Gene expression in the liver of female, but not male mice treated with rapamycin resembles changes observed under dietary restriction - PubMed (original) (raw)

Gene expression in the liver of female, but not male mice treated with rapamycin resembles changes observed under dietary restriction

Zhen Yu et al. Springerplus. 2015.

Abstract

It is well known that in mice the extension in lifespan by rapamycin is sexually dimorphic, in that it has a larger effect in females than males. In a previous study we showed that in male C57BL6 mice, rapamycin had less profound effects in both gene expression and liver metabolites when compared to dietary restriction (DR), but no data was available in females. Because recent studies showed that rapamycin increases longevity in a dose dependent manner and at every dose tested the effect remains larger in females than in males, we hypothesized that rapamycin should have a stronger effect on gene expression in females, and this effect could be dose dependent. To test this hypothesis, we measured the changes in liver gene expression induced by rapamycin (14 ppm) with a focus on several genes involved in pathways known to play a role in aging and that are altered by DR. To investigate whether any effects are dose dependent, we also analyzed females treated with two additional doses of rapamycin (22 and 42 ppm). We observed striking differences between male and female in gene expression at 14 ppm, where females have a larger response to rapamycin than males, and the effects of rapamycin in females resemble what we observed under DR. However, these effects were generally not dose dependent. These data support the notion that female mice respond better to rapamycin, and at least with the set of genes studied here, the effect of rapamycin in females resemble the effect of DR.

Keywords: Dietary restriction; Female mice; Gene expression; Longevity pathways; Rapamycin.

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Figures

Figure 1

Figure 1

Rapamycin increases expression of Foxo and Sirtuin genes in females but not in males. The effect of dietary restriction (DR) and rapamycin (Rapa) on the expression of Foxo and Sirtuin genes was measured in liver samples from female (A) and male (B) mice. Open bars: AL; solid bars: DR; Gray bars: Rapa 14 ppm. The data were obtained from 6 male and 8 female mice per group and expressed as mean ± SEM. An asterisk denotes values that are significantly different (p ≤ 0.05) from AL mice.

Figure 2

Figure 2

In female but not male mice, rapamycin and dietary restriction alter the expression of circadian rhythm genes similarly. The effect of dietary restriction (DR) and rapamycin (Rapa) on the expression of circadian rhythm genes was measured in liver samples from female (A) and male (B) mice. Open bars: AL; solid bars: DR; Gray bars: Rapa 14 ppm. The data were obtained from 6 male and 8 female mice per group and expressed as mean ± SEM. An asterisk denotes those values that are significantly different (p ≤ 0.05) from AL mice.

Figure 3

Figure 3

Rapamycin changed the expression of gene related to proteolytic pathways like dietary restriction only in female. The effect of dietary restriction (DR) and Rapamycin (Rapa), on the expression of genes related to ubiquitin-proteasome (A and B) and autophagy (C and D) pathways was measured in liver samples of male (B and D) and female (A and C) mice. The data were obtained from 6 male and 8 female mice per group and expressed as mean ± SEM. An asterisk denotes those values that are significantly different (p ≤ 0.05) from AL mice. Open bars: AL; solid bars: DR; Gray bars: Rapa 14 ppm.

Figure 4

Figure 4

Rapamycin changes significantly the expression of genes involved in the ER stress pathway only in females. The effect of dietary restriction (DR) and rapamycin (Rapa) on the expression of genes involved in the ER stress pathway was measured in liver samples from female (A) and male (B) mice. The data were obtained from 6 male and 8 female mice per group and expressed as mean ± SEM. An asterisk denotes those values that are significantly different (p ≤ 0.05) from AL mice. Open bars: AL; solid bars: DR; Gray bars: Rapa 14 ppm.

Figure 5

Figure 5

Effect of dietary restriction (DR) and rapamycin on protein levels in the liver. The effect of dietary restriction (DR) and rapamycin (Rapa) on protein levels was measured by Western blot analysis in livers obtained from 8 female mice per group and expressed as mean ± SEM. An asterisk denotes those values that are significantly different (p ≤ 0.05) from AL mice. Open bars: AL; Solid bars: DR; Gray bars: Rapa 14 ppm.

Figure 6

Figure 6

Rapamycin and DR exert similar effects on gene expression in subcutaneous fat from female mice. The effect of dietary restriction (DR) and rapamycin (Rapa) on gene expression was measured in subcutaneous fat from 6 female mice per group. The data was expressed as mean ± SEM, and an asterisk denotes those values that are significantly different (p ≤ 0.05) from AL mice. Open bars: AL; Solid bars: DR; Gray bars: Rapa 14 ppm.

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