Anatomy and Neuroscience - Theses
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ItemIron homeostasis in models of skeletal muscle atrophy( 2022)Skeletal muscle is one of the most active, adaptive, and resilient tissues in the human body, with an innate capacity to regenerate after injury. Dysregulation of protein synthesis and protein breakdown can lead to skeletal muscle wasting which is associated with a wide range of conditions, including genetic mutations (e.g., Duchenne muscular dystrophy), age-related wasting (sarcopenia) and different forms of injury (including ischemic reperfusion damage). Despite differences in their causality, all of these chronic and acute illnesses/injuries are linked by mechanisms that include abnormal ROS generation and inflammation. Iron, one of the most abundant trace metals, plays a crucial role in oxidative metabolism but it can also generate ROS. Due to the high energetic demand, skeletal muscle contains a significant iron load, but few studies have investigated the detrimental consequences of excess iron. To this end, my thesis research investigated the contribution of iron dysregulation to muscle atrophy. We discovered and characterised skeletal muscle iron overload using novel laser ablation-inductively coupled-mass spectrometry (LA-ICP-MS) technology in multiple models of muscle atrophy, including genetic murine models of Duchenne muscular dystrophy (mdx and dko), aged mice relative to adult controls, and in injured muscles using a model of ischemia-reperfusion injury. We subsequently investigated the therapeutic potential of reducing iron levels via iron chelation (deferiprone; DFP) and by overexpressing myoglobin, the muscle specific iron binding protein. In Chapter 3, we showed that DFP treatment (4 weeks; 100 mg/kg/day) could improve aspects of the dystrophic pathology: fibrosis and ROS generation (DHE) were reduced in diaphragm muscles of DFP treated mdx mice. However, the reduction in iron decreased the abundance of haemoproteins (myoglobin and cytochrome c) and compromised mitochondrial function (reduced citrate synthase activity). To overcome this paradox, in Chapter 4 we demonstrated that overexpression of myoglobin in dko mice maintained haemoprotein expression while decreasing fibrosis. In Chapter 5 we review the literature regarding iron chemistry in skeletal muscle and discuss the emerging field of iron homeostasis in sarcopenia. In Chapter 6 we identified an exacerbated iron overload in an aged mouse model of haemochromatosis (a common genetic disorder). The increased skeletal muscle iron was associated with decreased haemoproteins, and proteins involved in oxidative metabolism. In Chapter 7 we found chronic (12-week) DFP treatment in aged mice reduced iron and ferritin in the liver but not in skeletal muscle. We found that iron overload was associated with increased lipid peroxidation (4HNE) and ischemia-reperfusion injury exacerbated the accumulation of iron, ferritin and lipid peroxidation in muscles of aged mice compared to adult controls. However, an attempt to reduce iron pre- or post-injury in aged mice exacerbated the already impaired regeneration. The lack of efficacy of DFP prompted a shift from iron to ferritin. In Chapter 8 we conducted preliminary experiments regarding the administration of ferritin to skeletal muscle and found it impeded muscle regeneration (after ischemia-reperfusion injury), which was associated with an exacerbated inflammatory response and dysregulation of haem metabolism. In conclusion, my thesis research characterised an underlying iron dyshomeostasis (increase in iron and ferritin) in multiple models of muscle atrophy associated with chronic inflammation and elevated ROS (including DMD, sarcopenia and IRI). We identified that iron chelation/reduction in skeletal muscle is largely ineffective and propose that future studies should alter iron distribution via modulating haem synthesis, increasing myoglobin and/or ferritin breakdown/clearance.