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Ovarian transcriptome associated with reproductive senescence in the long-living Ames dwarf mice.

ABSTRACT: The aim of the current work was to evaluate the ovarian follicle reserve and the ovarian transcriptome in Ames dwarf (df/df) mice. The results suggest a delayed ovarian aging in df/df mice compared to normal (N) mice. Although a high number of genes were differentially expressed during aging of N mice, only a small fraction of these changed with aging in df/df mice. These alterations involved more than 500 categorized biological processes. The majority of these biological processes, including inflammatory/immune responses, were up-regulated with aging in N mice, while old df/df mice were characterized by down-regulation of these same processes in comparison to age matched N mice. However, biological processes related to DNA damage and repairing were commonly down-regulated with aging in both genotypes. In conclusion, delayed ovarian aging in long-living df/df mice was associated with reduced expression of genes related to the inflammatory and immune responses.

SUBMITTER: Schneider A

PROVIDER: S-EPMC5123904 | biostudies-literature | 2017 Jan

REPOSITORIES: biostudies-literature

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Ovarian transcriptome associated with reproductive senescence in the long-living Ames dwarf mice.

Schneider Augusto A Matkovich Scot J SJ Saccon Tatiana T Victoria Berta B Spinel Lina L Lavasani Mitra M Bartke Andrzej A Golusinski Pawel P Masternak Michal M MM

Molecular and cellular endocrinology 20160920

The aim of the current work was to evaluate the ovarian follicle reserve and the ovarian transcriptome in Ames dwarf (df/df) mice. The results suggest a delayed ovarian aging in df/df mice compared to normal (N) mice. Although a high number of genes were differentially expressed during aging of N mice, only a small fraction of these changed with aging in df/df mice. These alterations involved more than 500 categorized biological processes. The majority of these biological processes, including in ...[more]

PMID: 27663076

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Project description:Long-lived Ames dwarf mice lack growth hormone, prolactin, and thyroid stimulating hormone. Additionally the dwarf mice have enzyme activities and levels that combat oxidative stress more efficiently than those of normal mice. We have shown that methionine metabolism in Ames mice is markedly different than in their wild type littermates. In our previous work we hypothesized that the flux of methionine to the transsulfuration pathway is enhanced in the dwarf mice. The current study was designed to determine whether the flux of methionine to the transsulfuration pathway is increased. We did this by injecting either l-[methyl-(3)H]-methionine or l-[(35)S]-methionine into dwarf or normal mice and then determined retained label (in form of S-adenosylmethionine) 45 min later. The amount of retained hepatic (3)H and (35)S label was significantly reduced in the dwarf mice; at 45 min the specific radioactivity of SAM (pCi/nmol SAM) was 56% lower (p < 0.05) for (3)H-label and 64% lower (p < 0.005) for (35)S-label in dwarf than wild type mice. Retention of (35)S was significantly lower in the brain (37%, p < .04) and kidney (47%, p < 0.02) of the dwarf compared to wild type mice; there was no statistical difference in retained (3)H-label in either brain or kidney. This suggests that both the methyl-moiety and the carbon chain of methionine are lost much faster in the dwarf compared to the wild type mouse, implying that both transmethylation in the liver and transsulfuration in the liver, brain, and kidney are increased in the dwarf mice. As further support, we determined by real-time RT PCR the expression of methionine metabolism genes in livers of mice. Compared to wild type, the Ames dwarf had increased expression of methionine adenosyltransferase 1a (2.3-fold, p = 0.013), glycine N-methyltransferase (3.8-fold, p = 0.023), betaine homocysteine methyltransferase (5.5-fold, p = 0.0006), S-adenosylhomocysteine hydrolase (3.8-fold, p = 0.0005), and cystathionase (2.6-fold; tended to be increased, p = 0.055). Methionine synthase expression was significantly decreased in dwarf compared to wild type (0.48-fold, p = 0.023). These results confirm that the flux of methionine to transsulfuration is enhanced in the Ames dwarf. This, along with data from previous studies support the hypothesis that altered methionine metabolism plays a significant role in the oxidative defense of the dwarf mouse and that the mechanism for the enhanced oxidative defense may be through altered GSH metabolism as a result of the distinctive methionine metabolism.

Project description:BackgroundExtending mammalian health span and life span has been achieved under a variety of dietary restriction protocols. Reducing the intake of a specific amino acid has also been shown to extend health and longevity. We recently reported that methionine (MET) restriction is not effective in life span extension in growth hormone (GH) signaling mutants. To better understand the apparent necessity of GH in the 'sensing' of altered dietary MET, the current study was designed to evaluate MET and glutathione (GSH) metabolism (as well as other pathways) in long-living GH-deficient Ames dwarf and wild-type mice following 8 weeks of restricted (0.16%), low (0.43%), or enriched (1.3%) dietary MET consumption. Metabolite expression was examined in liver tissue, while gene and protein expression were evaluated in liver, kidney, and muscle tissues.ResultsBody weight was maintained in dwarf mice on the MET diets, while wild-type mice on higher levels of MET gained weight. Liver MET levels were similar in Ames mice, while several MET pathway enzymes were elevated regardless of dietary MET intake. Transsulfuration enzymes were also elevated in Ames mice but differences in cysteine levels were not different between genotypes. Dwarf mice maintained higher levels of GSH on MET restriction compared to wild-type mice, while genotype and diet effects were also detected in thioredoxin and glutaredoxin. MET restriction increased transmethylation in both genotypes as indicated by increased S-adenosylmethionine (SAM), betaine, and dimethylglycine. Diet did not impact levels of glycolytic components, but dwarf mice exhibited higher levels of key members of this pathway. Coenzyme A and measures of fatty acid oxidation were elevated in dwarf mice and unaffected by diet.ConclusionsThis component analysis between Ames and wild-type mice suggests that the life span differences observed may result from the atypical MET metabolism and downstream effects on multiple systems. The overall lack of responsiveness to the different diets is well reflected across many metabolic pathways in dwarf mice indicating the importance of GH signaling in the ability to discriminate dietary amino acid levels.

Dataset Information

Ovarian transcriptome associated with reproductive senescence in the long-living Ames dwarf mice.

Publications

Ovarian transcriptome associated with reproductive senescence in the long-living Ames dwarf mice.

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