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| Pàgina inicial > Articles > Articles publicats > Age-related metabolic changes limit efficacy of deoxynucleoside-based therapy in thymidine kinase 2-deficient mice |
(Hospital Universitari Vall d'Hebron. Institut de Recerca) (Hospital Universitari Vall d'Hebron. Institut de Recerca) (Centro de Investigación Biomédica en Red de Enfermedades Raras) (Hospital Universitari Vall d'Hebron. Institut de Recerca)| Data: | 2019 |
| Resum: | Thymidine kinase 2 (TK2) catalyses the phosphorylation of deoxythymidine (dThd) and deoxycytidine (dCtd) within mitochondria. TK2 deficiency leads to mtDNA depletion or accumulation of multiple deletions. In patients, TK2 mutations typically manifest as a rapidly progressive myopathy with infantile onset, leading to respiratory insufficiency and encephalopathy in the most severe clinical presentations. TK2-deficient mice develop the most severe form of the disease and die at average postnatal day 16. dThd+dCtd administration delayed disease progression and expanded lifespan of a knockin murine model of the disease. We daily administered TK2 knockout mice (Tk2 KO) from postnatal day 4 with equimolar doses of dThd+dCtd, dTMP+dCMP, dThd alone or dCtd alone. We monitored body weight and survival and studied different variables at 12 or 29 days of age. We determined metabolite levels in plasma and target tissues, mtDNA copy number in tissues, and the expression and activities of enzymes with a relevant role in mitochondrial dNTP anabolism or catabolism. dThd+dCtd treatment extended average lifespan of Tk2 KO mice from 16 to 34 days, attenuated growth retardation, and rescued mtDNA depletion in skeletal muscle and other target tissues of 12-day-old mice, except in brain. However, the treatment was ineffective in 29-day-old mice that still died prematurely. Bioavailability of dThd and dCtd markedly decreased during mouse development. Activity of enzymes catabolizing dThd and dCtd increased with age in small intestine. Conversely, the activity of the anabolic enzymes decreased in target tissues during mouse development. We also found that administration of dThd alone had the same impact on survival to that of dThd+dCtd, whereas dCtd alone had no influence on lifespan. dThd+dCtd treatment recruits alternative cytosolic salvage pathways for dNTP synthesis, suggesting that this therapy would be of benefit for any Tk2 mutation. dThd accounts for the therapeutic effect of the combined treatment in mice. During the first weeks after birth, mice experience marked tissue-specific metabolic regulations and ontogenetic changes in dNTP metabolism-related enzymes that limit therapeutic efficacy to early developmental stages. This study was funded by grants from the Spanish Ministry of Industry, Economy and Competitiveness, the Spanish Instituto de Salud Carlos III, the Fundación Inocente, Inocente, AFM Téléthon and the Generalitat de Catalunya. The disclosed funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. |
| Ajuts: | Ministerio de Economía y Competitividad FU2014-52618-R Ministerio de Economía y Competitividad SAF2017-87506-R Instituto de Salud Carlos III PI15/00465 Instituto de Salud Carlos III PMP15/00025 Agència de Gestió d'Ajuts Universitaris i de Recerca SLT002/16/00370 |
| Drets: | Aquest document està subjecte a una llicència d'ús Creative Commons. Es permet la reproducció total o parcial, la distribució, i la comunicació pública de l'obra, sempre que no sigui amb finalitats comercials, i sempre que es reconegui l'autoria de l'obra original. No es permet la creació d'obres derivades.  |
| Llengua: | Anglès |
| Document: | Article ; recerca ; Versió publicada |
| Matèria: | TK2 ; Deoxynucleoside therapy ; Mtdna depletion ; Encephalomyopathy ; Thymidine ; Deoxycytidine ; CDA, cytidine deaminase ; CNS, central nervous system ; Dck, deoxycytidine kinase ; Dcmp, deoxycytidine monophosphate ; Dctd, deoxycytidine ; Dn, deoxynucleoside ; Dnmp, deoxynucleoside monophosphate ; Dntp, deoxynucleoside triphosphate ; Dthd, deoxythymidine ; Dtmp, deoxythymidine monophosphate ; KO, knockout ; Mtdna, mitochondrial DNA ; Ndna, nuclear DNA ; PBS, phosphate buffered saline ; Thy, thymine ; TK1, thymidine kinase 1 ; TK2, thymidine kinase 2 ; TP, thymidine phosphorylase ; Tymp, thymidine phosphorylase gene ; WT, wild-type |
| Publicat a: | EBioMedicine, Vol. 46 (july 2019) , p. 342-355, ISSN 2352-3964 |
