A multitrack translational study combining murine physiological models, cell culture respirometry, and an exploratory analysis of human clinical trial cohorts has revealed that intravenous iron formulations drive distinct structural, functional, and metabolic recovery rates in skeletal muscle during the treatment of iron deficiency anaemia. Iron deficiency anaemia affects approximately twenty-five percent of the global population, with markedly elevated prevalence among children and females of reproductive age. While the systemic haematological manifestations of the disorder—including hypochromic, microcytic anaemia and reactive thrombocytosis—are well documented in medical literature, the direct consequences of systemic iron deprivation on peripheral tissues with substantial bioenergetic demands remain critical areas of ongoing physiological research. Skeletal muscle performance relies intrinsically on an uninterrupted delivery of oxygen to generate cellular adenosine triphosphate through mitochondrial oxidative phosphorylation. When oxygen availability is compromised by circulating red blood cell deficits or when the catalytic activity of iron-dependent mitochondrial enzymes is depressed, skeletal muscle tissue exhibits rapid fatigue, severe functional impairment, and cellular atrophy.

Although intravenous administration of iron complexes has long served as an established clinical strategy to replenish depleted systemic iron reserves and normalize circulatory haemoglobin parameters, mechanistic evidence demonstrating how iron replacement directly coordinates the metabolic, architectural, and contractile restoration of skeletal muscle tissue has remained sparse. Widely utilized clinical formulations, including ferric carboxymaltose and ferric derisomaltose, possess distinct carbohydrate shell architectures and divergent pharmacokinetic properties that influence their physiological handling. Both therapeutics effectively correct systemic anaemia and reconstitute total body iron stores in patient populations, yet they exhibit markedly divergent secondary safety profiles. Most notably, treatment-induced hypophosphatemia has been documented to occur in approximately forty-seven to seventy-five percent of clinical cohorts receiving ferric carboxymaltose, compared to documented rates of only four to eight percent among individuals administered ferric derisomaltose. To resolve whether these carbohydrate shell architectures and distinct pharmacokinetic kinetics translate into divergent skeletal muscle tissue remodelling, investigators established a multifaceted research protocol evaluating muscle architecture, metabolic intermediates, and mitochondrial respiration across three biological scales.

In the primary animal model, three-week-old female C57BL/6J mice were allocated into four experimental cohorts under controlled environmental conditions: an untreated healthy control group, an iron deficiency anaemia group receiving point-nine percent sodium chloride infusions, and two anaemic groups administered two milligrams, equivalent to one hundred milligrams per kilogram, of either ferric carboxymaltose or ferric derisomaltose. Iron deficiency anaemia was experimentally induced via an iron-deficient dietary regimen coupled with serial phlebotomy sessions, with successful disease induction verified through marked reductions in circulating haemoglobin concentrations, mean corpuscular volume, and overall body mass. Functional endurance was evaluated four weeks post-treatment using standardized wire hang latency assessments, where physical performance was quantified as holding impulse by multiplying latency to fall by mouse body weight up to a maximum duration of five minutes. Morphological adaptations were subsequently determined across isolated gastrocnemius, soleus, plantaris, and diaphragm muscles harvested one and four weeks following intravenous intervention.

Functional evaluation during repeated wire hang testing revealed that untreated anaemic mice exhibited a progressive reduction in latency to fall across successive repetitions, establishing pronounced functional fatigue and reduced physical endurance. Animals treated with ferric derisomaltose demonstrated a statistically significant improvement in holding time during the second repetition, whereas mice treated with ferric carboxymaltose failed to show comparable immediate functional gains. Quantitative cross-sectional histological examination of diaphragm tissue further delineated notable architectural divergence between the treatment groups. Untreated anaemic animals exhibited widespread fibre atrophy across all identified muscle fibre types compared to healthy controls. Following therapeutic iron repletion, administration of ferric derisomaltose produced significant increases in the cross-sectional area of slow-twitch Type I oxidative fibres and fast-twitch Type IIb glycolytic fibres four weeks post-injection. Conversely, animals receiving ferric carboxymaltose failed to demonstrate meaningful cross-sectional area expansion over the identical four-week post-treatment window, despite exhibiting comparable improvements in circulating haemoglobin concentrations.

To investigate the underlying molecular machinery responsible for these distinct morphological and functional trajectories, researchers conducted quantitative proteomic profiling on gastrocnemius muscle samples harvested one week after intravenous iron administration. Restricting analysis to two thousand nine hundred and twenty proteins identified across all individual specimens, differential protein abundance was evaluated. Although no individual proteins retained statistical significance following rigorous Benjamini-Hochberg adjustment for multiple testing, exploratory pathway analyses based on nominal probability thresholds and log2 fold-change cutoffs revealed substantial proteomic reorganization. Untreated anaemic muscle displayed pronounced downregulation of vital mitochondrial respiratory chain subunits, specifically NADH dehydrogenase complex components Ndufa12 and Ndufv2, alongside succinate dehydrogenase complex iron-sulfur subunit B. Gene Ontology enrichment analysis confirmed profound suppression of oxidative phosphorylation and adenosine triphosphate synthesis pathways. When comparing therapeutic cohorts, mice treated with ferric derisomaltose exhibited marked upregulation of contractile machinery proteins, including myosin heavy chains and troponin complexes, along with enriched protein-protein interaction clusters governing active muscle contraction.

Direct biochemical quantification of tissue iron concentrations revealed that bulk skeletal muscle iron levels were numerically reduced in anaemic mice relative to controls, though the difference did not achieve statistical significance prior to treatment. Intravenous administration of both ferric carboxymaltose and ferric derisomaltose produced robust and sustained increases in total skeletal muscle iron concentrations that remained elevated through four weeks post-injection. Concurrently, transcriptional profiling demonstrated that the pronounced baseline upregulation of transferrin receptor mRNA observed in anaemic muscle was completely suppressed within one week of iron therapy across both treatment groups. Histological iron tracking using 3,3-diaminobenzidine enhancement and transmission electron microscopy localized trivalent ferric iron deposits exclusively to the endomysium surrounding muscle fibres. These deposits were concentrated within membrane-bound endo-lysosomes of interstitial macrophages, without detectable iron granules inside myofibres themselves. These structural observations indicate that systemic intravenous complexes undergo primary sequestration by resident interstitial macrophages rather than direct bulk entry into contractile muscle cells.

Targeted metabolomic profiling of glycolytic and tricarboxylic acid cycle intermediates in murine gastrocnemius muscle one week post-treatment illuminated the bioenergetic underpinnings of these physiological differences. Skeletal muscle from anaemic mice demonstrated a distinct metabolic shift toward anaerobic glycolysis, characterized by accumulated intracellular glucose, elevated combined glucose- and fructose-6-phosphate pools, and a significant buildup of intracellular lactate driven by marked downregulation of pyruvate carboxylase. Following iron repletion, administration of ferric derisomaltose reversed this glycolytic skew, normalizing intracellular glucose concentrations, lowering lactate levels, restoring pyruvate carboxylase expression, and elevating citrate intermediates. In contrast, muscle tissue from mice treated with ferric carboxymaltose maintained elevated glucose concentrations and sustained lactate accumulation. Furthermore, key iron-dependent enzymes including aconitase 2 and succinate dehydrogenase subunits exhibited suppressed expression in anaemic muscle, displaying variable recovery rates across the two therapeutic formulations that suggest divergent metabolic clearance and anaplerotic pathway flux.

To establish whether the divergent metabolic responses observed in vivo were mediated by cell-autonomous mechanisms or dependent upon local microenvironmental factors such as macrophage processing, investigators turned to in vitro cultures of differentiated murine C2C12 myotubes. Myotubes subjected to iron chelation via twenty-four-hour desferrioxamine exposure displayed sweeping disruptions across central bioenergetic pathways, accumulating upstream intermediates in glycolysis, purine and pyrimidine biosynthesis, polyamine generation, and fatty acid oxidation. Seahorse extracellular flux respirometry revealed that iron chelation severely diminished basal and maximal oxygen consumption rates while increasing cellular dependence on glycolytic acidification. When iron-chelated myotubes were replenished in vitro with either ferric carboxymaltose or ferric derisomaltose at concentrations of two hundred micrograms per millilitre, both formulations produced equivalent and significant recoveries in mitochondrial oxygen consumption, cellular bioenergetic flexibility, and transferrin receptor transcriptional normalization, confirming that isolated muscle cells internalize and metabolize both iron complexes identically when interstitial macrophages are absent.

To evaluate whether the superior functional recovery elicited by ferric derisomaltose in preclinical animal models translated into measurable clinical benefits in human subjects, investigators conducted a secondary exploratory analysis of respiratory muscle performance within the randomized Phosphare-IDA clinical trials. This clinical dataset comprised adult patients presenting with iron deficiency anaemia attributed primarily to gynaecological blood loss or gastrointestinal pathologies who had previously documented intolerance or unresponsiveness to oral iron supplementation. Patients had been randomized to receive either a single one-thousand-milligram infusion of ferric derisomaltose on Day Zero or two separate seven-hundred-and-fifty-milligram doses of ferric carboxymaltose administered on Day Zero and Day Seven. Respiratory muscle strength was tracked across baseline, Day Fourteen, and Day Thirty-Five via serial assessments of maximal expiratory pressure and maximal inspiratory pressure using restricted maximum likelihood-based mixed models for repeated measures.

The clinical findings closely mirrored the preclinical observations: adult patients receiving ferric derisomaltose achieved a statistically significant, rapid improvement in maximal expiratory pressure relative to baseline that was firmly established by Day Fourteen and sustained through Day Thirty-Five. Conversely, patients treated with ferric carboxymaltose demonstrated no statistically significant improvement in maximal expiratory pressure across the identical monitoring interval, while improvements in maximal inspiratory pressure showed less separation between cohorts. Furthermore, stratifying patient responses by serum phosphate status confirmed that the observed functional advantage of ferric derisomaltose occurred independently of post-treatment hypophosphatemia, which arose in seventy-four percent of ferric carboxymaltose recipients compared to only eight percent of ferric derisomaltose recipients. Although investigators caution that human findings remain exploratory and that wire hang performance integrates multidimensional neuromuscular variables, the synchronized preclinical and clinical data demonstrate that intravenous iron formulations possess distinct tissue-level pharmacokinetics that critically govern the speed of skeletal muscle rehabilitation.

Subject of Research: Skeletal muscle remodelling and metabolic recovery following intravenous iron therapy in iron deficiency anaemia

Article Title: Remodelling of Skeletal Muscle During Iron Deficiency Anaemia and Recovery After Intravenous Iron Therapy

Article References: Pertler, E., Wagner, S. A., Panzer, M., Obholzer, L., Sonnenburger, Y., Troppmair, M. R., Saretto, M., Schaefer, B., Manzl, C., Oberacher, H., Sarg, B., Faserl, K., Redl, S., Hess, M. W., Telser, T., Popottnigg, J. P., Gronich‐Wondrak, P., Tilg, H., & Zoller, H. (2026). Remodelling of Skeletal Muscle During Iron Deficiency Anaemia and Recovery After Intravenous Iron Therapy. Journal of Cachexia, Sarcopenia and Muscle, 17(6), Article e70415. https://doi.org/10.1002/jcsm.70415

Image Credits: AI Generated

DOI: 10.1002/jcsm.70415

Keywords: Iron Deficiency Anaemia, Skeletal Muscle, Ferric Derisomaltose, Ferric Carboxymaltose, Mitochondrial Metabolism, Muscle Strength, Translational Research, Proteomics, Remodelling, Skeletal, Muscle, During