Creatine metabolism in the uterus: potential implications for reproductive biology

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INVITED REVIEW

Creatine metabolism in the uterus: potential implications for reproductive biology Mamatha Philip1 · Rodney J. Snow1 · Paul A. Della Gatta1 · Nadia Bellofiore2,3 · Stacey J. Ellery2,3  Received: 8 July 2020 / Accepted: 19 September 2020 / Published online: 29 September 2020 © Springer-Verlag GmbH Austria, part of Springer Nature 2020

Abstract 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 upregulated 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. Keywords  Creatine · Phosphocreatine · Uterus · Female reproductive cycle · Pregnancy

Introduction The mechanisms of energy supply in uterine tissues are similar to those in most cells, with the immediate source of energy being adenosine triphosphate (ATP) (Dawson and Raman 1990). The energy required to resynthesize ATP in the uterus is obtained principally from oxidative phosphorylation and aerobic breakdown of lipids and carbohydrate. Handling Editor: J. D. Wade. * Stacey J. Ellery [email protected] 1



Institute for Physical Activity and Nutrition (IPAN), School of Exercise and Nutrition Sciences Deakin University, Geelong, VIC, Australia

2



The Ritchie Centre, Hudson Institute of Medical Research, Clayton, Australia

3

Department of Obstetrics and Gynecology, Monash University, Melbourne, Australia



Intrinsic to spatial and temporal maintenance of ATP in all cells is the creatine kinase system (Wyss and KaddurahDaouk 2000). There is evidence that the creatine kinase system operates in uterine tissue (Payne et al. 1993; Satyaswaroop and Mort