Remodelling of Skeletal Muscle During Iron Deficiency Anaemia and Recovery After Intravenous Iron Therapy
8 affiliations
- 1Christian Doppler Laboratory for Iron and Phosphate Biology, Department of Internal Medicine I Medical University of Innsbruck Innsbruck Austria
- 2Department of Internal Medicine I, Gastroenterology, Hepatology and Endocrinology Medical University of Innsbruck Innsbruck Austria
- 3Institute of Neuropathology and Neuromolecular Pathology Medical University of Innsbruck Innsbruck Austria
- 4Institute of Legal Medicine and Core Facility Metabolomics Medical University of Innsbruck Innsbruck Austria
- 5Institute of Medical Biochemistry, Protein Core Facility, Biocenter Medical University of Innsbruck Innsbruck Austria
- 6Institute of Neuroanatomy Medical University of Innsbruck Innsbruck Austria
- 7Institute of Histology and Embryology Medical University of Innsbruck Innsbruck Austria
- 8Institute of Human Genetics Medical University of Innsbruck Innsbruck Austria
Abstract
Background: The global prevalence of iron deficiency anaemia (IDA) is about 25% and even higher in women of reproductive age and children. IDA can impair skeletal muscle by disrupting oxygen utilization, energy production and contractile function. Haematological effects of intravenous (IV) iron therapy in IDA are well studied, but its impact on muscle and energy metabolism is less clear. We investigated the molecular and functional effects of IDA on skeletal muscle in a mouse model and C2C12 myotubes. The effects of different IV iron formulations on skeletal muscle were compared in iron deficient C2C12 myotubes, in IDA‐mice and patients with IDA.
Methods: Treatment effects of the IV iron formulations ferric carboxymaltose (FCM) and ferric derisomaltose (FDI) were studied in IDA mice by tail vein injection of 2‐mg iron. Analyses were carried out 7 days and 4 weeks post‐treatment. C2C12 myotubes were treated with desferrioxamine, followed by incubation with FCM or FDI before mitochondrial respiration, gene expression and metabolite profiles were analysed. Respiratory muscle function was investigated in adults with IDA treated with FCM or FDI as exploratory endpoint in a randomized clinical trial.
Results: In our mouse model IDA induced a trend towards impaired skeletal muscle function and a shift to anaerobic metabolism. Only treatment with FDI resulted in a significant increase in muscle type I and type IIb fibre cross‐sectional area when compared to IDA. FDI also induced earlier recovery of contractile protein expression and energy metabolism than FCM. Exploratory proteomic and metabolic analyses revealed that treatment with FDI might restore mitochondrial enzymes and reduce lactate accumulation after 7 days. In vitro, iron‐deficient C2C12 myotubes showed reduced mitochondrial respiration and increased glycolysis with partial recovery by both IV iron formulations. Two weeks after treatment of IDA in adults, FDI caused a significantly better improvement in maximal expiratory pressure than FCM (mean pressure difference between treatments 5.06 cmH2O, p = 0.013). This difference appeared unrelated to post‐treatment hypophosphatemia.
Conclusions: IDA shows a trend towards impaired skeletal muscle function through metabolic and structural remodelling in mice, which is restored with different kinetics by FDI and FCM. These findings are in accord with exploratory findings from a clinical study indicating better respiratory muscle recovery in FDI‐treated than FCM‐treated IDA patients. Cell culture experiments confirm the effects of IDA on impaired metabolism but did not show differential effects of FCM and FDI. Different tissue pharmacokinetics could explain the distinct in vivo response of both formulations.
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BibTeX
@article{pertler2026remodelling,
title = {{Remodelling of Skeletal Muscle During Iron Deficiency Anaemia and Recovery After Intravenous Iron Therapy}},
author = {Elke Pertler and Sonja A. Wagner and Marlene Panzer and Laura Obholzer and Ylena Sonnenburger and Maria R. Troppmair and Martina Saretto and Benedikt Schaefer and Claudia Manzl and Herbert Oberacher and Bettina Sarg and Klaus Faserl and Stefan Redl and Michael W. Hess and Theresia Telser and Jessica P. Popottnigg and Petra Gronich‐Wondrak and Herbert Tilg and Heinz Zoller},
journal = {Journal of Cachexia, Sarcopenia and Muscle},
year = {2026},
month = nov,
doi = {10.1002/jcsm.70415},
url = {https://doi.org/10.1002/jcsm.70415},
note = {CC BY 4.0},
}
RIS
TY - JOUR
TI - Remodelling of Skeletal Muscle During Iron Deficiency Anaemia and Recovery After Intravenous Iron Therapy
AU - Elke Pertler
AU - Sonja A. Wagner
AU - Marlene Panzer
AU - Laura Obholzer
AU - Ylena Sonnenburger
AU - Maria R. Troppmair
AU - Martina Saretto
AU - Benedikt Schaefer
AU - Claudia Manzl
AU - Herbert Oberacher
AU - Bettina Sarg
AU - Klaus Faserl
AU - Stefan Redl
AU - Michael W. Hess
AU - Theresia Telser
AU - Jessica P. Popottnigg
AU - Petra Gronich‐Wondrak
AU - Herbert Tilg
AU - Heinz Zoller
PY - 2026
DA - 2026/11/04
JO - Journal of Cachexia, Sarcopenia and Muscle
DO - 10.1002/jcsm.70415
UR - https://doi.org/10.1002/jcsm.70415
AB - Background: The global prevalence of iron deficiency anaemia (IDA) is about 25% and even higher in women of reproductive age and children. IDA can impair skeletal muscle by disrupting oxygen utilization, energy production and contractile function. Haematological effects of intravenous (IV) iron therapy in IDA are well studied, but its impact on muscle and energy metabolism is less clear. We investigated the molecular and functional effects of IDA on skeletal muscle in a mouse model and C2C12 myotubes. The effects of different IV iron formulations on skeletal muscle were compared in iron deficient C2C12 myotubes, in IDA‐mice and patients with IDA. Methods: Treatment effects of the IV iron formulations ferric carboxymaltose (FCM) and ferric derisomaltose (FDI) were studied in IDA mice by tail vein injection of 2‐mg iron. Analyses were carried out 7 days and 4 weeks post‐treatment. C2C12 myotubes were treated with desferrioxamine, followed by incubation with FCM or FDI before mitochondrial respiration, gene expression and metabolite profiles were analysed. Respiratory muscle function was investigated in adults with IDA treated with FCM or FDI as exploratory endpoint in a randomized clinical trial. Results: In our mouse model IDA induced a trend towards impaired skeletal muscle function and a shift to anaerobic metabolism. Only treatment with FDI resulted in a significant increase in muscle type I and type IIb fibre cross‐sectional area when compared to IDA. FDI also induced earlier recovery of contractile protein expression and energy metabolism than FCM. Exploratory proteomic and metabolic analyses revealed that treatment with FDI might restore mitochondrial enzymes and reduce lactate accumulation after 7 days. In vitro, iron‐deficient C2C12 myotubes showed reduced mitochondrial respiration and increased glycolysis with partial recovery by both IV iron formulations. Two weeks after treatment of IDA in adults, FDI caused a significantly better improvement in maximal expiratory pressure than FCM (mean pressure difference between treatments 5.06 cmH2O, p = 0.013). This difference appeared unrelated to post‐treatment hypophosphatemia. Conclusions: IDA shows a trend towards impaired skeletal muscle function through metabolic and structural remodelling in mice, which is restored with different kinetics by FDI and FCM. These findings are in accord with exploratory findings from a clinical study indicating better respiratory muscle recovery in FDI‐treated than FCM‐treated IDA patients. Cell culture experiments confirm the effects of IDA on impaired metabolism but did not show differential effects of FCM and FDI. Different tissue pharmacokinetics could explain the distinct in vivo response of both formulations.
SN - 2190-5991
SN - 2190-6009
ER -