Iron deficiency leads to increased insulin-induced glucose uptake in parallel with mitochondrial dyfunction in skeletal muscle

• Published in: The Journal of nuclear medicine (1978) Vol. 60
• Main Authors: Thackeray, James, Chung, Bomee, Rostami, Fatemeh, Wollert, Kai, Bengel, Frank, Kempf, Tibor
• Format: Journal Article
• Language: English
• Published: New York Society of Nuclear Medicine 01.05.2019
• Subjects: Abnormalities; Atrophy; Breeding; Cachexia; Clonal deletion; Congestive heart failure; Coronary artery disease; Deoxyribonucleic acid; Depletion; Disruption; DNA; Dosage; Drug delivery systems; Glucose; Glucose metabolism; Heart; Heart failure; Homeostasis; Insulin; Iron; Iron deficiency; Liquid oxygen; Metabolic rate; Metabolism; Mice; Mitochondria; Mitochondrial DNA; Muscles; Musculoskeletal system; Nutrient deficiency; Oxidative phosphorylation; Oxidative stress; Phosphorylation; Positron emission; Positron emission tomography; Proteins; Quadriceps muscle; Regulatory proteins; Skeletal muscle; Supplements; Tomography
• ISSN: 0161-5505; 1535-5667

Objectives: Iron deficiency affects up to 50% of the heart failure population, and is associated with reduced exercise capacity and skeletal muscle atrophy. Iron regulatory proteins (IRP) control iron transport and may influence cellular metabolism. Disruption of iron homeostasis can contribute to mitochondrial dysfunction, oxidative stress, metabolic abnormalities and muscular atrophy. We evaluated the contribution of iron depletion by genetic IRP deletion on skeletal muscle metabolism using 18F-fluorodeoxyglcuose (FDG) PET imaging. Methods: To simulate iron deficiency and cachexia in heart failure, skeletal muscle-selective deletion of IRP-1 and IRP-2 by cre-lox breeding generated double knockout (n=8) and control (IRP1/2 fl/fl, n=8) mice. To stimulate glucose uptake in resting skeletal muscle, mice were pre-treated with insulin (6mU/g, 30min prior), and dynamic 30min PET scans were acquired following a bolus injection of FDG (13±1MBq). Regions of interest were defined for quadriceps femoris, heart, and liver. FDG uptake was compared as percent injected dose (ID)/g tissue. Rate of uptake was assessed as Patlak slope ki and metabolic rate of glucose utilization. Results: Skeletal muscle selective-IRP double-knockout mice displayed lower iron content in the skeletal muscle (ng/µg protein: 73±4 vs. 47±5, p=0.002). FDG uptake was significantly higher after insulin stimulation in targeted IRP double-knockout mice compared to controls (%ID/g: 2.5±0.8 vs 1.7±0.4, p=0.022). Similar elevations were identified in Patlak slope (ki: 0.009±0.007 vs 0.003±0.001 ml/g/min, p=0.004) and metabolic rate of glucose utilization (6.1±5.0 vs 2.5±1.0 µmol/min/100g, p=0.009). By contrast, no difference in cardiac FDG uptake was identified (%ID/g: 49±10 vs 52±8, p=NS). Elevated glucose metabolism in skeletal muscle was associated with reduced expression of oxidative phosphorylation proteins compared to control (complex I: -95±1%, p<0.001; complex II: -65±6%, p=0.001; complex IV: -74±6%, p<0.001). Double knockout mice also exhibited shifted muscle fibre composition and a 50% reduction in mitochondrial DNA content (p=0.022). Conclusions: These results indicate that iron deficiency adversely affects oxidative phosphorylation in mitochondria with a compensatory increase in glucose uptake in skeletal muscle. Accordingly, iron supplementation may spare muscle metabolism and integrity in the setting of chronic disease such as heart failure.