Impaired telomere pathway and fertility in Senescence-Accelerated Mice Prone 8 females with reproductive senescence

Abstract

Ovarian aging is the main cause of infertility and telomere attrition is common to both aging and fertility disorders. Senescence-Accelerated Mouse Prone 8 (SAMP8) model has shortened lifespan and premature infertility, reflecting signs of reproductive senescence described in middle-aged women. Thus, our objective was to study SAMP8 female fertility and the telomere pathway at the point of reproductive senescence. The lifespan of SAMP8 and control mice was monitored. Telomere length (TL) was measured by in situ hybridization in blood and ovary. Telomerase activity (TA) was analyzed by telomere-repeat amplification protocol, and telomerase expression, by real-time quantitative PCR in ovaries from 7-month-old SAMP8 and controls. Ovarian follicles at different stages of maturation were evaluated by immunohistochemistry. Reproductive outcomes were analyzed after ovarian stimulation. Unpaired t -test or Mann-Whitney test were used to calculate p -values, depending on the variable distribution. Long-rank test was used to compare survival curves and Fisher’s exact test was used in contingency tables. Median lifespan of SAMP8 females was reduced compared to SAMP8 males ( p = 0.0138) and control females ( p < 0.0001). In blood, 7-month-old SAMP8 females presented lower mean TL compared to age-matched controls ( p = 0.041). Accordingly, the accumulation of short telomeres was higher in 7-month-old SAMP8 females ( p = 0.0202). Ovarian TA was lower in 7-month-old SAMP8 females compared to controls. Similarly, telomerase expression was lower in the ovaries of 7-month-old SAMP8 females ( p = 0.04). Globally, mean TL in ovaries and granulosa cells (GCs) were similar. However, the percentage of long telomeres in ovaries ( p = 0.004) and GCs ( p = 0.004) from 7-month-old SAMP8 females was lower compared to controls. In early-antral and antral follicles, mean TL of SAMP8 GCs was lower than in age-matched controls ( p = 0.0156 for early-antral and p = 0.0037 for antral follicles). Middle-aged SAMP8 showed similar numbers of follicles than controls, although recovered oocytes after ovarian stimulation were lower ( p = 0.0068). Fertilization rate in oocytes from SAMP8 was not impaired, but SAMP8 mice produced significantly more morphologically abnormal embryos than controls (27.03% in SAMP8 vs. 1.22% in controls; p < 0.001). Our findings suggest telomere dysfunction in SAMP8 females, at the time of reproductive senescence.

Disruption of mitochondrial unfolded protein response results in telomere shortening in mouse oocytes and somatic cells

“…liver or spleen) in a primary cell culture through the high number of cell divisions needed to achieve a measurable change in telomere length. Therefore, like others before us [ 33 ], we used an in vivo animal model, allowing us to study cells in their respective tissues after rounds of mitosis, and compare Clpp −/− to WT. In 6- and 9-month-old Clpp -deficient mice, we found shorter telomere length in the liver when compared with WT, suggesting that the impaired mitochondrial function within the liver in Clpp −/− mice could be triggering hepatic cellular changes that culminate in telomere shortening.…”