The role of myostatin in female fertility

As scientists gain a better understanding of the mysteries of human physiology, it has been repeatedly proven that the protein called myostatin (MSTN) plays a central role in human reproduction. A new Reproductive Biology and Endocrinology study discusses some of the key functions of MSTN in female reproductive health and diseases.

Study: Myostatin: a multifunctional role in human female reproduction and fertility – a brief overview. Image Credit: StudioMolekuul / Shutterstock.com

Introduction

MSTN, also known as growth differentiation factor 8 (GDF8), is encoded on chromosome 2. This protein reduces skeletal muscle growth and thereby prevents the overgrowth of this tissue in various mammalian and fish species.

MSTN is part of the transforming growth factor-β (TGF-β) superfamily, which also includes growth differentiation factors (GDFs), bone morphogenetic proteins (BMPs), TGF-βs, activins, inhibin and anti-Müllerian hormone (AMH). . The TGF-β family of proteins regulates cell proliferation and differentiation, wound healing, immune function and skeletal pathologies, in addition to cancer and fibrosis.

AMH, BMP15 and GDF9 are found at high levels in the female reproductive system. It has recently been found that MSTN also plays an important role in this system.

Myostatin in early development

MSTN is expressed in the skeletal muscle of the developing embryo. Its level is currently the highest; however, it is also found in adulthood.

Other sites of MSTN include adipose tissue and heart. The absence of MSTN causes muscle cell hyperplasia.

MSTN acts by activin receptor type II or IIb on the cell surface, where it down-regulates the proliferation and differentiation of muscle stem cells by various pathways. The result is reduced muscle fiber protein in adulthood and, as a result, reduced muscle mass.

Other activities of MSTN include cardiac energy homeostasis and the prevention of ventricular overgrowth in response to ischemia and heart failure. In type 2 diabetes, MSTN is also upregulated, as in obese people with high insulin levels. With exercise, insulin sensitivity increases, thus indicating a role of MSTN in regulating the uptake and utilization of glucose by muscle cells.

MSTN levels are high in patients with cancer, heart or kidney failure, and Acquired Immune Deficiency Syndrome (AIDS), during which this protein is likely to regulate muscle cell atrophy under stress. Elderly individuals and those who have been confined to bed for long periods also have higher MSTN levels.

MSTN Features Summary

Myostatin in female reproduction

MSTN regulates ovarian function. In addition, this protein may regulate the growth of the gonads, the absence of which is apparently associated with reduced fertility in animals. The rate-limiting enzyme in the steroid synthetic pathway, steroidogenic acute regulatory (StAR), is also downregulated by MSTN.

MSTN is present in ovarian granulosa cells that convert testosterone to estradiol through aromatase enzyme activity, as well as the follicular fluid, in which it reduces progesterone concentrations. While testosterone is synthesized by the ovarian theca cells, estradiol is essential in female reproductive physiology.

MSTN increases estradiol synthesis by increased cytochrome P450 aromatase expression. This protein increases the levels of follicle-stimulating hormone (FSH) receptors, and thus promotes the effects of this hormone.

Thus, the effect of MSTN is probably an essential aspect of gonadotropin responses and sex hormone production.

MSTN also acts by upregulating connective tissue growth factor (CTGF), which causes signaling pathways to regulate the recruitment of ovarian theca cells, regulate follicular growth, and help ensure a good vascular supply to the corpus luteum. Both of these factors inhibit granulosa cell proliferation.

An increase in CTGF also leads to higher levels of lysis oxidase (LOX), an enzyme that is essential for the formation of the extracellular matrix (ECM). Therefore, CTGF is indispensable for the coordinated function of various cell types by hormones, as well as autocrine and paracrine factors within the ovarian follicle, resulting in a mature oocyte.

MSTN is also essential for regulating the growth of cumulus cells, which form the complex that contains the adult follicle. It is regulated by hormonal interactions between the oocyte and its follicular cells.

MSTN inhibits pentraxin 3 (PTX3), which plays a central role in female fertility. PTX3 regulates the crucial process of ECM formation and thus ensures proper expansion of the cumulus oocyte complex, ovulation and fertilization. MSTN can also be a regulatory factor produced by the ovary to regulate intra-ovarian processes.

MSTN and ovarian pathology

MSTN, by increasing aromatase and estradiol levels within the granulosa cells, may be involved in the common and sometimes serious adverse effect of fertility treatment known as ovarian hyperstimulation syndrome (OHSS).

In OHSS, the stimulation of ovarian follicular development leads to enlargement of the ovaries. This leads to the extravasation of fluid containing abundant proteins from the blood to the extracellular space due to the hyperpermeability of the vessel wall. This increased vascular permeability is due to the high concentration of human chorionic gonadotropin (hCG), which activates the blood vessel wall.

As pre-hCG estradiol levels are higher in women developing OHSS, the role of MSTN is clear and may help in the development of new therapies for this condition in the future. Similarly, these findings may also help treat polycystic ovary syndrome (PCOS), which affects up to one in ten women of childbearing age and is responsible for up to 75% of infertility in women due to anovulation.

In PCOS, multiple follicles develop with high androgen levels and impaired ovulation. MSTN was also increased in the granulosa cells and large antral follicles in PCOS ovaries, thus indicating that MSTN regulation escaped.

MSTN in follicular fluid is high in PCOS and consequently reduces StAR expression and suppresses the expression of progesterone. Only obese PCOS patients showed elevated MSTN levels, which may be associated with the inhibitory effect of MSTN on glucose metabolism in granulosa lutein cells.

MSTN and assisted reproduction

MSTN levels predict pregnancy rates in patients who have undergone in vitro fertilization / intracytoplasmic sperm injection-embryo transfer (IVF / ICSI-ET). Implantation of the embryo can also be predicted by MSTN expression, as this molecule can inhibit the growth of both uterine smooth muscle growth and endometrial epithelium, thus regulating this important process.

These results show that MSTN plays a critical role in ensuring a successful pregnancy, with an emphasis on the possible involvement of MSTN levels in ovarian response during COH [controlled ovarian hyperstimulation] process. ”

MSTN and placenta

MSTN can affect placental development by its effect on cytokines, which regulate trophoblast growth, differentiation and invasion, all of which are essential for proper placement of the embryo. During early pregnancy, MSTN increases the level of follistatin-like 3 (FSTL3), which is a protein that binds to TGF superfamily members to suppress their activity, especially that of MSTN. Interestingly, FSTL is up to 20 times as high in the placenta as any other organ.

When FSTL3 is high in the placenta and blood during the second trimester, the risk of developing pre-eclampsia is higher. It may be a response to hypoxia of the trophoblastic cells and may help to predict future pre-eclampsia and intrauterine growth restriction (IUGR). Conversely, low FSTL3 reduces trophoblast invasion.

MSTN is expressed at lower levels in the adult placenta than in early pregnancy. To this end, this protein regulates the homeostasis of glucose in the placenta and can help treat a wide range of conditions from placental insufficiency to gestational diabetes mellitus (GDM). Normal MSTN with low FSTL3 levels in the maternal blood and placenta may indicate GDM

MSTN and uterine physiology

MSTN induces proliferation of the uterine muscle myometrium; however, it is found to fluctuate in concentration during the menstrual cycle. Together with activins, MSTN regulates gonadal activity.

MSTN also responds to steroid hormones, as their levels decrease with exposure to estradiol, but not after progesterone treatment. However, MSTN levels are higher after menopause.

In the common uterine tumor called fibroid (leiomyoma), activin A, MSTN and FSTL3 are expressed at higher levels than in normal uterine tissue, without evidence of higher transcription. Thus, abnormal MSTN signaling is linked to fibroid growth, as this molecule inhibits the growth of healthy uterine muscles but causes fibrosis of leiomyoma cells.

These proteins are also increased in adenomyosis, indicating that they have a local effect in this condition.

Conclusions

MSTN has several functions in various tissues of the human reproductive system, including its involvement in the steroidogenic pathway, response of ovarian granulosa theca cells to gonadotropin hormones, cell proliferation, and the expression of many intermediate signaling molecules.

These findings suggest that MSTN may play a critical role in influencing the final differentiation processes in emerging follicles. ”

The discovery of aberrant MSTN levels in uterine, placental and ovarian diseases indicates its major regulatory function in oocyte maturation. In addition, MSTN administration is associated with multiple adverse effects, including metabolic dysregulation and muscle wasting.

Much more work is needed to understand how MSTN works; however, these observations may lead to the development of better and / or new treatment approaches in reproductive health.