Abnormal whole-body energy metabolism in iron-deficient humans despite preserved skeletal muscle oxidative phosphorylation

Abstract

Iron deficiency impairs skeletal muscle metabolism. The underlying mechanisms are incompletely characterised, but animal and human experiments suggest the involvement of signalling pathways co-dependent upon oxygen and iron availability, including the pathway associated with hypoxia-inducible factor (HIF). We performed a prospective, case–control, clinical physiology study to explore the effects of iron deficiency on human metabolism, using exercise as a stressor. Thirteen iron-deficient (ID) individuals and thirteen iron-replete (IR) control participants each underwent 31P-magnetic resonance spectroscopy of exercising calf muscle to investigate differences in oxidative phosphorylation, followed by whole-body cardiopulmonary exercise testing. Thereafter, individuals were given an intravenous (IV) infusion, randomised to either iron or saline, and the assessments repeated ~ 1 week later. Neither baseline iron status nor IV iron significantly influenced high-energy phosphate metabolism. During submaximal cardiopulmonary exercise, the rate of decline in blood lactate concentration was diminished in the ID group (P = 0.005). Intravenous iron corrected this abnormality. Furthermore, IV iron increased lactate threshold during maximal cardiopulmonary exercise by ~ 10%, regardless of baseline iron status. These findings demonstrate abnormal whole-body energy metabolism in iron-deficient but otherwise healthy humans. Iron deficiency promotes a more glycolytic phenotype without having a detectable effect on mitochondrial bioenergetics.

Systematic review and meta‐analysis of intravenous iron therapy for adults with non‐anaemic iron deficiency: An abridged Cochrane review

“… 54 , 55 , 56 The divergence in findings have been explained, at least in part, by a recent prospective case control study, which demonstrated that although non‐anaemic iron‐deficient individuals treated with intravenous iron showed no differences in both aerobic respiration and VO 2 max, intravenous iron increased lactate threshold during exercise, implying an increased ability to generate work aerobically with increasing exercise intensities in the absence of fatigue. 57 These findings are in keeping with previous physiological experiments in animals with clinical implications. 13 Further research investigating changes in lactate concentration in iron‐deficient individuals treated with intravenous iron is needed to confirm this.…”

“…Impact of intravenous iron on muscle function and performance has demonstrated a mix of results, with studies reporting both increases 22,24,53 and no change in exercise capacity in response to iron therapy 54–56 . The divergence in findings have been explained, at least in part, by a recent prospective case control study, which demonstrated that although non‐anaemic iron‐deficient individuals treated with intravenous iron showed no differences in both aerobic respiration and VO 2 max, intravenous iron increased lactate threshold during exercise, implying an increased ability to generate work aerobically with increasing exercise intensities in the absence of fatigue 57 . These findings are in keeping with previous physiological experiments in animals with clinical implications 13 .…”

Menstrual cycle affects iron homeostasis and hepcidin following interval running exercise in endurance-trained women

“…This leads to reduced iron supply into plasma by blocking the absorption of dietary iron in the duodenum, iron recycling in macrophages and the release of body iron stores (Xiao et al 2020). Iron deficiency (ID) in athletes has been shown to reduce endurance capacity and athletic performance through altered energy metabolism, decreased lactate threshold, early onset of fatigue and worsened test times (Hinton 2014;Frise Communicated by Klaas R westerterp.…”

Influencia de las hormonas sexuales en la respuesta de la hepcidina y la homeostasis del hierro al ejercicio de resistencia en mujeres deportistas: Proyecto IronFEMME = Influence of sex hormones on the hepcidin and iron homeostasis response to endurance exercise in women athletes: IronFEMME study

“…However, this population also exhibits a considerable prevalence of ID and IDA, especially in women (Hinton, 2014;Pedlar et al, 2018;Sim et al, 2019). Iron deficiency in athletes has been shown to reduce endurance capacity and athletic performance through altered energy metabolism, decreased lactate threshold, early onset of fatigue and worsened test times (Frise et al, 2022;Hinton, 2014). Furthermore, ID may negatively There are many factors that determine the regulation of iron homeostasis in women athletes (Pedlar et al, 2018), which often makes maintaining a healthy iron status a challenge for female athletes and their coaches, nutritionists, and clinicians.…”

“…This leads to reduced iron supply into plasma by blocking the absorption of dietary iron in the duodenum, iron recycling in macrophages and the release of body iron stores (Xiao et al, 2020). Iron deficiency in athletes has been shown to reduce endurance capacity and athletic performance through altered energy metabolism, decreased lactate threshold, early onset of fatigue and worsened test times (Frise et al, 2022;Hinton, 2014). Furthermore, ID may negatively impact athletes' health and well-being, by affecting different domains of cognitive performance such as motivation, concentration and decision making (Pedlar et al, 2018).…”