Radiation-induced metabolic disorders: potential role for the mitochondria in skeletal muscle

Abstract

Over 2/3 of childhood cancer survivors treated with total body irradiation develop metabolic complications. Given that skeletal muscle plays a major role in insulin-stimulated glucose disposal, we aimed to investigate the role of skeletal muscle in impaired whole body metabolism following irradiation.Mice were exposed to a single dose of 5.95Gy and 5 weeks post-irradiation (baseline) were fed a high-fat diet (HFD) for 12 weeks. Energy expenditure, glucose homeostasis and insulin sensitivity were assessed throughout the HFD period and metabolic functions were measured at baseline and endpoint in skeletal muscles and muscle stem cells.Irradiated mice had increased respiratory exchange ratio on HFD despite similar food intake. Lipid metabolism and citrate synthase activity in muscle were impaired compared to the non-irradiated mice suggesting altered fat utilisation and compromised mitochondrial function. Irradiated mice showed altered fasting glucose and impaired ex-vivo insulin-stimulated glucose uptake in muscles after 12 weeks of HFD. Muscle stem cells isolated from irradiated mice showed both impaired lipid and glucose oxidation, suggesting long-term memory of the exposure to irradiation.We propose that irradiation may alter skeletal muscle mitochondrial metabolism resulting in impaired whole body metabolism and insulin resistance.