The Application of NMN in Improving Oocyte Quality in T1D Mice
Introduction
Reproductive dysfunction is frequent in female suffering from type 1 diabetes (T1D), up to 40% of whom will develop a variety of reproductive dysfunctions throughout their lives. T1D patients often have a declined oocyte maturation rate and low-quality oocytes. Noteworthily, nicotinamide mononucleotide (NMN) has been ascertained to be effective in improving the maturation rate and oocyte quality, which brings new hope to diabetic patients who are plagued by infertility problems.
The detrimental effect of T1D on reproductive function
T1D is harmful to the oocyte maturation, pre-implantation embryo development and pregnancy outcome, which can lead to delayed menarche, menstrual cycle abnormalities, ovulatory dysfunction, polycystic ovary syndrome, low fertility, pregnancy complications, and potential early menopause. The mother with T1D could produce fetuses with higher incidences of malformations and death. T1D can diminish the ovarian size and ovarian weight to some extent, raising the risk of infertility. Under diabetic condition, elevated glucose can diminish the extrusion rate of first polar body, thereby impairing the growth and development ability of oocytes.
The effects of NMN on oocyte maturation of mouse with T1D mouse
NMN can recover actin dynamics, as signified by the substantially elevated actin fluorescence intensity on the plasma membrane of the diabetic mouse oocytes following NMN treatment. In addition, NMN reverses meiotic defects in in vitro matured oocytes of the mice with diabetes. The spindle defects are frequently observed in MII oocytes of the mice with diabetes, while NMN supplementation markedly reduces the frequency of defect spindles caused by diabetes.
Meanwhile, NMN improves the mitochondrial function of in vitro matured diabetic oocytes, as indicated by the restored mitochondrial signals as well as the dramatically increased levels of genes related to mitochondrial fusion (Opa1, Mfn2) and mitochondrial fission (Drp1) in in vitro matured diabetic oocytes post NMN treatment.
Oocyte quality is prone to be affected by high ROS-induced DNA damage in diabetes. Remarkably, NMN can reduce ROS level, attenuate DNA damage, and reduce oxidative stress, as manifested by decreased ROS level, weak γH2A.X signal and upregulated mRNA level of anti-oxidation Sod1, respectively.
Furthermore, the histone acetylation and methylation play important roles in oocyte maturation and early embryo development. Herein, aberrant histone modifications caused by diabetes are restored by NMN, as evidenced by the elevated levels of Sirt1 and Sirt3 as well as weak H4K16acin signal and strong H3K4me3 signal in diabetic oocytes following NMN treatment.
Meanwhile, NMN improves the mitochondrial function of in vitro matured diabetic oocytes, as indicated by the restored mitochondrial signals as well as the dramatically increased levels of genes related to mitochondrial fusion (Opa1, Mfn2) and mitochondrial fission (Drp1) in in vitro matured diabetic oocytes post NMN treatment.
Oocyte quality is prone to be affected by high ROS-induced DNA damage in diabetes. Remarkably, NMN can reduce ROS level, attenuate DNA damage, and reduce oxidative stress, as manifested by decreased ROS level, weak γH2A.X signal and upregulated mRNA level of anti-oxidation Sod1, respectively.
Furthermore, the histone acetylation and methylation play important roles in oocyte maturation and early embryo development. Herein, aberrant histone modifications caused by diabetes are restored by NMN, as evidenced by the elevated levels of Sirt1 and Sirt3 as well as weak H4K16acin signal and strong H3K4me3 signal in diabetic oocytes following NMN treatment.
Conclusion
NMN might be an effective reagent to improve in vitro maturation percentage of oocytes and oocyte quality from female mice with diabetes partially through improving mitochondrial function, reversing meiotic defects, reducing ROS level, rescuing actin dynamics, suppressing DNA damage and restoring histone modifications, which provides a significant clue for the treatment of infertility of the patients with diabetes.
Reference
[1] Guo F, Wang L, Chen Y, Zhu H, Dai X, Zhang X. Nicotinamide Mononucleotide improves oocyte maturation of mice with type 1 diabetes. Nutr Diabetes. 2024;14(1):23. doi:10.1038/s41387-024-00280-8
[2] Thong EP, Codner E, Laven JSE, Teede H. Diabetes: a metabolic and reproductive disorder in women. Lancet Diabetes Endocrinol. 2020;8(2):134-149. doi:10.1016/S2213-8587(19)30345-6
[2] Thong EP, Codner E, Laven JSE, Teede H. Diabetes: a metabolic and reproductive disorder in women. Lancet Diabetes Endocrinol. 2020;8(2):134-149. doi:10.1016/S2213-8587(19)30345-6
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