MUSCULAR ADAPTATIONS TO IRON DEFICIENCY ANEMIA AND THE REVERSIBILITY AFTER INTRAVENOUS IRON

Elke PERTLER^1,2, Heinz ZOLLER^1,2, Sonja WAGNER^1,2, Laura OBHOLZER², Benedikt SCHÄFER², Marlene PANZER^1,2, Herbert OBERACHER³, Bettina SARG⁴, Klaus FASERL⁴, Herbert TILG²

¹Christian Doppler Laboratory for Iron and Phosphate Biology, Department of Internal Medicine I, Medical University of Innsbruck, Innsbruck, Austria
²Department of Internal Medicine I, Medical University of Innsbruck, Innsbruck, Austria
³Institute of Legal Medicine and Core Facility of Metabolomics, Medical University of Innsbruck, Innsbruck, Austria
⁴Division of Medical Biochemistry, Protein Core Facility, Biocenter, Medical University of Innsbruck, Innsbruck, Austria

Background: Fatigue is a cardinal symptom of iron deficiency anemia (IDA) that can rapidly improve after intravenous (IV) iron. Iron is essential for mitochondrial function and energy production. Hormonal control, training, substrate- and oxygen availability determine which nutrients are used for energy production in muscles. We aimed to investigate the effects of IDA on muscle cells and the reversibility of adaptive changes after IV iron treatment.

Methods: IDA was induced in three-week-old C57Bl/6 mice with dietary iron deficiency and controlled phlebotomy. Animals were injected with three different IV iron formulations. Seven days after IV injection, full blood count, gastrocnemius-, soleus-, plantaris-muscle, the diaphragm and the myocardium were analyzed. Gene expression was quantified by RT-qPCR. Metabolites and protein abundances were measured by untargeted LC-MS/MS. Fiber types were visualized by immunofluorescence staining.

Results: In IDA, energy production in skeletal muscle switched to anaerobic metabolism. Furthermore, oxidative fibers were significantly smaller, which correlated with hemoglobin concentration. Myocardial glucose metabolism was upregulated in IDA. However, pyruvate dehydrogenase was inactivated, resulting in increased lactate production. Respiratory chain and energy production were downregulated in both organs. IV iron treatment reversed most of the alterations caused by IDA, but the time course of the reversibility differed between the IV iron formulation tested.

Conclusion: The metabolic profile and preferred energy source differ between skeletal muscle and the myocardium in our IDA model. The structural and biochemical remodeling in skeletal muscle of IDA animals can be differentially reversed by IV irons. Signals controlling these adaptations will be further investigated.