Genetic drivers of age-related changes in urinary magnesium excretion

Although age-dependent alterations in urinary magnesium (Mg$^{2+}$) excretion have been described, the underlying mechanism remains elusive. As heritability significantly contributes to variations in urinary Mg$^{2+}$ excretion, we measured urinary Mg$^{2+}$ excretion at different ages in a cohort of genetically variable Diversity Outbred (DO) mice. Compared with animals aged 6 mo, an increase in Mg$^{2+}$ excretion was observed at 12 and 18 mo. Quantitative trait locus (QTL) analysis revealed an association of a locus on chromosome 10 with Mg$^{2+}$ excretion at 6 mo of age, with Oit3 (encoding oncoprotein-induced transcript 3; OIT3) as our primary candidate gene. To study the possible role of OIT3 in renal Mg$^{2+}$ handling, we generated and characterized Oit3 knockout (Oit3$^{-/-}$) mice. Although a slightly lower serum Mg$^{2+}$ concentration was present in male Oit3$^{-/-}$ mice, this effect was not observed in female Oit3$^{-/-}$ mice. In addition, urinary Mg$^{2+}$ excretion and the expression of renal magnesiotropic genes were unaltered in Oit3$^{-/-}$ mice. For animals aged 12 and 18 mo, QTL analysis revealed an association with a locus on chromosome 19, which contains the gene encoding TRPM6, a known Mg$^{2+}$ channel involved in renal Mg$^{2+}$ reabsorption. Comparison with RNA sequencing (RNA-Seq) data revealed that Trpm6 mRNA expression is inversely correlated with the QTL effect, implying that TRPM6 may be involved in age-dependent changes in urinary Mg$^{2+}$ excretion in mice. In conclusion, we show here that variants in Oit3 and Trpm6 are associated with urinary Mg$^{2+}$ excretion at distinct periods of life, although OIT3 is unlikely to affect renal Mg$^{2+}$ handling.NEW & NOTEWORTHY Aging increased urinary magnesium (Mg$^{2+}$) excretion in mice. We show here that variation in Oit3, a candidate gene for the locus associated with Mg$^{2+}$ excretion in young mice, is unlikely to be involved as knockout of Oit3 did not affect Mg$^{2+}$ excretion. Differences in the expression of the renal Mg$^{2+}$ channel TRPM6 may contribute to the variation in urinary Mg$^{2+}$ excretion in older mice.