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. 2025 Dec 9;121(15):2404-2418.
doi: 10.1093/cvr/cvaf173.

Iron regulatory proteins secure iron availability in skeletal muscle to preserve exercise tolerance in heart failure

Bomee Chung  1   2 , Wenke Jonas  3   4 , Fatemeh Rostami  1   2 , Zulaikha Malik  1   2 , Malgorzata Szaroszyk  5 , Magdolna Levay  6 , James Thackeray  7 , Mario Ost  8 , Steven Nowak  9 , Jan Hegermann  10 , Thomas Wieland  6 , Andreas Pich  11 , Frank M Bengel  7 , Johann Bauersachs  1 , Kai C Wollert  1   12 , Joerg Heineke  13   14 , Annette Schürmann  3   4   15 , Tibor Kempf  1   2   16
Affiliations

Iron regulatory proteins secure iron availability in skeletal muscle to preserve exercise tolerance in heart failure

Bomee Chung et al. Cardiovasc Res. .

Abstract

Aims: Iron deficiency (ID) is a frequent comorbidity in heart failure (HF) and contributes to exercise intolerance. Tissue iron levels are maintained by cellular iron uptake, sequestration, and release, processes that are tightly controlled by iron regulatory proteins (IRP). Our aim was to explore the role of IRP activity in skeletal muscle function and exercise capacity during HF.

Methods and results: We observed that skeletal muscle ID is associated with IRP1 and 2 inactivation 12 weeks after transverse aortic constriction (TAC) in mice with left ventricular (LV) dysfunction and cachexia. To understand the functional implications of IRP inactivation in skeletal muscle, we generated skeletal muscle-specific Irp1/2 knock-out mice (SkM-Irp1/2-KO). These mice developed muscle ID, along with lower transferrin receptor 1 (TFR1) levels and decreased non-haem iron content, within 5 weeks after birth. SkM-Irp1/2-KO mice exhibited shorter running distances and slower velocities during treadmill exercise. Transcriptomic analysis revealed up-regulation of gene clusters associated with endoplasmic reticulum stress, atrophy, mitochondrial dysfunction, and inflammation. Moreover, enhanced glycolysis, increased 18F-deoxyglucose uptake in quadriceps, and faster plasma glucose clearance were detected in SkM-Irp1/2-KO vs. control mice. In contrast, SkM-Irp1/2-KO mice had markedly reduced complex I and II expression, a change that confirmed defects in oxidative phosphorylation.

Conclusion: HF leads to IRP1/2 inactivation, ID, and metabolic dysfunction in skeletal muscle in mice. IRP1/2 inactivation in skeletal muscle causes ID, impairs oxidative energy production, and promotes exercise intolerance by reducing the capacity for effective energy utilization.

Keywords: Exercise capacity; Heart failure; Iron deficiency; Iron regulatory proteins; Skeletal muscle.

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Conflict of interest statement

Conflict of interest: T.K. has received honoraria for consultations or lectures from Abbott, AstraZeneca, Boehringer Ingelheim, Bayer, Bristol Myers Squibb, Novartis, Roche Diagnostics, Medtronic, Edwards, Norgine, Pharmacosmos, Vifor Pharma Ltd., and Sciarc, and has received an unrestricted research grant from Vifor Pharma Ltd. J.B. received honoraria for lectures/consulting from Novartis, Abbott, Bayer, Pfizer, BoehringerIngelheim, AstraZeneca, Cardior, CVRx, BMS, Amgen, Edwards, Roche, Zoll not related tothis article; and research support for the department from Zoll, CVRx, Abiomed, Norgine, Roche, all not related to this article. Vifor Pharma Ltd. had no role in study design and conduct; data collection, management, analysis, and interpretation; or manuscript preparation and approval.

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