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JOURNAL OF BIOLOGICAL CHEMISTRY
Volume 299, Issue 3, Pages -Publisher
ELSEVIER
DOI: 10.1016/j.jbc.2023.103002
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Rodents have higher plasma thymidine levels compared to other mammals, including humans. A new knock-in mouse model with high expression of human thymidine phosphorylase was generated to study this difference in nucleotide metabolism. The knock-in mice exhibited growth retardation, decreased plasma thymidine levels, and various phenotypic abnormalities, which could be partially or completely rescued by the administration of a thymidine phosphorylase inhibitor. These findings suggest that the knock-in mouse model can be used to study mitochondrial diseases and investigate differences in nucleotide metabolism between humans and mice.
Plasma thymidine levels in rodents are higher than in other mammals including humans, possibly due to a different pattern and lower level of thymidine phosphorylase expression. Here, we generated a novel knock-in (KI) mouse line with high systemic expression of human thymidine phosphorylase to investigate this difference in nucleotide metabolism in rodents. The KI mice showed growth retardation around weaning and died by 4 weeks of age with a decrease in plasma thymidine level compared with the litter-control WT mice. These phenotypes were completely or partially rescued by administration of the thymidine phosphorylase inhibitor 5-chloro-6-(2drochloride or thymidine, respectively. Interestingly, when thymidine phosphorylase inhibitor administration was discontinued in adult animals, KI mice showed deteriorated grip strength and locomotor activity, decreased bodyweight, and subsequent hind-limb paralysis. Upon histological analyses, we observed axonal degeneration in the spinal cord, muscular atrophy with morphologically abnormal mitochondria in quadriceps, retinal degeneration, and abnormality in the exocrine pancreas. Moreover, we detected mitochondrial DNA depletion in multiple tissues of KI mice. These results indicate that the KI mouse represents a new animal model for mitochondrial diseases and should be applicable for the study of differences in nucleotide metabolism between humans and mice.
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