Mathematical Modeling of Magnesium Homeostasis in Male Rats

Abstract

Magnesium (Mg2+) is an important cofactor for numerous biological processes, including protein synthesis, nucleic acid stability, and neuromuscular excitability. Extracellular magnesium is tightly regulated, with plasma [Mg2+] maintained relatively constant between 1.6 and 2.3 mg/dL under normal physiological conditions. Almost all of the body’s Mg2+ (approximately 99%) is either stored in bone or within cells (DOI: 10.1053/j.ackd.2018.01.003). A normal daily Mg2+ intake averages around 300 mg, about half of which is absorbed by the intestine. The kidneys reabsorb 95-98% of the filtered Mg2+ and excrete only 2-5% through urine. To understand the interplay between intestine, kidneys, and bones to maintain Mg2+ homeostasis, we developed a computational model of Mg2+ homeostasis for male rats and incorporated it with a male rat calcium (Ca2+) homeostasis model. Our model consists of five compartments: plasma, intestine, kidneys, bones, and parathyroid gland. The model also includes parathyroid hormone and vitamin D3 since they significantly regulate Mg2+ and Ca2+ homeostasis. We used this model to simulate three conditions: change in dietary Mg2+, change in dietary vitamin D3, and administration of proton-pump inhibitors. In the case of variation in dietary Mg2+, our model predicted that the body compensates mainly through decreasing (in case of low dietary Mg2+) and increasing (in case of high dietary Mg2+) urinary Mg2+ excretion and the Mg2+ content in the rapidly exchangeable bone pool. Change in dietary Mg2+ does not have any significant effect on Ca2+ homeostasis. On the other hand, change in dietary vitamin D3 has significant effect on both Mg2+ and Ca2+ homeostasis, with the effect being more pronounced for Ca2+ compared to Mg2+. Our model predicted significant changes in intestinal Mg2+ and Ca2+ absorption, PTH secretion, urinary Mg2+ and Ca2+ excretion, and Mg2+ and Ca2+ content in the rapidly exchangeable bone pool following change in dietary vitamin D3. Administration of proton pump inhibitors (PPIs) such as omeprazole, which are a class of medicine commonly used to reduce stomach acid production, affect Mg2+ and Ca2+ transport in the intestine. PPIs reduce intestinal Mg2+ and Ca2+ absorption by 3.5-fold and 40%, respectively. The body compensates for this huge drop in intestinal Mg2+ absorption by tapping into the Mg2+ stored in the rapidly exchangeable bone pool in addition to decreasing urinary Mg2+ excretion. By contrast, the body can compensate for the drop in intestinal Ca2+ absorption by only decreasing urinary Ca2+ excretion. Thus, this model can be used to understand the compensatory mechanisms adopted by the body to maintain Mg2+ and Ca2+ homeostasis under various pathophysiological conditions and drug administrations. This work was supported by the Canada 150 Research Chair program, National Sciences and Engineering Research Council of Canada (NSERC) Discovery Grant, and Canada Institutes of Health Research (CIHR) Project Grant to Anita Layton. This is the full abstract presented at the American Physiology Summit 2024 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.