Metabolomics,Unknown,Transcriptomics,Genomics,Proteomics

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Comparative genomic hybridization of mouse liver and tumors from Acd mutant and wild type strains in p53 deficient background

ABSTRACT: DNA from tumors of 10 male mice were competitively hybridized with DNA from liver samples from the same mouse on NimbleGen CGH arrays to assess copy number changes in the tumors. Four of the mice were wildtype for Acd (ortholog of human TPP1), 2 of which were p53-/- and 2 of which were p53-/+. The other 6 mice were homozygous for the mutant acd allele of Acd. 3 of these mice were p53-/- and the other 3 were p53-/+. Mice were crosses from double heterozygote parental mice. These parental mice were crosses of heterozygous Acd mutant mice (in a mixed DW/JxCAST/Ei background) with heterozygous null p53 mice (C57BL6/J; Trp53-tm1Tyj).

ORGANISM(S): Mus musculus

DISEASE(S): tumor

SUBMITTER: Rork Kuick

PROVIDER: E-TABM-680 | biostudies-arrayexpress |

REPOSITORIES: biostudies-arrayexpress

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Project description:Exercise is a fundamental component of human health that is associated with greater life expectancy and reduced risk of chronic diseases. While the beneficial effects of endurance exercise on human health are well established, the molecular mechanisms responsible for these observations remain unclear. Endurance exercise reduces the accumulation of mitochondrial DNA (mtDNA) mutations, alleviates multisystem pathology, and increases the lifespan of the mtDNA mutator mouse model of aging, in which the proof-reading capacity of mitochondrial polymerase gamma (POLG1) is deficient. Clearly, exercise recruited a POLG1-independent mtDNA repair pathway to induce these adaptations, a novel finding as POLG1 is canonically considered to be the sole mtDNA repair enzyme. Here we investigate the identity of this pathway, and show that endurance exercise prevents mitochondrial oxidative damage, attenuates telomere erosion, and mitigates cellular senescence and apoptosis in mtDNA mutator mice. Unexpectedly, we observe translocation of tumour suppressor protein p53 to mitochondria in response to endurance exercise that facilitates mtDNA mutation repair. Indeed, endurance exercise failed to prevent mtDNA mutations, induce mitochondrial biogenesis, preserve mitochondrial morphology, reverse sarcopenia, and mitigate premature mortality in mtDNA mutator mice with muscle-specific deletion of p53. Our data establish an exciting new role for p53 in exercise-mediated maintenance of the mtDNA genome, and presents mitochondrially-targeted p53 as a novel therapeutic modality for aging-associated diseases of mitochondrial etiology. Microarray analysis of gene expression from skeletal muscle (quadriceps femoris) from Mus musculus. N=23 samples per treatment were analysed for whole transcriptiome gene expression profile using NimbleGen Arrays. The treatment groups included wild-type C57Bl/6J mice as the control group, then two treatment groups which both contained homozygous knock-in mtDNA mutator mice (PolG; PolgAD257A/D257A). Once group of these heterozygous knock out mice received regular endurance exercise sessions while the other group remained sedentraty for 6 months. The control group specimens were wild-type litter mates to the transgenic knockout mice.

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Comparative genomic hybridization of mouse liver and tumors from Acd mutant and wild type strains in p53 deficient background

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