The influence of iron deficiency on the functioning of skeletal muscles: experimental evidence and clinical implications

Stugiewicz, Magdalena; Tkaczyszyn, Michał; Kasztura, Monika; Banasiak, Waldemar; Ponikowski, Piotr; Jankowska, Ewa A.

doi:10.1002/ejhf.467

Cited by 123 publications

(109 citation statements)

References 121 publications

(247 reference statements)

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“…As previously reported, iron participates in skeletal muscle function [69]. Although this issue has been poorly addressed in age-associated muscle changes, research on diseases such as heart failure and chronic obstructive pulmonary disease have suggested that iron deficiency may impair physical capacity.…”

Section: Nutritionmentioning

confidence: 95%

“…Iron deficiency has been linked to several alterations such as decreased physical capacity and muscle mass; altered oxidative-to-glycolytic fiber ratio; reduced myoglobin pool; decreased mitochondria and mitochondrial cristae density; and reduced oxidative metabolism with increased glycolytic activity [69]. Despite this information suggesting iron deficiency plays a role in impairing physical capacity, iron status has been poorly addressed in age-associated muscle changes.…”

Section: Etiology and Intracellular Pathways Involved In Aging-associmentioning

confidence: 99%

“…Although this issue has been poorly addressed in age-associated muscle changes, research on diseases such as heart failure and chronic obstructive pulmonary disease have suggested that iron deficiency may impair physical capacity. Therefore, iron status should be evaluated when muscle dysfunction is present without an apparent reason and iron deficiency treatment should be viewed as an emerging therapeutic target [69]. …”

Section: Nutritionmentioning

confidence: 99%

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Skeletal muscle aging: influence of oxidative stress and physical exercise

et al. 2017

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Skeletal muscle abnormalities are responsible for significant disability in the elderly. Sarcopenia is the main alteration occurring during senescence and a key public health issue as it predicts frailty, poor quality of life, and mortality. Several factors such as reduced physical activity, hormonal changes, insulin resistance, genetic susceptibility, appetite loss, and nutritional deficiencies are involved in the physiopathology of muscle changes. Sarcopenia is characterized by structural, biochemical, molecular and functional muscle changes. An imbalance between anabolic and catabolic intracellular signaling pathways and an increase in oxidative stress both play important roles in muscle abnormalities. Currently, despite the discovery of new targets and development of new drugs, nonpharmacological therapies such as physical exercise and nutritional support are considered the basis for prevention and treatment of age-associated muscle abnormalities. There has been an increase in information on signaling pathways beneficially modulated by exercise; nonetheless, studies are needed to establish the best type, intensity, and frequency of exercise to prevent or treat age-induced skeletal muscle alterations.

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Section: Nutritionmentioning

confidence: 95%

Section: Etiology and Intracellular Pathways Involved In Aging-associmentioning

confidence: 99%

Section: Nutritionmentioning

confidence: 99%

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Skeletal muscle aging: influence of oxidative stress and physical exercise

et al. 2017

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“…The effect of reduced iron availability on cardiac and skeletal muscle cells may be to impair oxygen storage through reduced myoglobin and to directly reduce energy generation by mitochondria and, thereby, the efficiency of the heart and skeletal muscle to maintain contractile strength and endurance (Jankowska et al, 2010;Frise et al, 2016;Stugiewicz et al, 2016). The effects of iron deficiency on patients with cardiac disease therefore go far beyond any reduction in oxygen supply but may contribute to directly to worsening cardiac or skeletal muscle function (Von Haehling et al, 2015).…”

Section: Pathophysiology Of Iron Deficiency In the Failing Heartmentioning

confidence: 99%

Investigation and treatment for iron deficiency in heart failure: the unmet need in Lower and Middle Income Countries

Makubi

Roberts

2017

Br J Haematol

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Summary Frank iron deficiency has been associated with a wide range of cardiac and pulmonary abnormalities including non‐ischaemic cardiomyopathy. Iron deficiency anaemia and isolated iron deficiency are well‐defined adverse prognostic factors in non‐ischaemic cardiac failure. Furthermore, iron‐deficient patients in chronic heart failure with a serum ferritin of <100 μg/l or <300 μg/l with reduced transferrin saturation of <20%, who were given intravenous iron showed improved clinical outcomes. Iron deficiency with or without anaemia affects over a quarter of the world's population, but the impact of iron deficiency in heart failure and the effective management of iron deficiency in heart failure in Lower and Middle Income Countries (LMICs) is not well described. Heart failure in African cohorts occurs at a younger age than in North America and Europe and is more likely to be due to hypertension. Recent studies suggest that iron deficiency anaemia, which is very common in heart failure patients in Africa, and iron deficiency are independently associated with a poor prognosis in heart failure. Preliminary data suggest that iron deficiency in patients with heart failure can be treated with oral iron, with significant beneficial effects on haematological and physiological variables. Cost may prohibit the use of intravenous iron on a large scale in LMICs and optimal regimes to treat iron deficiency in heart failure patients with oral iron therapy remain to be defined.

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“…Spearman's rank correlation coefficient (R) is reflecting the interrelationship between the mRNA expression of respective genes (FTH -ferritin heavy chain; FTL -ferritin light chain; FPN1 -ferroportin type 1; TfR1 -transferrin receptor type 1; MB -myoglobin; HAMP -hepcidin) within H9C2 or L6G8C5 in the whole spectrum of iron concentration been performed mainly in the cells involved in systemic iron homeostasis, such as hepatocytes, macrophages, enterocytes, or erythroid precursor cells [24][25][26]. However, it is worth mentioning that local iron homeostasis may differ from the systemic one [27]; therefore, we aimed to investigate the molecular machinery present in the cells of high energy demand, such as cardiomyocytes and skeletal myocytes. In our study we confirmed the presence of the molecular machinery involved in iron import, export, storage, and regulation in rat cardiomyocytes H9C2 and myocytes L6, which represent cells of high energy demand.…”

Section: Discussionmentioning

confidence: 99%

Both iron excess and iron depletion impair viability of rat H9C2 cardiomyocytes and L6G8C5 myocytes

Kasztura¹,

Dzięgała²,

Kobak³

et al. 2017

Kardiol Pol

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A b s t r a c tBackground: Iron is presumed to play an important role in the functioning of cardiomyocytes and skeletal myocytes. There is scarcity of direct data characterising the cells functioning when exposed to iron depletion or iron overload in a cellular environment. There is some clinical evidence demonstrating that iron deficiency has serious negative prognostic consequences in heart failure (HF) patients and its correction brought clinical benefit. Aim:The viability of the cells upon unfavourable iron concentration in the cell culture medium and the presence of the molecular system of proteins involved in intracellular iron metabolism in these cells have been studied.Methods: H9C2 rat adult cardiomyocytes and L6G8C5 rat adult skeletal myocytes were cultured for 24 h in optimal vs. reduced vs. increased iron concentrations. Intracellular iron content was measured by flame atomic absorption spectroscopy (FAAS). We analysed the mRNA expression of: ferritin heavy and light chains (FTH and FTL; iron storage proteins), myoglobin (MB, oxygen storage protein) ferroportin type 1 (FPN1; iron exporter), transferrin receptor type 1 (TfR1; iron importer), hepcidin (HAMP; iron metabolism regulator) using qPCR, the level of respective proteins using Western Blot (WB), and the viability of the cells using flow cytometry and cell viability tetrazolium reduction assay (MTS).Results: Cardiomyocytes exposed to gradually reduced iron concentrations in the medium demonstrated a decrease in the mRNA expression of FTH, FTL, FPN1, MB, and HAMP (all R = -0.75, p < 0.05), indicating depleted iron status in the cells. As a consequence, the expression of TfR1 (R = 0.7, p < 0.05) was increased, reflecting a facilitated entrance of iron to the cells. The inverse changes occurred in H9C2 cells exposed to increased iron concentrations in the medium in comparison to control cells. The same pattern of changes in the mRNA expressions was observed in myocytes, and there was a strong correlation between analogous genes in both cell lines (all R > 0.9, p < 0.0001). WB analysis revealed the analogous pattern of changes in protein expression as an mRNA profile. Both iron depletion and iron excess impaired viability of cardiomyocytes and skeletal myocytes. Conclusions:Both rat cardiomyocytes and myocyte cells contain the set of genes involved in the intracellular iron metabolism, and both types of investigated cells respond to changing iron concentrations in the cultured environment. Both iron deficiency (ID) and iron overload is detrimental for the cells. This data may explain the beneficial effects of iron supplementation in patients with ID in HF.

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The influence of iron deficiency on the functioning of skeletal muscles: experimental evidence and clinical implications

Cited by 123 publications

References 121 publications

Skeletal muscle aging: influence of oxidative stress and physical exercise

Skeletal muscle aging: influence of oxidative stress and physical exercise

Investigation and treatment for iron deficiency in heart failure: the unmet need in Lower and Middle Income Countries

Both iron excess and iron depletion impair viability of rat H9C2 cardiomyocytes and L6G8C5 myocytes

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