The effects of iron deficiency and iron repletion on mitochondrial function: An in vivo study

Iron plays a central role in mitochondrial energy production, and this thesis provides insight into the mechanism by which mitochondria of energy demanding tissues are affected by iron deficiency and intravenous iron repletion in the mouse. Administration of an iron-deficient diet in mice led to iron deficiency, and in some cases anaemia. This deficiency was tested by measuring haemoglobin, serum ferritin, cardiac iron, and spleen iron concentrations and comparing them with a group of mice fed a control diet. Using biochemical assays and high resolution respirometry, it was shown that iron deficiency induced a decrease in activity of some, but not all, mitochondrial complexes within cardiac muscle, which is restored following intravenous iron repletion. Mitochondrial function in skeletal muscle tissue, namely the soleus and not the quadriceps, decreased in response to iron deficiency, but was partially restored following intravenous iron repletion. Iron deficiency also led to a decrease in in-gel activity of supramolecular complex II of the soleus, which remained uncorrected following iron repletion. Immunohistochemistry and western blot analysis of skeletal muscle tissue demonstrated that these functional changes occur in the absence of structural differences, i.e., the number of mitochondria, or the connectedness of mitochondria. Changes in cortical oxygenation and metabolism were assessed non-invasively, using broadband near-infrared spectroscopy. Iron deficient mice show a metabolic vulnerability, and an attenuated response in changes of deoxygenated haemoglobin during exposure to hypoxia, while iron repleted mice demonstrate an enhanced metabolic recovery following hypoxia. Additionally, iron deficiency induced a drop in synaptic marker expression in the brain, which was partially restored after repletion in certain areas of the brain. This research validated a murine model of adult iron deficiency and intravenous iron repletion and provided new insights into the effects iron deficiency and intravenous iron repletion on mitochondrial physiology

Somatosensory modulation of perceptual vestibular detection

Vestibular-multisensory interactions are essential for self-motion, navigation and postural stability. Despite evidence suggesting shared brain areas between vestibular and somatosensory inputs, no study has yet investigated whether somatosensory information influences vestibular perception. Here, we used signal detection methods to identify whether somatosensory stimulation might interact with vestibular events in a vestibular detection task. Participants were instructed to detect near-threshold vestibular roll-rotation sensations delivered by galvanic vestibular stimulation in one-half of experimental trials. A vibrotactile signal occurred to the index fingers of both hands in half of the trials, independent of vestibular signals. We found that vibrotactile somatosensory stimulation decreased perceptual vestibular sensitivity. The results are compatible with a gain regulation mechanism between vestibular and somatosensory modalities

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

Abstract Iron is an essential nutrient for oxygen supply and aerobic metabolism. Iron deficiency impacts cellular respiration and mitochondrial energy metabolism, which can lead to reduced skeletal muscle function and muscle mass, causing sarcopenia. Intravenous iron offers the ability to rapidly correct iron deficiency, but the functional impact on patient mental and physical health is unclear. We assessed the effects of intravenous iron therapy on physical function and quality of life in the treatment of adults with non‐anaemic iron deficiency. An update and reanalysis of a previously published Cochrane systematic review was performed to assess randomized controlled trials that compared any intravenous iron preparation with placebo in adults. The primary functional outcome measure was physical performance as defined by the trial authors. Secondary outcome measures included fatigue and quality‐of‐life scores, and adverse effects at the end of follow‐up. Biochemical efficacy was assessed by change in serum ferritin and haemoglobin concentration levels. Twenty‐one randomized controlled trials, comprising 3514 participants, were included. Intravenous iron compared with placebo resulted in significantly increased physical function measured by mean peak oxygen consumption (mean difference [MD] 1.77 mL/kg/min, 95% confidence interval [CI] 0.57 to 2.97). An overall improvement in fatigue was seen (standardized MD 0.30, 95% CI −0.52 to −0.09) but no overall difference in quality of life (MD 0.15, 95% CI −0.01 to 0.31). Biochemically, intravenous iron resulted in improved serum ferritin (MD 245.52 μg/L, 95% CI 152.1 to 338.9) and haemoglobin levels (MD 4.65 g/L, 95% CI 2.53 to 6.78). There was a higher risk of developing mild adverse events in the intravenous iron group compared with the placebo group (risk ratio 1.77, 95% CI 1.10 to 2.83); however, no differences were seen in serious adverse events (risk difference 0, 95% CI −0.01 to 0.01). The quality of evidence was rated ‘low’ and ‘very low’ for all outcome variables, except for fatigue, mainly due to most studies being judged as having a high risk of bias. In non‐anaemic iron‐deficient adults, the use of intravenous iron compared with placebo improved physical function and reduced fatigue scores. However, we remain uncertain about the efficacy in this population due to low‐quality evidence, and there is a need for further studies to address potential impact on overall quality of life