CELLULAR PRION PROTEIN ABLATION REDUCES AEROBIC EXERCISE CAPACITY AS A FUNCTION OF AGE

The prion protein PrPC is infamous for its role in fatal neurodegenerative disorders, called transmissible spongiform encephalopathies, yet its normal physiological function remains enigmatic. A major conceptual obstacle to this issue is that genetically modified mice with the targeted disruption of the PrP gene do not show apparent alterations in lifespan, development, or behaviour. During the last years, however, several observations have suggested that changes may occur in these animals, and that such changes can be revealed only under specific stress conditions. Although neurons are generally regarded as the model of election to study the function of PrPC, important information on its biological role may equally come from the analysis of extra-neural tissues. In the present study, we investigated the possible involvement of PrPC in physical exercise capacity using PrP-knockout (PrP-KO) mice. To this purpose, we evaluated PrP-KO mice of different ages in the treadmill test, and compared their performance to that of age-matched congenic wild-type (WT) mice, and of transgenic mice in which the expression of natural levels of PrPC has been rescued starting from a PrP-KO genotype (line Tg46). PrP-KO mice showed an age-dependent impairment of the aerobic performance with respect to both WT and Tg46 animals. In searching for possible mechanisms associated with the reduced resistance of aged PrP-KO mice to run, we analysed different nervous, muscular and metabolic parameters in these animals, compared to those of age-matched Tg46 mice. We concluded that aged PrP-KO mice had a remarkable demyelination of the sciatic nerve, a reduction in muscle force, a variation in the skeletal muscle expression of myosin isoforms, and an increase of the plasma levels of lactic acid, with respect to the PrP-expressing counterpart. Taken together, these findings may concur to explain the impairment of the aerobic performance in PrP-KO mice subjected to the extreme exercise conditions of the treadmill test.