Induction of an increase in mitochondrial matrix enzymes in muscle of iron-deficient rats

1987 ◽  
Vol 253 (5) ◽  
pp. C639-C644 ◽  
Author(s):  
Y. Ohira ◽  
L. J. Cartier ◽  
M. Chen ◽  
J. O. Holloszy
Keyword(s):  
Skeletal Muscle ◽  
Iron Deficiency ◽  
Mitochondrial Biogenesis ◽  
Citrate Synthase ◽  
Weight Bearing ◽  
Mitochondrial Matrix ◽  
Vigorous Exercise ◽  
Deficient Diet ◽  
Coa Transferase ◽  
Iron Deficient

Young rats maintained on an iron-deficient diet developed severe anemia and had large decreases in the levels of the iron-containing flavoproteins and cytochromes of the mitochondrial respiratory chain in skeletal muscle. In contrast, the levels of a number of mitochondrial matrix marker enzymes, including citrate synthase, isocitrate dehydrogenase, 3-hydroxyacyl-CoA dehydrogenase, 3-ketoacid-CoA transferase, and aspartate aminotransferase, increased in red skeletal muscle but not in white muscle. Phosphocreatine concentration was decreased and inorganic phosphate concentration was increased in soleus muscle frozen in situ. We hypothesize that the increase in mitochondrial matrix enzymes reflects a stimulus to mitochondrial biogenesis in posture-maintaining and weight-bearing red muscle fibers in severely iron-deficient rats. It is our working hypothesis that this stimulus to mitochondrial biogenesis arises from mild activity of the red fibers and is due to the same perturbation in cellular homeostasis that is normally caused by vigorous exercise or hypoxia. In iron deficiency, the stimulus to mitochondrial biogenesis can induce an increase in only those enzymes not prevented from increasing by iron deficiency, resulting in formation of mitochondria of grossly abnormal composition.

5'-Aminolevulinate synthase activity is decreased in skeletal muscle of anemic rats

1992 ◽  
Vol 263 (2) ◽  
pp. C429-C435 ◽  
Author(s):  
L. A. McNabney ◽  
D. A. Essig
Keyword(s):  
Skeletal Muscle ◽  
Enzyme Activity ◽  
Citrate Synthase ◽  
Muscle Growth ◽  
Biosynthetic Enzyme ◽  
Deficient Diet ◽  
Aminolevulinate Synthase ◽  
Iron Deficient ◽  
Old Rats ◽  
Rate Limiting

Expression of the rate-limiting heme biosynthetic enzyme 5'-aminolevulinate synthase (ALAS) was investigated in skeletal muscle of 3-wk-old rats fed an iron-deficient diet. After 14 days, ALAS activity had declined 70% relative to control (2.1 +/- 0.2 vs. 0.6 +/- 0.1 nmol.h-1.g-1; P less than 0.005). Similar decreases were observed for blood hemoglobin (11.4 +/- 0.2 vs. 3.9 +/- 0.3 g/dl; P less than 0.005) and muscle cytochrome c (14.5 +/- 1.3 vs. 7.1 +/- 0.6 nmol/g; P less than 0.005). An iron-deficient diet decreased body and skeletal muscle growth by 15 (P less than 0.005) and 10% (P less than 0.05), respectively, whereas concentrations of protein, RNA, ALAS mRNA, and citrate synthase activity in muscle were not different from control. One mechanism by which heme biosynthesis may be slowed in muscle of young anemic rats is a decrease in ALAS activity. At a time when enzyme activity was decreased, ALAS mRNA expression was not affected by an iron-deficient diet, suggesting that steps after transcription of the ALAS gene may regulate the decrease in activity.

Curcumin induces mitochondrial biogenesis by increasing cAMP levels via PDE4A inhibition in skeletal muscle

2021 ◽  
pp. 1-34
Author(s):  
Hamidie Ronald D Ray ◽  
Tsubasa Shibaguchi ◽  
Tatsuya Yamada ◽  
Rikuhide Koma ◽  
Rie Ishizawa ◽  
...  
Keyword(s):  
Skeletal Muscle ◽  
Protein Expression ◽  
Mitochondrial Biogenesis ◽  
Mitochondrial Respiration ◽  
Citrate Synthase ◽  
Signalling Pathway ◽  
Curcumin Treatment ◽  
Camp Content ◽  
Signalling Molecules ◽  
Camp Levels

Abstract Background: Previous research has suggested that curcumin potentially induces mitochondrial biogenesis in skeletal muscle via increasing cAMP levels. However, the regulatory mechanisms for this phenomenon remain unknown. The purpose of the present study was to clarify the mechanism by which curcumin activates cAMP-related signalling pathways that upregulate mitochondrial biogenesis and respiration in skeletal muscle. Methods: The effect of curcumin treatment (i.p., 100 mg/kg-BW/day for 28 days) on mitochondrial biogenesis was determined in rats. The effects of curcumin and exercise (swimming for 2 h/day for 3 days) on the cAMP signalling pathway were determined in the absence and presence of phosphodiesterase (PDE) or protein kinase A (PKA) inhibitors. Mitochondrial respiration, citrate synthase (CS) activity, cAMP content, and protein expression of cAMP/PKA signalling molecules were analysed. Results: Curcumin administration increased COX-IV protein expression, and CS and complex I activity, consistent with the induction of mitochondrial biogenesis by curcumin. Mitochondrial respiration was not altered by curcumin treatment. Curcumin and PDE inhibition tended to increase cAMP levels with or without exercise. In addition, exercise increased the phosphorylation of PDE4A, whereas curcumin treatment strongly inhibited PDE4A phosphorylation regardless of exercise. Furthermore, curcumin promoted AMPK phosphorylation and PGC-1α deacetylation. Inhibition of PKA abolished the phosphorylation of AMPK. Conclusion: The present results suggest that curcumin increases cAMP levels via inhibition of PDE4A phosphorylation, which induces mitochondrial biogenesis through a cAMP/PKA/AMPK signalling pathway. Our data also suggest the possibility that curcumin utilizes a regulatory mechanism for mitochondrial biogenesis that is distinct from the exercise-induced mechanism in skeletal muscle.

Developmental iron deficiency dysregulates TET activity and DNA hydroxymethylation in the rat hippocampus and cerebellum

2022 ◽  
Author(s):  
Amanda K. Barks ◽  
Montana M. Beeson ◽  
Timothy C. Hallstrom ◽  
Michael K. Georgieff ◽  
Phu V. Tran
Keyword(s):  
Iron Deficiency ◽  
Neural Circuit ◽  
Epigenetic Modification ◽  
Rat Hippocampus ◽  
Dietary Iron ◽  
Deficient Diet ◽  
Dna Hydroxymethylation ◽  
Iron Treatment ◽  
Iron Deficient ◽  
Increased Risk

Iron deficiency (ID) during neurodevelopment is associated with lasting cognitive and socioemotional deficits, and increased risk for neuropsychiatric disease throughout the lifespan. These neurophenotypical changes are underlain by gene dysregulation in the brain that outlasts the period of ID; however, the mechanisms by which ID establishes and maintains gene expression changes are incompletely understood. The epigenetic modification 5-hydroxymethylcytosine (5hmC), or DNA hydroxymethylation, is one candidate mechanism because of its dependence on iron-containing TET enzymes. The aim of the present study was to determine the effect of fetal-neonatal ID on regional brain TET activity, Tet expression, and 5hmC in the developing rat hippocampus and cerebellum, and to determine whether changes are reversible with dietary iron treatment. Timed pregnant Sprague-Dawley rats were fed iron deficient diet (ID; 4 mg/kg Fe) from gestational day (G)2 to generate iron deficient anemic (IDA) offspring. Control dams were fed iron sufficient diet (IS; 200 mg/kg Fe). At postnatal day (P)7, a subset of ID-fed litters was randomized to IS diet, generating treated IDA (TIDA) offspring. At P15, hippocampus and cerebellum were isolated for subsequent analysis. TET activity was quantified by ELISA from nuclear proteins. Expression of Tet1, Tet2, and Tet3 was quantified by qPCR from total RNA. Global %5hmC was quantified by ELISA from genomic DNA. ID increased DNA hydroxymethylation (p=0.0105), with a corresponding increase in TET activity (p<0.0001) and Tet3 expression (p<0.0001) in the P15 hippocampus. In contrast, ID reduced TET activity (p=0.0016) in the P15 cerebellum, with minimal effect on DNA hydroxymethylation. Neonatal dietary iron treatment resulted in partial normalization of these changes in both brain regions. These results demonstrate that the TET/DNA hydroxymethylation system is disrupted by developmental ID in a brain region-specific manner. Differential regional disruption of this epigenetic system may contribute to the lasting neural circuit dysfunction and neurobehavioral dysfunction associated with developmental ID.

scholarly journals The Treatment of Iron Deficiency Anemia

Blood ◽  
1955 ◽  
Vol 10 (6) ◽  
pp. 567-581 ◽  
Author(s):  
DANIEL H. COLEMAN ◽  
ALEXANDER R. STEVENS ◽  
CLEMENT A. FINCH
Keyword(s):  
Iron Deficiency ◽  
Gastrointestinal Symptoms ◽  
The Body ◽  
Deficiency Anemia ◽  
Deficient Diet ◽  
Significant Group ◽  
Body Iron ◽  
Iron Stores ◽  
Iron Deficient ◽  
Full Complement

Abstract In the normal individual the amount of iron absorbed and lost from the body each day is exceedingly small. There are certain periods during life when body iron requirements are increased; the most important of these is infancy. Here, existing iron stores are rapidly depleted, and a deficient diet can soon produce iron deficiency. Once a full complement of body iron has been accrued, the adult is independent of iron intake and becomes iron deficient only through blood loss. In the production of iron deficiency, iron stores are exhausted before anemia appears. If any question in diagnosis from usual laboratory tests exists, the direct. examination of marrow for hemosiderin will establish the diagnosis. It is of obvious importance to confirm the diagnosis by specific therapy and to determine the cause of the iron depletion. Response to oral iron is highly predictable and failure of response usually in dictates a mistaken diagnosis. In a small but significant group of patients, either unable to take iron because of gastrointestinal symptoms, unable to absorb iron, or in need of iron reserves, parenteral administration of iron has distinct advantages. The saccharated oxide of iron is an effective preparation for this purpose.

scholarly journals Standardization & Development of Rat Model with Iron Deficiency Anaemia Utilising Commercial Available Iron Deficient Food

2019 ◽  
Vol 16 (1) ◽  
pp. 71-77
Author(s):  
Mansee Kapil Thakur ◽  
Smital Sameer Kulkarni ◽  
Nimain Mohanty ◽  
Nitin. N. Kadam ◽  
Niharika S. Swain
Keyword(s):  
Iron Deficiency ◽  
Rat Model ◽  
Iron Deficiency Anaemia ◽  
Test Group ◽  
Peripheral Smear ◽  
Deficient Diet ◽  
Deficiency Anaemia ◽  
Iron Deficient ◽  
Body Weights ◽  
Before And After

Many research centres have developed various animal models with Iron Deficiency Anaemia (IDA) by using iron deficient feeds as well as different chemicals. Model for iron deficiency anaemia (IDA) in rats has been created by the use of iron elimination from diet components as much as possible. The present study elaborates and concludes the development of IDA rat model by investigating different parameters like body weight, haematological indices, peripheral smear, immunoassay studies and histopathological studies using commercially available iron deficient diet. 12 Wistar albino female rats weighing 180-200 gm were selected with normal haemoglobin range of 12 - 15 g/dL purchased from Bombay Veterinary College, Parel and divided into two groups – Control (3 no. of rats) and Test (9 no. of rats). The test group was fed with iron deficient diet (VRK Nutritional Solutions) whereas control group was fed with standard diet. The time duration of the study was 5 weeks (35 days) and 6 weeks (42 days). Retro orbital blood for both control and treated was drawn at both time intervals so as to analyse haematological and immunoassay studies. Peripheral smear staining was carried out to observe the gross morphology of RBCs for iron deficient and control rats. The body weights were recorded before and after treatment and statistical significance was calculated. Post exposure rats were dissected and organs like heart, kidney, liver, lungs and spleen were collected for histopathological analysis. Our results showed decreased levels of hemoglobin (Hb), hematocrit (HCT), mean corpuscular hemoglobin (MCH), mean corpuscular volume (MCV), reticulocyte count, serum iron (SI), serum ferritin (SF) and an increase in total iron binding capacity (TIBC). in IDA animals exposed to 42 days of iron deficient diet. Significant difference (p<0.5) was observed in body weights of rats when compared with the data before and after treatment. The peripheral smear has indicated microcytic hypochromic RBCs in test group confirming development of IDA model. The histopathological results revealed the abnormality at cellular level like congestion of blood vessels in heart, congestion and centrilobular hepatocyte with inflammatory cell infiltration in liver, perivasculitis in lungs and decrease in white pulp in spleen whereas kidney were found normal. Our results clearly demonstrate iron deficient rat model when administered with IDA feed. This model can be used for estimation of efficiency of new food products and food supplements enriched with iron.

Dietary iron-deficient anemia induces a variety of metabolic changes and even apoptosis in rat liver: a DNA microarray study

2010 ◽  
Vol 42 (2) ◽  
pp. 149-156 ◽  
Author(s):  
Asuka Kamei ◽  
Yuki Watanabe ◽  
Tomoko Ishijima ◽  
Mariko Uehara ◽  
Soichi Arai ◽  
...  
Keyword(s):  
Lipid Metabolism ◽  
Iron Deficiency ◽  
Dna Microarray ◽  
Global Analysis ◽  
Control Diet ◽  
Diet Group ◽  
Iron Level ◽  
Dietary Iron ◽  
Deficient Diet ◽  
Iron Deficient

Anemia can be induced by dietary iron deficiency, as well as by hemorrhagia. It may also be associated with changes in lipid metabolism. However, no global analysis detailing the consequences of iron deficiency in the liver has yet been conducted. Since the liver is a metabolically important organ and also a major iron-storing organ, we performed a comprehensive transcriptome analysis to determine the effects of iron deficiency on hepatic gene expression. Four-week-old rats were fed an iron-deficient diet, ∼3 ppm iron, ad libitum for 16 days. These rats were compared with similar rats pair-fed a control diet with a normal iron level, 48 ppm iron. The 16-day iron-deficient diet apparently induced anemia. On day 17, the rats were killed under anesthesia, and their livers were dissected for DNA microarray analysis. We identified 600 upregulated and 500 downregulated probe sets that characterized the iron-deficient diet group. In the upregulated probe sets, genes involved in cholesterol, amino acid, and glucose metabolism were significantly enriched, while genes related to lipid metabolism were significantly enriched in the downregulated probe sets. We also found that genes for caspases 3 and 12, which mediate endoplasmic reticulum (ER)-specific apoptosis, were upregulated in the iron-deficient group. Combined, these results suggest that iron deficiency exerts various influences, not only on nutrient metabolism but also on apoptosis, as a consequence of ER stress in the liver.

Histological Evaluation of Megakaryocytes and Angiogenic Signaling Molecules of Bone Marrow in Experimentally Induced Iron Deficiency Anemia

Blood ◽  
2015 ◽  
Vol 126 (23) ◽  
pp. 953-953
Author(s):  
Jessica Garcia ◽  
Peggy Mankin ◽  
Pedro De Alarcon
Keyword(s):  
Bone Marrow ◽  
Iron Deficiency ◽  
Factor Viii ◽  
Iron Deficiency Anemia ◽  
Plasma Levels ◽  
Signaling Molecules ◽  
Histological Evaluation ◽  
Deficiency Anemia ◽  
Deficient Diet ◽  
Iron Deficient

Abstract Iron deficiency Anemia (IDA) induced reactive thrombocytosis occurs in children. The mechanisms involved in this phenomenon are indeterminate. Traditional cytokines involved in megakaryopoiesis such as Thrombopoietin (TPO), IL-6, and IL-11 have not been shown to be associated with this IDA induced thrombocytosis. Recent studies suggest that growth factors and signaling molecules involved in angiogenesis influence the proliferation and/or differentiation of megakaryocytes. A recent study observed that VEGFR1-mediated pathway up-regulates CXCR4 on megakaryocytes, leading to enhanced platelet production via distribution of megakaryocytes. We previously reported a statistically increased serum/plasma levels of FLT-3 and PDGF, but did not find an increase in plasma levels of TPO, VEGF and CXCR4 in an experimentally induced IDA in rats, when compared to control rats. We now present the histological evaluation of megakaryocytes and the expression of angiogenic signaling molecules, VEGF and CXCR4, in bone marrows of control and IDA rats. Six week old male Sprague-Dawley rats with jugular vein cannulas were obtained. Diet for control rats (N=9) and iron deficient diet rats (N=18) had 50 ppm and 7-8 ppm iron in Purina chow respectively. CBC, Iron Panel, and cytokines were drawn at baseline and five weeks later. On day 0, 1.5 mL of blood was drawn from iron deficient diet rats to further induce anemia. Rats were euthanized by CO2 asphyxiation and cardiac puncture. Femurs were collected, decalcified, and embedded in paraffin. Thin sliced sections were obtained to make slides. The slides were stained with hematoxylin and eosin (H&E), and with peroxidase linked anti factor VIII, VEGF, and CXCR4 according to manufacturer's instructions. The slides were evaluated under 40x microscopy. An area of 0.1 mm2 was selected and the numbers of megakaryocytes in the selected area were visually quantitated. Immunoperoxidase stained slides were analyzed using Image J software. When reviewing H&E stained bone marrow slides per 0.1 mm2, control rats contained 4 megakaryocytes, while those from IDA rats contained 11 megakaryocytes (P=0.0001). In Factor VIII stained slides, quantitative analysis of peroxidase stained megakaryocytes in control group contained 49,271 pixels, while staining in the IDA rats was 185,076 pixels (P=0.00002). When the analysis was carried out looking at vessel staining, there was a significant difference between controls (3.6) and IDA (8.5) per 0.1 mm2 (P=0.00001). In the VEGF stained slides, visual analysis of peroxidase stain showed increased intensity of staining per cell in the IDA rats. In the CXCR4 stained slides, visual inspection of the control bone marrows showed a rare small round cell weakly stained while these cells were more frequent and strongly stained in IDA rats. We successfully induced IDA in an animal model with coexisting thrombocytosis. Bone marrow slides in IDA rats documented the expected increase in number of megakaryocytes. In addition, we documented a marked increase in vascular structures of IDA rats. Contrary to our previously reported plasma levels, VEGF intensity of stain was greater within IDA rat megakaryocytes when compared to control rat megakaryocytes. We also documented an increase of CXCR4 in the bone marrows of IDA rats. However, this increase was limited to early stage megakaryocyte development cells suggesting a role during the differentiation process of megakaryocytes. Both our previous report on circulating angiogenic signaling molecules and the current histological data suggest an important role for angiogenesis in the development of IDA induced thrombocytosis. Disclosures No relevant conflicts of interest to declare.

scholarly journals Gastrin-Deficient Mice Have Disturbed Hematopoiesis in Response to Iron Deficiency

Endocrinology ◽  
2011 ◽  
Vol 152 (8) ◽  
pp. 3062-3073 ◽  
Author(s):  
Suzana Kovac ◽  
Gregory J. Anderson ◽  
Warren S. Alexander ◽  
Arthur Shulkes ◽  
Graham S. Baldwin
Keyword(s):  
Iron Deficiency ◽  
Acid Secretion ◽  
Gastric Acid Secretion ◽  
Gastric Acid ◽  
Iron Homeostasis ◽  
Transferrin Saturation ◽  
Deficient Diet ◽  
Direct Role ◽  
Iron Deficient

Gastrins are peptide hormones important for gastric acid secretion and growth of the gastrointestinal mucosa. We have previously demonstrated that ferric ions bind to gastrins, that the gastrin-ferric ion complex interacts with the iron transport protein transferrin in vitro, and that circulating gastrin concentrations positively correlate with transferrin saturation in vivo. Here we report the effect of long-term dietary iron modification on gastrin-deficient (Gas−/−) and hypergastrinemic cholecystokinin receptor 2-deficient (Cck2r−/−) mice, both of which have reduced basal gastric acid secretion. Iron homeostasis in both strains appeared normal unless the animals were challenged by iron deficiency. When fed an iron-deficient diet, Gas−/− mice, but not Cck2r−/−mice, developed severe anemia. In iron-deficient Gas−/−mice, massive splenomegaly was also apparent with an increased number of splenic megakaryocytes accompanied by thrombocytosis. The expression of the mRNA encoding the iron-regulatory peptide hepcidin, Hamp, was down-regulated in both Cck2r−/− and Gas−/−mice on a low-iron diet, but, interestingly, the reduction was greater in Cck2r−/− mice and smaller in Gas−/− mice than in the corresponding wild-type strains. These data suggest that gastrins play an important direct role, unrelated to their ability to stimulate acid secretion, in hematopoiesis under conditions of iron deficiency.

scholarly journals THE EFFECTS OF IRON DEFICIENCY ON THE HEPATOCYTE: A BIOCHEMICAL AND ULTRASTRUCTURAL STUDY

1971 ◽  
Vol 48 (1) ◽  
pp. 79-90 ◽  
Author(s):  
Peter R. Dallman ◽  
Joseph R. Goodman
Keyword(s):  
Iron Deficiency ◽  
Cytochrome B5 ◽  
Deficient Diet ◽  
Fourfold Increase ◽  
Iron Administration ◽  
Iron Deprivation ◽  
Complete Diet ◽  
Iron Deficient ◽  
Mitochondrial Number ◽  
Cytochrome P 450

Effects of iron deficiency on the hepatocyte were studied quantitatively in the rat by combining ultrastructural and biochemical techniques. After 3–8 wk of an iron-deficient diet, the percentage of cytoplasm occupied by mitochondria increased progressively compared with complete diet values. The increment resulted primarily from an enlargement of individual mitochondria rather than from an increased mitochondrial number. Many mitochondria were completely divided by a double membrane, often at a point of constriction. After 2 days of iron administration, mitochondria were of heterogeneous size, shape, and electron opacity. After 5 days, essentially all mitochondria had become normal in configuration. The rate of reversal of the morphological abnormality was more rapid than would be anticipated if it coincided with known rates of renewal of mitochondrial DNA or protein. The concentrations of mitochondrial cytochromes were more rapidly depressed as a result of iron deprivation than those of microsomal cytochromes. Cytochromes c and a were decreased after 3 and 8 wk of exposure to the deficient regimen. Cytochrome P 450 was not decreased after a 3 wk exposure to the deficient diet and responded normally to phenobarbital treatment with a fourfold increase in total hepatic content; its concentration was depressed only after 8 wk of exposure to the deficient diet. There was no reduction in cytochrome b5 concentration.

scholarly journals Metabolic Abnormalities of Erythrocytes in Severe Iron Deficiency

Blood ◽  
1971 ◽  
Vol 37 (6) ◽  
pp. 725-732 ◽  
Author(s):  
ROBERT T. CARD ◽  
LEWIS R. WEINTRAUB
Keyword(s):  
Iron Deficiency ◽  
Glucose Deprivation ◽  
Deficient Diet ◽  
Impaired Ability ◽  
Iron Deficient ◽  
Abnormal Cells ◽  
Increased Susceptibility ◽  
Millipore Filters

Abstract Severe iron deficiency was induced in rabbits by repeated phlebotomy and maintenance on an iron-deficient diet. Erythrocytes from these animals were studied at periods of 2-10 wk following the cessation of bloodletting and were found to have a shortened survival in vivo by the 51Cr technique. These cells were found to be more susceptible than normal cells to lysis during sterile 24-hr incubation in glucose-free balanced salt solution. The severely iron deficient erythrocyte also demonstrated an increased susceptibility to sulfhydryl inhibitors in vitro. Iron-deficient erythrocytes, despite their smaller volume, were found to have an impaired ability to filter through 5-µ Millipore filters. These studies suggest the following pathogenesis for the hemolysis seen in severe iron deficiency. The abnormal plasticity may lead to excessive trapping of these cells by the spleen and reticuloendothelial cells. Within this environment these metabolically abnormal cells are exposed to hostile conditions of stasis and glucose deprivation, which may then enhance their lysis.

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