Improvements in childhood cancer treatments have led to an increase on the survival rate, but 2/3 of the survivors treated with total body irradiation further develop metabolic disorders. Skeletal muscle is responsible for up to 80% of insulin-stimulated glucose disposal and insulin resistance in skeletal muscle precedes the onset of impairment in other metabolically competent tissues.
Our study aims to determine the long-term effects of radiation on skeletal muscle metabolic functions and regenerative capacity. Mice were exposed to a single sub-lethal dose of 5.95Gy and 5 weeks post-irradiation (baseline) were fed a high-fat diet (HFD) for 12 weeks (endpoint). Body composition (MRI), glucose homeostasis (fasting plasma glucose and insulin levels), glucose clearance and whole body insulin sensitivity were assessed at baseline and during the 12 weeks of HFD. Mice were placed in metabolic cages at the baseline and after 12 weeks HFD. Glucose uptake and fatty acid oxidation were measured at baseline and at endpoint in both skeletal muscles and myotubes. Impact on regeneration was assessed using a myotoxin-induced injury assay and muscle regeneration was assessed 14 and 28 days post injury. Oxidative fibres were visualised through NADH staining.
Irradiated mice showed reduced BW gain and impaired fat and lean mass. The impaired lean mass gain did not recover over time, suggesting reduced muscle growth. This could be supported not only by the impairment in muscle regenerative capacity, but also in satellite cells proliferative capacity observed in irradiated mice. Irradiation did not impact on glucose clearance, but altered glucose uptake and fatty acid oxidation in muscles and in satellite cells. Irradiation also reduced the number of oxidative fibres.
Our data suggest that irradiation alters muscle tissue biology, leading to impaired glucose and fatty acid metabolism and delayed muscle regeneration. Given the role of skeletal muscle on glucose and lipid homeostasis, we propose that irradiation may alter skeletal muscle resulting in impaired turn-over and tissue insulin resistance in cancer survivors.