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Published in final edited form as: Biometals. 2020 Nov 25;34(1):97–105. doi: 10.1007/s10534-020-00266-w

Iron and zinc homeostases in female rats with physically active and sedentary lifestyles

Andrew J Ghio 1, Joleen M Soukup 1, Caroline Ghio 1, Christopher J Gordon 1, Judy E Richards 1, Mette C Schladweiler 1, Samantha J Snow 1, Urmila P Kodavanti 1
PMCID: PMC8299713  NIHMSID: NIHMS1682024  PMID: 33237470

Abstract

To determine the effects of repeated physical activity on iron and zinc homeostases in a living system, we quantified blood and tissue levels of these two metals in sedentary and physically active Long-Evans rats. At post-natal day (PND) 22, female rats were assigned to either a sedentary or an active treatment group (n=10/group). The physically active rats increased their use of a commercially-constructed stainless steel wire wheel so that, by the end of the study (PND 101), they were running an average of 512.8 ± 31.9 (mean ± standard error) minutes/night. After euthanization, plasma and aliquots of liver, lung, heart, and gastrocnemius muscle were obtained. Following digestion, non-heme iron and zinc concentrations in plasma and tissues were measured using inductively coupled plasma optical emission spectroscopy. Concentrations of both non-heme iron and zinc in plasma and liver were significantly decreased among the physically active rats relative to the sedentary animals. In the lung, both metals were increased in concentration among the physically active animals but the change in zinc did not reach significance. Similarly, tissue non-heme iron and zinc levels were both increased in heart and muscle from the physically active group. It is concluded that repeated physical activity in an animal model can be associated with a translocation of both iron and zinc from sites of storage (e.g. liver) to tissues with increased metabolism (e.g. the lung, heart, and skeletal muscle).

Keywords: Exercise, iron, zinc, ferritins, liver, muscle

Introduction

Iron is an essential nutrient utilized in almost every aspect of normal cell and tissue function because of 1) its interactions with O2, 2) its tendency towards complex formation (coordination), and 3) the variability of the redox potential when the metal is chemically complexed. Zinc is similarly an essential trace element which participates in 1) a provision of structural integrity, 2) catalytic functions, and 3) the regulation of intracellular signaling pathways. Both metals are present in all tissues and body fluids of multicellular organisms. As a result of an absolute requirement, living systems have evolved complex mechanisms for the regulation of iron and zinc (Colvin et al. 2003; Kawakami and Bhullar 2018; Ross 2017).

The homeostases of the two metals in a living system can be influenced by a myriad of pathways; physical activity is one such process. It is generally accepted that iron deficiency can develop with repeated physical activity, including exercise, in humans with a decrease in both serum/plasma iron and chronic reductions in iron stores. With repeated physical activity and exercise, there can be changes in numerous indices of iron homeostasis including serum iron, ferritin, transferrin, transferrin saturation, red blood cell count, hemoglobin, hematocrit, and erythrocytic indices (Auersperger et al. 2013; Coimbra et al. 2017; Di Santolo et al. 2008; Inoue et al. 2005; Jastrzebska et al. 2017; Mainous and Diaz 2009; Wilkinson et al. 2002). Accordingly, it has been established that athletes have a greater risk of iron depletion and anemia (i.e. a “sports” anemia); this is especially true for females, elite runners, and professional athletes (Coates et al. 2017; Fallon 2004; Landahl et al. 2005; Martinez et al. 2002; Ostojic and Ahmetovic 2008; Reinke et al. 2012). Changes in iron homeostasis are considered a possible result of hemodilution, increased destruction of erythrocytes, depressed iron absorption, and increased iron loss in sweat and through the gastrointestinal tract (Fuji et al. 2014; Ottomano and Franchini 2012; Smith 1995; Waller and Haymes 1996). Changes in zinc homeostasis with repeated physical activity remain to be clearly defined (Chu et al. 2017). However, several studies have suggested that, comparable to iron, serum zinc can be decreased with repeated physical activity (Brun et al. 1995; Karakukcu et al. 2013; Wochynski and Sobiech 2014).

To determine the effects of repeated physical activity on iron and zinc homeostases, we quantified blood and tissue levels of these two metals and metal-related proteins in groups of animals either precluded from or allowed access to a running wheel.

Materials and methods

Animals.

All experiments were approved by the US Environmental Protection Agency institutional animal care and use committee. Long-Evans female rats were selected for study because female rats are active and use a running wheel when afforded the opportunity while male rats do not generally use a wheel voluntarily (Gordon et al. 2017). Charles River Laboratories (Raleigh, NC) shipped 21-day old female rats (n= 20). They were pair-housed in the vivarium for 24 hr to allow for recovery from the possible stress of shipment.

Sedentary and physically active treatments.

At post-natal day (PND) 22, the rats were assigned to either a sedentary or a physically active treatment group (n=10/group). Sedentary and physically active animals were then single housed in acrylic cages (25 × 15 × 50 cm) on hardwood chip bedding (Beta Chip®), without and with running wheels, respectively. Rats were provided with a small handful of Enviro-Dri for use for nest building and enrichment. Food was added to the hopper on top of the cage for adult animals. For PND 22–33 days, food was also added to the floor of the cage to allow the smaller rats greater access. A water bottle was placed in the top of the cage.

The running wheel system consisted of a commercially-constructed (Starr Life Sciences, Oakmont, PA) stainless steel wire wheel (33 cm diameter; 1.02 m circumference) that was placed in the standard acrylic cage. Wheel revolutions were detected with a magnetic switch. The activity of the running wheel was monitored and analyzed using Vitaview software (Starr Life Sciences). The wheel was positioned in a standard acrylic rat cage. The cages with wheels along with the cages without wheels were housed in the animal vivarium. The computer was also placed in the vivarium and its output monitored remotely through data ports.

Physically active rats had continuous access to the running wheel which they used primarily during the dark cycle (that is, at night). This running wheel model is designed for adult rats with a body weight of at least 150 g. However, the young rats were fully capable of using the wheel and quickly learned to walk and then run on the wheel after a few days with the wheel in their cage. The 22-day old physically active rats housed in cages with running wheels increased their use on the wheel each day for about 38 days. In the first week of activity on the wheels, there was a gradual increase in total running with a marked rise at the beginning and end of each dark phase and a relative quiescent period during the middle of the night. There was an abrupt increase in wheel activity at an age of 36 days. Wheel activity peaked at approximately 60 days of age. By PND 100, the end of the study, the physically active rats were running an average of 512.8 ± 31.9 (mean ± standard error) minutes/night (over 8 hours).

Body weights, hematologic indices, and tissue collection.

On PND 101, rats were weighed and euthanized with an intraperitoneal injection of >200 mg/kg sodium pentobarbital (Fatal-Plus diluted 1:1 with saline; Vortech Pharmaceuticals, Ltd., Dearborn, MI). When animals were completely non-responsive to hind paw pinch after Fetal-Plus injection (>200 mg/kg pentobarbital), blood samples were collected through the abdominal aorta. Blood was collected directly into vacutainer tubes containing ethylenediaminetetraacetic acid (EDTA) for complete blood count and plasma preparation. Red blood cell number, hemoglobin concentration, hematocrit, mean corpuscular volume (MCV), mean corpuscular hemoglobin (MCH), and mean corpuscular hemoglobin concentration (MCHC) were determined using the Beckman Coulter AcT blood analyzer (Beckman-Coulter Inc., Fullerton, CA). The heart was removed en bloc and weighed. Aliquots of liver, lung, heart (left ventricle), and gastrocnemius muscle were resected, blotted to remove contaminating blood, and frozen in liquid nitrogen for later analysis of iron and zinc.

Plasma and tissue iron and zinc concentrations.

Non-heme iron and zinc concentrations in plasma and tissues were measured following digestion and precipitation of hemoglobin (Torrance 1980). When cells and tissues disintegrate during incubation in 3 N HC1 and 10% trichloroacetic acid (TCA), a clear extract and a small residue were noted. The separation of heme from non-heme iron is possible by the fact that the heme molecule is very resistant to acid hydrolysis. It precipitates and is sequestered in the residue. Plasma (0.3 mL) was hydrolyzed in 2.7 mL 3 N HCl/10% TCA while tissue was hydrolyzed in the same 3 N HCl/10% TCA solution (1.00 gm: 10.0 ml) at 70°C for 16 hours. The hydrolyzed plasma and tissues were centrifuged at 1200g for 10 minutes, and an aliquot of the extract was taken for determination of iron and zinc. Iron and zinc concentrations were quantified using inductively coupled plasma optical emission spectroscopy (ICPOES; Model Optima 4300DV, Perkin Elmer, Norwalk, CT) operated at λ= 238.204 and 206.200 nm respectively. Plasma iron concentration was also measured by a colorimetric assay (Roche Modular Analyzer; Roche Diagnostics Corporation).

Measurement of plasma ferritin.

The concentrations of ferritin in the plasma were quantified using an immunoturbidimetric assay (Kamiya Biomedical Company, Seattle, WA).

Statistics.

GraphPad Prism (6.0) was used for all data analysis. Data are expressed as mean values ± standard error unless specified otherwise. T-tests of independent means were used to analyze for differences between sedentary and physically active groups. Two-tailed tests of significance were employed. The level of significance was set at p <0.05.

Results

Physically active animals, those allowed access to running wheels, had no change in body weight relative to sedentary animals (Table 1). There were no changes in red blood cell (RBC) count and hemoglobin between the two groups, but hematocrit was significantly decreased in the physically active animals relative to the sedentary animals (Table 1). No disparities in MCV, MCH, and MCHC were observed between the two groups of animals (Table 1).

Table 1.

Body weights and hematologic indices in physically active and sedentary rats

Sedentary rats Physically active rats
Body weight (g) 340±28 340±39
Red blood cell count (106 cells per µL) 7.1±0.3 7.0±0.4
Hemoglobin (g/dL) 14.5±0.5 14.7±0.7
Hematocrit (%) 38.6±1.8 33.3±2.1
Mean corpuscular volume (fL) 54.7±1.3 56.1±1.5
Mean corpuscular hemoglobin (pg) 20.6±0.4 21.0±0.8
Mean corpuscular hemoglobin concentration (g/dL) 37.7±0.5 37.4±0.7
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The concentrations of non-heme iron in plasma were significantly decreased among the physically active relative to the sedentary animals (Figure 1A). Similarly, measuring plasma iron using a colorimetric methodology provided values of 224 ± 16 and 175 ± 6 µg/dL in the sedentary and physically active rats respectively. Absolute values of plasma zinc levels were greater than non-heme iron concentrations. Comparable to plasma iron, plasma zinc concentrations were decreased in physically active animals (Figure 1B). Plasma concentrations of the metal storage protein ferritin were also diminished among the physically active animals relative to the sedentary animals, but disparities did not reach significance (Figure 1B).

Figure 1.

Figure 1.

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Plasma concentrations of metals and ferritin in sedentary and physically active rats. Plasma [Fe] and [Zn] both decreased with repeated physical activity (A). While plasma ferritin decreased among physically active rats, this did not reach significance (B). * significantly different relative to sedentary rats

Liver non-heme iron concentrations correspond to values of stored iron and can correlate with blood ferritin levels (Park et al. 2017). Compared to plasma and lung, heart, and muscle tissues, liver demonstrated the highest concentrations of both iron and zinc. Levels of non-heme iron in the liver were greater than those of zinc. Liver non-heme iron concentrations were significantly decreased among the physically active rats relative to the sedentary rats (Figure 2A). Comparable to liver iron, liver zinc levels were diminished among those animals in the physically active group (Figure 2A).

Figure 2.

Figure 2.

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Liver, lung, heart, and muscle concentrations of metals in sedentary and physically active rats. While liver concentrations of iron and zinc decreased with repeated physical activity (A), the levels of these metals increased in lung (B), heart (C), and muscle (D). Increased zinc concentrations in lung tissue did not reach significance. * significantly different relative to sedentary rats

Relative to non-heme iron concentrations, zinc concentrations were less in lung and heart but greater in muscle. Differences in metals concentrations of lung, heart and muscle tissues between physically active and sedentary animals revealed changes which were opposite to those observed in the plasma and liver. In the lung, both non-heme iron and zinc were increased in concentration among the physically active animals but the change in zinc did not reach significance (Figure 2B). Heart weight was significantly increased in those animals included in the physically active group relative to those in the sedentary group (1.05 and 0.95 g respectively). In heart, non-heme iron and zinc levels were both increased in the physically active group (Figure 2C). Finally, muscle concentrations of metals revealed the lowest absolute values among the tissues. Levels of both non-heme iron and zinc in muscle increased among those rats in the physically active group (Figure 2D).

Discussion

The physically active group of rats (i.e. those with access to the running wheel) did not demonstrate differences in red blood cell count and hemoglobin concentration despite repeated physical activity for 78 days. However, the hematocrits were decreased among the physically active animals. It is unclear why other indices of red blood cell number and mass did not decrease in the rats with repeated physical activity. The decrement in hematocrit among the physically active animals corresponds to decreased indices of red blood cell mass (e.g. decreased red blood cell count, hemoglobin, and hematocrit) among human populations who frequently exercise (Coates et al. 2017; Fallon 2004; Landahl et al. 2005; Martinez et al. 2002; Ostojic and Ahmetovic 2008; Reinke et al. 2012). Plasma non-heme iron concentrations also decreased in the cohort of rats which were physically active. Comparable changes in either serum or plasma iron have been observed in animals and humans with repeated physical activity (Di Santolo et al. 2008; Qian et al. 1999).

Plasma ferritin levels decreased in the physically active group of animals. Serum ferritin has been observed to decrease in humans with frequent physical activity (Pate et al. 1993; Woolf et al. 2009). Decrements in the blood levels of this iron-storage protein with repeated physical activity are reproducible and use of the serum ferritin concentration as a marker of human cardiovascular fitness has been recommended fitness (Mainous and Diaz 2009). Blood ferritin levels can correlate with stored iron (Angelucci et al. 2000; Lipschitz et al. 1974; Porter et al. 2017). Accordingly, decrements in plasma and serum ferritin concentrations can reflect decreased quantities of iron in the liver, a major site of metal storage (Reeves and Haurani 1980; Powell et al. 1978). In this study, liver non-heme iron concentrations decreased in rats who had repeated physical activity relative to sedentary animals. In prior investigation, liver iron “trended” toward decreased levels among rats which swam for 1 and ½ hours per day, 5 days per week for 9 weeks (Ruckman and Sherman 1981) and was significantly diminished among rats which swam for 2 hours per day for 3 months (Qian et al. 1999). Bleomycin-detectable iron was decreased in liver tissue from animals who swam for 3 months (Xiao et al. 2004). Repeated physical activity which does not increase the oxygen consumption to higher levels has not been associated with changes in liver iron (Fujii et al. 2011). The results of this study strengthen an association between repeated physical activity with decreased concentrations of stored iron.

In contrast to the decreased plasma metal, ferritin, and liver metal concentrations, levels of iron in lung, heart, skeletal muscle tissues all increased with repeated physical activity in this study of rats given access to a running wheel. Changes in lung iron with exercise have not previously been examined. The iron content in skeletal and heart muscle was previously demonstrated to be increased among a group of animals who swam for 9 weeks (Ruckman and Sherman 1981). The concentration of iron in both heart and skeletal muscles were similarly demonstrated to increase in the rat following running to exhaustion (Strause 1983). Finally, iron concentrations of iron in the heart, as well as the kidney and spleen, decreased in a group of rats swimming for 2 hr per day for 3 months (Qian et al. 1999). Therefore, the results of this study support prior investigation demonstrating elevations of iron in muscle tissue with repeated physical activity and exercise. Changes in organ weight with physical active are unlikely to explain the altered metal concentrations since organ weight has not been demonstrated to change with physical activity, except for the heart where both increased rather than the inverse relationship predicted.

This investigation revealed changes in zinc homeostasis following repeated physical activity which were comparable to those in iron homeostasis with decreased plasma and liver concentrations and increased levels in lung, heart, and skeletal muscle with exercise. Changes in zinc concentrations with repeated physical activity have not been studied with the frequency that iron has. Prior studies have demonstrated a decrement in serum zinc among humans who participate in repeated physical activity (Brun et al. 1995; Karakukcu et al. 2013; Wochynski and Sobiech 2014). Zinc concentrations in the kidney were previously shown to be increased with exercise (Kuru et al. 2003). Similarly, three months of training (swimming 2 hours per day for 5 days per week) decreased zinc levels in the striatum of rats (Wu and Xiao 2017). Further investigation is warranted into the impact of repeated physical activity and exercise on metals other than iron.

Perturbations of metal homeostases can include not only changes in uptake and loss but also redistribution in cells, tissues, and living systems. Results of this study support a translocation of both iron and zinc from sites of storage (e.g. liver) to tissues with increased metabolism following repeated physical activity (e.g. the lung, heart, and skeletal muscle). A previous investigation has suggested that exercise could influence the distribution and reutilization of iron with decrements in liver iron being associated with an increase in hemoglobin (Ruckman and Sherman 1981). However, numerous studies have established the converse relationship between physical activity and metal homeostasis with exercise decreasing indices of red blood cell mass (Coates et al. 2017; Fallon 2004; Landahl et al. 2005; Martinez et al. 2002; Ostojic and Ahmetovic 2008; Reinke et al. 2012). Decrements in indices of red blood cell mass, and blood levels of ferritin, following repeated physical activity have been attributed to hemodilution, increased destruction of erythrocytes, depressed iron absorption, and increased iron loss in sweat and through the gastrointestinal tract (Fuji et al. 2014; Ottomano and Franchini 2012; Smith 1995; Waller and Haymes 1996). This study supports a translocation of metal to those tissues most metabolically active (i.e. those tissues in greatest need of these metals). Mechanisms by which prioritization of iron delivery to tissues in a living system is regulated have not been delineated. With repeated physical activity, prioritization of available iron is likely to be assigned to those tissues with the greatest metabolic need (e.g. lung, heart, and skeletal muscle). Subsequently, metal can be preferentially delivered to these tissues with an anemia potentially resulting. A comparable redistribution of iron occurs in plants with photosynthesis as the plant redistributes the metal to sites of greatest need (Kobayashi and Nishizawa 2012). Plants demonstrate a similar capacity to translocate zinc and it is predicted that this metal similarly can be transported between tissues to meet varying requirements (Impa et al. 2013).

A major limitation of this study is the small number of animals included in the cohorts. In addition, this study can be confounded by aging. Defining an effect of repeated physical activity in an animal model requires some usually prolonged duration of time and during this aging, iron has been demonstrated to increase in almost every tissue studied (Assenza et al. 2016). It is assumed that the sedentary cohort controlled for this potential confounding. Finally, the basic pathways underlying the association between physical activity and iron homeostasis were not defined. However, skeletal muscles express several cytokines. In the acute response to exercise, interleukin (IL)-6 is synthesized by skeletal muscle and released into the circulation (Hennigar et al. 2017; Reihmane and Dela 2014; Pedersen 2017). Cytokines, besides their immunoregulatory roles, can participate in metabolism. IL-6 is thought to possibly function as an ‘energy sensor’ secreted by skeletal muscle activating glycogenolysis in the liver and lipolysis in fat tissue in order to provide muscle with the growing energy demands during exercise. In addition, IL-6 levels in the blood can impact iron homeostasis including through an enhancement of hepcidin production by the liver (Coimbra et al. 2017; Raja et al. 2005). Accordingly, pathways are recognized which support the relationship between physical activity and iron homeostasis.

It is concluded that repeated physical activity in an animal model can impact iron and zinc homeostases with decreased concentrations of both metals in the plasma and liver and increased levels in the lung, heart, and skeletal muscle. Numerous human diseases demonstrate some relationship to iron and zinc homeostases (e.g. metabolic syndrome, coronary artery disease, and cancer) (Basuli et al. 2014; Alkhateeb and Connor 2013; Fabris and Mocchegiani 1995). The risk for these diseases can be diminished with repeated physical activity. The effects of repeated physical activity, such as exercise, on human disease may occur through impacting metal homeostases (Lauffer 1991).

Acknowledgement.

The authors would like to thank Ms. Pamela Phillips of the US EPA (currently retired) for her help in the animal care and exercise protocol.

The research described in this article has been reviewed by the Center for Public Health and Environmental Assessment, U.S. Environmental Protection Agency, and approved for publication. Approval does not signify that the contents necessarily reflect the views and policies of the Agency, nor does the mention of trade names of commercial products constitute endorsement or recommendation for use.

Abbreviations:

EDTA

Ethylenediaminetetraacetic acid

ICPOES

Inductively coupled plasma optical emission spectroscopy

MCH

Mean corpuscular hemoglobin

MCV

Mean corpuscular volume

MCHC

Mean corpuscular hemoglobin concentration

PND

Post-natal day

RBC

Red blood cell

TCA

Trichloroacetic acid

Footnotes

Conflict of Interest: The authors declare that they have no conflict of interests.

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