Myoglobin leaching into the serum of IDA mice is associated with elevated sGC activation under anemic conditions that correlates with increased myoglobin expression.

Our earlier study showed that sGC is critical for myoglobin (Mb) heme-maturation, while iron restriction is known to increase Mb expression which under anemic conditions may suggest an increase in heme-free Mb. We analyzed mice tissues to determine the link between sGC activation and Mb expression. Our study revealed that status of the sGC heterodimer or its subsequent activation aligned with active erythropoiesis, and also correlated with the expression of Mb and hemeoxygenase 1 (HO1). Tissues from iron deficiency anemia (IDA) mice developed either by nutritional iron deprivation or by ferroportin (Fpn) gene ablation or from iron refractory iron deficiency anemia (IRIDA) mice found variable Mb expression. In anemic (IDA, Fe < 5 ppm or IDA, Fpn) mice, elevated Mb expression largely correlated with elevated sGC heterodimer abundance and greater sGC activation, however this association was not consistent across all tissues groups, indicating that additional factors may also contribute to Mb expression. Importantly we found significant leaching of Mb into the serum of these anemic (IDA) mice from both models and we hypothesize this Mb to be heme-free (Apo-Mb). The Mb leaching in anemia seemed to be the cumulative impact of Mb secretion from various tissues including lungs, spleen, skeletal or cardiac muscles wherever Mb was robustly expressed. Based on these findings we construct a working model of anemia, where iron restriction under anemic conditions (Fpn ablation or restricted Fe diet) induces Mb expression, which then leaches out into the serum.