Calorie restriction does not influence oocyte quality in oocytes from POLG mitochondrial mutator mice.

It has recently been demonstrated that moderate adult onset caloric restriction (e.g. calorie restriction; CR) has a positive impact on female fertility in aged mice, due in large to preventing the age-associated decline in the quality of oocytes available for fertilization. The impact of CR on oocyte quality has been attributed, at least in part, to mitochondrial functions. In mitochondrial DNA (mtDNA) mutator mice (PolgD257A/D257A), which harbor a mutation in the proofreading mtDNA polymerase-gamma (POLG), mitochondrial mutations rapidly accumulate, resulting in a premature aging phenotype and female infertility. As CR has been shown to extend both lifespan and 'healthspan' as well as improve oocyte quality in aged mice, we investigated whether adult onset CR could improve oocyte quality in the POLG mouse. Female PolgD257A/D257A mice exhibited infertility based on an inability to produce litters through natural mating. Analysis of oocytes from 8-9-month-old PolgD257A/D257A mice on CR following hormone stimulation revealed no improvement in the number of oocytes ovulated. Furthermore, CR did not result in a greater percentage of metaphase II oocytes, with the majority of the oocytes prematurely arrested at the germinal vesicle stage. Finally, CR did not improve the abnormal mitochondrial distribution or pronounced defects in meiotic spindle assembly and chromosomal distribution observed in the ad libitum fed PolgD257A/D257A. Taken together, these data suggest that although CR benefits oocyte quality and fertility outcomes in naturally aged female mice, it does not sufficiently improve oocyte quality in PolgD257A/D257A.

Impact of exercise on oocyte quality in the POLG mitochondrial DNA mutator mouse.

The mtDNA 'mutator' mouse, also called the 'POLG' mouse, is a well-characterized model frequently used for studies of progeroid aging. Harboring a mutation in the proofreading domain of the mitochondrial polymerase, polymerase-γ (Polg), POLG mice acquire mtDNA mutations at an accelerated rate. This results in premature mitochondrial dysfunction and a systemic aging phenotype. Previous work has demonstrated that the progeroid phenotype in POLG is attenuated following endurance exercise, the only reported intervention to extend health span and lifespan of these mice. Herein, oocyte quality was evaluated in sedentary and exercised POLG mice. In mice homozygous for the Polg mutation, litter size is dramatically reduced as compared to heterozygous Polg mice. Following ovarian hyper-stimulation, oocytes were retrieved until 9 months of age in exercised and sedentary groups, with no oocytes ovulated thereafter. Although ovulated oocyte numbers were not impacted by exercise, we did find a modest improvement in both the ovarian follicle reserve and in oocyte quality based on meiotic spindle assembly, chromosomal segregation and mitochondrial distribution at 7 months of age in exercised POLG mice as compared to sedentary counterparts. Of note, analysis of mtDNA mutational load revealed no differences between exercised and sedentary groups. Collectively, these data indicate that exercise differentially influences somatic tissues of the POLG mouse as compared to oocytes, highlighting important mechanistic differences between mitochondrial regulatory mechanisms in the soma and the germline.