![]() Chronic inflammation hampers iron absorption from the diet and causes iron retention in reticuloendothelial cells, which results in insufficient iron availability to meet the body’s needs. ![]() Remarkably, iron deficiency is diagnosed in more than half of patients afflicted with colorectal, lung, and pancreatic cancers, which are also associated with high prevalence of cachexia (Ludwig et al, 2013). In cancer cachexia, systemic alterations contribute to the uncontrollable decrease in quality of life, insulin resistance, liver dysfunction, chronic inflammation, and even altered gut microbiota and nutrient absorption (Porporato, 2016). Indeed, the prevalence of cachexia reaches 80% in advanced-stage cancer patients and has been estimated to directly cause at least 20% of all cancer-related deaths (Tisdale, 2002). Massive skeletal muscle atrophy is the hallmark of a multi-organ wasting disorder known as cachexia, which causes severe asthenia and intolerance to therapies in patients with chronic diseases such as cardiac failure, COPD, and notably cancer, leading to poor clinical outcomes (Fearon et al, 2011 Porporato, 2016). In healthy humans, skeletal muscle makes up to 40% of the total body mass (Janssen et al, 2000), of which 20% are constituted by proteins. 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. Importantly, iron supplementation refuels mitochondrial oxidative metabolism and energy production. 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. We found that modulation of iron levels directly influences myotube size in vitro and muscle mass in otherwise healthy mice. 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. Knowledge regarding the mechanism of cancer-induced cachexia remains very scarce, making cachexia an unmet medical need. Tel: +39 0116706422 E-mail: Ĭachexia 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%. These authors contributed equally to this work as senior authors These authors contributed equally to this work as first authors 10 Center for Oncological Research (CORE), Integrated Personalized and Precision Oncology Network (IPPON), University of Antwerp, Antwerp, Belgium.9 Department of Medical Oncology, University Hospital Antwerp, Edegem, Belgium.8 Laboratory of Tumor Inflammation and Angiogenesis, Department of Oncology, Katholieke Universiteit Leuven (KUL), Leuven, Belgium.7 Laboratory of Tumor Inflammation and Angiogenesis, Center for Cancer Biology (CCB), Vlaams Instituut voor Biotechnologie (VIB), Leuven, Belgium.6 Department of Life Sciences and System Biology, University of Torino, Turin, Italy.5 Metabolism and Nutrition Research Group, Louvain Drug Research Institute, Université catholique de Louvain (UCLouvain), Brussels, Belgium.4 Department of Clinical and Biological Sciences, University of Torino, Turin, Italy.3 Department of Surgical, Oncological and Gastroenterological Sciences, Padova University Hospital, Padova, Italy.2 Department of Biomedical Sciences, University of Padova, Padova, Italy.1 Department of Molecular Biotechnology and Health Sciences, Molecular Biotechnology Center, University of Torino, Turin, Italy.
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