Aspects of human uterine creatine metabolism during the menstrual cycle and at term pregnancy†.

Creatine metabolism likely contributes to energy homeostasis in the human uterus, but whether this organ synthesizes creatine and whether creatine metabolism is adjusted throughout the menstrual cycle and with pregnancy are largely unknown. This study determined endometrial protein expression of creatine-synthesizing enzymes arginine:glycine amidinotransferase (AGAT) and guanidinoacetate methyltransferase (GAMT), creatine kinase (CKBB), and the creatine transporter (SLC6A8) throughout the menstrual cycle in fertile and primary infertile women. It also characterized creatine metabolism at term pregnancy, measuring aspects of creatine metabolism in myometrial and decidual tissue. In endometrial samples, AGAT, GAMT, SLC6A8, and CKBB were expressed in glandular and luminal epithelial cells. Except for SLC6A8, the other proteins were also located in stromal cells. Irrespective of fertility, AGAT, GAMT, and SLC6A8 high-intensity immunohistochemical staining was greatest in the early secretory phase of the menstrual cycle. During the proliferative phase, staining for SLC6A8 protein was greater (P = 0.01) in the primary infertile compared with the fertile group. Both layers of the term pregnant uterus contained creatine, phosphocreatine, guanidinoacetic acid, arginine, glycine, and methionine; detectable gene and protein expression of AGAT, GAMT, CKBB, and ubiquitous mitochondrial CK (uMt-CK); and gene expression of SLC6A8. The proteins AGAT, GAMT, CKBB, and SLC6A8 were uniformly distributed in the myometrium and localized to the decidual glands. In conclusion, endometrial tissue has the capacity to produce creatine and its capacity is highest around the time of fertilization and implantation. Both layers of the term pregnant uterus also contained all the enzymatic machinery and substrates of creatine metabolism.

Creatine metabolism in the uterus: potential implications for reproductive biology.

Creatine is an amino acid derivative synthesized from arginine, glycine and methionine. It serves as the substrate for the creatine kinase system, which is vital for maintaining ATP levels in tissues with high and fluctuating energy demand. There exists evidence that the creatine kinase system operates in both the endometrial and myometrial layers of the uterus. While use and regulation of this system in the uterus are not well understood, it is likely to be important given uterine tissues undergo phases of increased energy demand during certain stages of the female reproductive cycle, pregnancy, and parturition. This review discusses known adaptations of creatine metabolism in the uterus during the reproductive cycle (both estrous and menstrual), pregnancy and parturition, highlighting possible links to fertility and the existing knowledge gaps. Specifically, we discuss the adaptations and regulation of uterine creatine metabolite levels, cell creatine transport, de novo creatine synthesis, and creatine kinase expression in the various layers and cell types of the uterus. Finally, we discuss the effects of dietary creatine on uterine metabolism. In summary, there is growing evidence that creatine metabolism is up-regulated in uterine tissues during phases where energy demand is increased. While it remains unclear how important these adaptations are in the maintenance of healthy uterine function, furthering our understanding of uterine creatine metabolism may uncover strategies to combat poor embryo implantation and failure to conceive, as well as enhancing uterine contractile performance during labor.

Creatine Metabolism in Female Reproduction, Pregnancy and Newborn Health.

Creatine metabolism is an important component of cellular energy homeostasis. Via the creatine kinase circuit, creatine derived from our diet or synthesized endogenously provides spatial and temporal maintenance of intracellular adenosine triphosphate (ATP) production; this is particularly important for cells with high or fluctuating energy demands. The use of this circuit by tissues within the female reproductive system, as well as the placenta and the developing fetus during pregnancy is apparent throughout the literature, with some studies linking perturbations in creatine metabolism to reduced fertility and poor pregnancy outcomes. Maternal dietary creatine supplementation during pregnancy as a safeguard against hypoxia-induced perinatal injury, particularly that of the brain, has also been widely studied in pre-clinical in vitro and small animal models. However, there is still no consensus on whether creatine is essential for successful reproduction. This review consolidates the available literature on creatine metabolism in female reproduction, pregnancy and the early neonatal period. Creatine metabolism is discussed in relation to cellular bioenergetics and de novo synthesis, as well as the potential to use dietary creatine in a reproductive setting. We highlight the apparent knowledge gaps and the research "road forward" to understand, and then utilize, creatine to improve reproductive health and perinatal outcomes.

The relationship of endogenous plasma concentrations of ß-Hydroxy ß-Methyl Butyrate (HMB) to age and total appendicular lean mass in humans.

The maintenance of muscle mass and muscle strength is important for reducing the risk of chronic diseases. The age- related loss of muscle mass and strength is associated with adverse outcomes of physical disability, frailty and death. ß-Hydroxy ß-Methyl Butyrate (HMB), a metabolite of leucine, has beneficial effects on muscle mass and strength under various catabolic conditions. The objectives of the present study were to determine if age- related differences existed in endogenous plasma HMB levels, and to assess if HMB levels correlated to total appendicular lean mass and forearm grip strength. Anthropometry, dietary and physical activity assessment, and the estimation of fasting plasma HMB concentrations and handgrip strength were performed on the 305 subjects (children, young adults and older adults). Lean mass, which serves as a surrogate for muscle mass was measured using dual energy X-ray absorptiometry (DEXA). Mean plasma HMB concentrations were significantly lower with increasing age groups, with children having highest mean HMB concentration (p<0.01) followed by young adults and older adults. Female subjects (across all ages) had significantly lower plasma HMB concentrations. A significant positive correlation between HMB concentrations and appendicular lean mass normalized for body weight (%), appendicular lean mass (r=0.37; p<0.001) was observed in the young adults and older adults group. Handgrip strength was positively associated with plasma HMB concentrations in young adults (r=0.58; p<0.01) and the older adults group (r=0.28; p<0.01). The findings of the present study suggest that there is an age- related decline in endogenous HMB concentrations in humans and the HMB concentrations were positively correlated with appendicular lean mass and hand grip strength in young adults and older adults group.