All Muscle No Iron Pdf
Mystikal Vadlapatla
Sarcopenia is an age-related condition of slow, progressive loss of muscle mass and strength, which contributes to frailty, increased risk of hospitalization and mortality, and increased health care costs. The incidence of sarcopenia is predicted to increase to >200 million affected older adults worldwide over the next 40 years, highlighting the urgency for understanding biological mechanisms and developing effective interventions. An understanding of the mechanisms underlying sarcopenia remains incomplete. Iron in the muscle is important for various metabolic functions, including oxygen supply and electron transfer during energy production, yet these same chemical properties of iron may be deleterious to the muscle when either in excess or when biochemically unshackled (eg, in ferroptosis), it can promote oxidative stress and induce inflammation. This review outlines the mechanisms leading to iron overload in muscle with aging and evaluates the evidence for the iron overload hypothesis of sarcopenia. Based on current evidence, studies are needed to (a) determine the mechanisms leading to iron overload in skeletal muscle during aging; and (b) investigate whether skeletal muscles are functionally deficient in iron during aging leading to impairments in oxidative metabolism.
Cachexia is a wasting syndrome characterized by devastating skeletal muscle atrophy that dramatically increases mortality in various diseases, most notably in cancer patients with a penetrance of up to 80%. Knowledge regarding the mechanism of cancer-induced cachexia remains very scarce, making cachexia an unmet medical need. In this study, we discovered strong alterations of iron metabolism in the skeletal muscle of both cancer patients and tumor-bearing mice, characterized by decreased iron availability in mitochondria. We found that modulation of iron levels directly influences myotube size in vitro and muscle mass in otherwise healthy mice. Furthermore, iron supplementation was sufficient to preserve both muscle function and mass, prolong survival in tumor-bearing mice, and even rescues strength in human subjects within an unexpectedly short time frame. Importantly, iron supplementation refuels mitochondrial oxidative metabolism and energy production. Overall, our findings provide new mechanistic insights in cancer-induced skeletal muscle wasting, and support targeting iron metabolism as a potential therapeutic option for muscle wasting diseases.
Iron accelerates the production of reactive oxygen species (ROS). Excessive levels of ROS are thought to accelerate skeletal muscle fatigue and contribute to the loss of skeletal muscle mass and function with age. Patients with an iron overload disease frequently report symptoms of weakness and fatigue, which is attributed to reduced cardiac function. The contribution of skeletal muscle to these symptoms is unknown. Using a mouse model of iron overload, we determined the extent of iron accumulation in skeletal muscle and the concentrations of the iron storage protein ferritin. The level of oxidative stress, changes in antioxidant enzymes and exercise performance were also assessed. Compared with control mice, the iron overloaded mice had elevated levels of iron in the tibialis anterior muscle and a fourfold increase in ferritin light chain. The oxidative stress product malondialdehyde was increased in the iron group compared with the control group, as was the antioxidant enzyme activity of glutathione reductase and glutathione peroxidase. The iron group performed less work on an endurance test and produced less force in a strength test. Body weight and skeletal muscle weight were lower in the iron group following the intervention. Iron loading reduced the weight of the fast-twitch extensor digitorum longus muscle more than the slow-twitch soleus muscle. In summary, iron accumulation in skeletal muscle may play a significant role in the reduced exercise capacity seen in iron overload disorders and in ageing, and may play an underlying role in skeletal muscle atrophy.
Figure 1. Pathways regulated by oxidative stress induced by iron overload in muscle cells and leading to muscle atrophy, changes in endocrine functions, and contributing to neurodegeneration. FOXO3a transcription factor upregulates two main protein degradation pathways, ubiquitin-proteasome and autophagy-lysosome, both involved in muscle atrophy (see details in the text). Iron-mediated ROS elevation inhibits activity of FOXO3a negative regulator, Akt, and stimulates its positive regulator, AMPK. TRAF6 ubiquitin ligase is also involved in stimulation of muscle atrophy mediated by FOXO3a as well as inflammatory response and might be activated by ROS. Ferrous iron-induced ROS have been shown to activate TRAF6 in hepatic macrophages. ROS also induce production of myostatin which leads to muscle atrophy. On the other hand, exercise downregulates myostatin while such myokines as apelin or IL15 are increased and stimulate Akt in skeletal muscle and neuronal tissue thus protect against muscle and neurons atrophy. Loss of muscle mass thus, reduction in their endocrine functions may accelerate neurodegeneration and degeneration of motor neurons promotes muscle atrophy.
Figure 2. Stress-mediated ferritin degradation leads to increase in iron-dependent ROS formation. Overexpression of SOD1 G93A leads to JNK and p66Shc activation, ferritin ubiquitination, and degradation by proteasome. As a result, LIP and iron-dependent ROS formation increase. In addition, iron augments ferritin synthesis in order to overcome iron toxicity.
Figure 3. Model for mechanisms of iron accumulation in muscle. Expression of SOD1 G93A or other stresses lead to activation of JNK and inactivation of Akt. It results in activation of FOXO3a transcriptional factor. FOXO3a upregulates ferritin H expression that can cause decrease in labile iron pool and upregulate iron transport into a cell. Iron accumulation may negatively affect myokines synthesis and increase motor neuron vulnerability to degeneration. Exercise can prevent AKT inactivation and iron chelators can diminish skeletal muscle accumulation.
Iron is a mineral that the body needs for growth and development. Your body uses iron to make hemoglobin, a protein in red blood cells that carries oxygen from the lungs to all parts of the body, and myoglobin, a protein that provides oxygen to muscles. Your body also needs iron to make some hormones.
Your body absorbs iron from plant sources better when you eat it with meat, poultry, seafood, and foods that contain vitamin C, such as citrus fruits, strawberries, sweet peppers, tomatoes, and broccoli.
Iron is available in many multivitamin/mineral supplements and in supplements that contain only iron. Iron in supplements is often in the form of ferrous sulfate, ferrous gluconate, ferric citrate, or ferric sulfate. Dietary supplements that contain iron have a statement on the label warning that they should be kept out of the reach of children. Accidental overdose of iron-containing products is a leading cause of fatal poisoning in children under 6.
In the short term, getting too little iron does not cause obvious symptoms. The body uses its stored iron in the muscles, liver, spleen, and bone marrow. However, when levels of iron stored in the body become low, iron deficiency anemia sets in. Red blood cells become smaller and contain less hemoglobin. As a result, blood carries less oxygen from the lungs throughout the body.
Symptoms of iron deficiency anemia include GI upset, weakness, tiredness, lack of energy, and problems with concentration and memory. In addition, people with iron deficiency anemia are less able to fight off germs and infections, to work and exercise, and to control their body temperature. Infants and children with iron deficiency anemia might develop learning difficulties.
Iron deficiency anemia in infancy can lead to delayed psychological development, social withdrawal, and less ability to pay attention. By age 6 to 9 months, full-term infants could become iron deficient unless they eat iron-enriched solid foods or drink iron-fortified formula.
Yes, iron can be harmful if you get too much. In healthy people, taking high doses of iron supplements (especially on an empty stomach) can cause an upset stomach, constipation, nausea, abdominal pain, vomiting, and diarrhea. Large amounts of iron might also cause more serious effects, including inflammation of the stomach lining and ulcers. High doses of iron can also decrease zinc absorption. Extremely high doses of iron (in the hundreds or thousands of mg) can cause organ failure, coma, convulsions, and death. Child-proof packaging and warning labels on iron supplements have greatly reduced the number of accidental iron poisonings in children.
Some people have an inherited condition called hemochromatosis that causes toxic levels of iron to build up in their bodies. Without medical treatment, people with hereditary hemochromatosis can develop serious problems such as liver cirrhosis, liver cancer, and heart disease. People with this disorder should avoid using iron supplements and vitamin C supplements.
Iron deficiency is common in older patients. We investigated whether iron deficiency is an independent risk factor for functional impairment, low muscle function, fatigue, and rehabilitation progress in older hospitalized patients.
Iron deficiency is the most common nutritional deficiency worldwide, which includes absolute iron deficiency and functional iron deficiency [1, 2]. Absolute iron deficiency is defined as depleted body iron stores due to an imbalance between iron uptake and utilization [3, 4]. Low serum ferritin concentrations (
Noteworthy, anemia in geriatric patients is usually a consequence of multimorbidity and rarely caused by one single reason [13]. However, poor nutritional intake of iron [3] and diseases accompanied by inflammation followed by reduced iron absorption and availability are risk factors associated with systemic iron depletion [3, 14], due to increased inflammatory hepcidin expression, a regulator of intestinal iron absorption and metabolic iron availability [12]. Iron acts as an oxygen-binding element and is therefore crucial for oxygen supply of the organism [15]. Iron is not only an essential component of hemoglobin (Hb) and erythropoiesis but also of myoglobin and mitochondrial enzymes. Accordingly, iron deficiency may have important effects on muscle function, oxidative energy metabolism, immune, and nervous system [15, 16].
aa06259810