cerebellar folia, suggesting that PrP plays a role in the long-term survival of Purkinje neurons.

The purpose of this study was to test the hypothesis that the rate and extent of glycogen supercompensation in skeletal muscle are increased by endurance exercise training. Rats were trained by using a 5-wk-long swimming program in which the duration of swimming was gradually increased to 6 h/day over 3 wk and then maintained at 6 h/day for an additional 2 wk. Glycogen repletion was measured in trained and untrained rats after a glycogen-depleting bout of exercise. The rats were given a rodent chow diet plus 5% sucrose in their drinking water and libitum during the recovery period. There were remarkable differences in both the rates of glycogen accumulation and the glycogen concentrations attained in the two groups. The concentration of glycogen in epitrochlearis muscle averaged 13.1 +/- 0.9 mg/g wet wt in the untrained group and 31.7 +/- 2.7 mg/g in the trained group (P < 0.001) 24 h after the exercise. This difference could not be explained by a training effect on glycogen synthase. The training induced approximately 50% increases in muscle GLUT-4 glucose transporter protein and in hexokinase activity in epitrochlearis muscles. We conclude that endurance exercise training results in increases in both the rate and magnitude of muscle glycogen supercompensation in rats.

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It was recently found that the effect of an exercise-induced increase in muscle GLUT-4 on insulin-stimulated glucose transport is masked by a decreased responsiveness to insulin in glycogen-supercompensated muscle. We evaluated the role of hexosamines in this decrease in insulin responsiveness and found that UDP- N-acetyl hexosamine concentrations were not higher in glycogen-supercompensated muscles than in control muscles with a low glycogen content. We determined whether the smaller increase in glucose transport is due to translocation of fewer GLUT-4 to the cell surface with the 2- N-4-(1-azi-2,2,2-trifluroethyl)-benzoyl-1,3-bis(d-mannose-4-yloxy)-2-propylamine (ATB-[2-3H]BMPA) photolabeling technique. The insulin-induced increase in GLUT-4 at the cell surface was no greater in glycogen-supercompensated exercised muscle than in muscles of sedentary controls and only 50% as great as in exercised muscles with a low glycogen content. We conclude that the decreased insulin responsiveness of glucose transport in glycogen-supercompensated muscle is not due to increased accumulation of hexosamine biosynthetic pathway end products and that the smaller increase in glucose transport is mediated by translocation of fewer GLUT-4 to the cell surface.

Creutzfeldt-Jakob disease (CJD) is a transmissible neurodegenerative disease of humans caused by an unidentified infectious agent, the prion. To determine whether there was an involvement of the host-encoded prion protein (PrP c) in CJD development and prion propagation, mice heterozygous (PrP ؉/؊) or homozygous (PrP ؊/؊) for a disrupted PrP gene were established and inoculated with the mouse-adapted CJD agent. In keeping with findings of previous studies using other lines of PrP-less mice inoculated with scrapie agents, no PrP ؊/؊ mice showed any sign of the disease for 460 days after inoculation, while all of the PrP ؉/؊ and control PrP ؉/؉ mice developed CJD-like symptoms and died. The incubation period for PrP ؉/؊ mice, 259 ؎ 27 days, was much longer than that for PrP ؉/؉ mice, 138 ؎ 12 days. Propagation of the prion was barely detectable in the brains of PrP ؊/؊ mice and was estimated to be at a level at least 4 orders of magnitude lower than that in PrP ؉/؉ mice. These findings indicate that PrP c is necessary for both the development of the disease and propagation of the prion in the inoculated mice. The proteinase-resistant PrP (PrP res) was undetectable in the brain tissues of the inoculated PrP ؊/؊ mice, while it accumulated in the affected brains of PrP ؉/؉ and PrP ؉/؊ mice. Interestingly, the maximum level of PrP res in the brains of PrP ؉/؊ mice was about half of the level in the similarly affected brains of PrP ؉/؉ mice, indicating that PrP res accumulation is restricted by the level of PrP c .