@article{ab14405b4a6a4d9ca5fc2da6a8c47831,
title = "Irradiation impairs mitochondrial function and skeletal muscle oxidative capacity: significance for metabolic complications in cancer survivors",
abstract = "Background: Metabolic complications are highly prevalent in cancer survivors treated with irradiation but the underlying mechanisms remain unknown. Methods: Chow or high fat-fed C57Bl/6J mice were irradiated (6Gy) before investigating the impact on whole-body or skeletal muscle metabolism and profiling their lipidomic signature. Using a transgenic mouse model (Tg:Pax7-nGFP), we isolated muscle progenitor cells (satellite cells) and characterised their metabolic functions. We recruited childhood cancer survivors, grouped them based on the use of total body irradiation during their treatment and established their lipidomic profile. Results: In mice, irradiation delayed body weight gain and impaired fat pads and muscle weights. These changes were associated with impaired whole-body fat oxidation in chow-fed mice and altered ex vivo skeletal muscle fatty acid oxidation, potentially due to a reduction in oxidative fibres and reduced mitochondrial enzyme activity. Irradiation led to fasting hyperglycaemia and impaired glucose uptake in isolated skeletal muscles. Cultured satellite cells from irradiated mice showed decreased fatty acid oxidation and reduced glucose uptake, recapitulating the host metabolic phenotype. Irradiation resulted in a remodelling of lipid species in skeletal muscles, with the extensor digitorum longus muscle being particularly affected. A large number of lipid species were reduced, with several of these species showing a positive correlation with mitochondrial enzymes activity. In cancer survivors exposed to irradiation, we found a similar decrease in systemic levels of most lipid species, and lipid species that increased were positively correlated with insulin resistance (HOMA-IR). Conclusion: Irradiation leads to long-term alterations in body composition, and lipid and carbohydrate metabolism in skeletal muscle, and affects muscle progenitor cells. Such changes result in persistent impairment of metabolic functions, providing a new mechanism for the increased prevalence of metabolic diseases reported in irradiated individuals. In this context, changes in the lipidomic signature in response to irradiation could be of diagnostic value.",
keywords = "Cancer survivors, Irradiation, Metabolism, Mitochondria, Skeletal muscle",
author = "Amorim, {Nadia M.L.} and Anthony Kee and Coster, {Adelle C.F.} and Christine Lucas and Sarah Bould and Sara Daniel and Weir, {Jacquelyn M.} and Mellett, {Natalie A.} and Jayne Barbour and Meikle, {Peter J.} and Cohn, {Richard J.} and Nigel Turner and Hardeman, {Edna C.} and David Simar",
note = "Funding Information: This work was supported by a grant from the Cancer Council New South Wales, Australia ( RG 13-17 ) to E.C.H., D.S. and R.J.C., a grant from the Cancer Institute New South Wales, Australia ( RG093633 ) to R.J.C. and D.S., an International Scholarship from the Brazilian Government (CAPES, process 10448/13-6) to N.M.L.A. and an International Postgraduate Research Scholarship from UNSW Sydney, Australia to S.D. Funding Information: The authors are grateful to the Biological Resources Imaging Laboratory (Flow Cytometry Facility, UNSW Sydney, Australia) and in particular to Dr. Chris Brownly for his assistance with the flow cytometry and cell sorting experiments, Dr. Tzong-Tyng Hung for his assistance with the EchoMRI and Dr. Brendan Lee for his assistance with X-Ray. They are also grateful to Mrs. Karen Johnston for her assistance with the recruitment of the childhood cancer survivors. This work was supported by a grant from the Cancer Council New South Wales, Australia (RG 13-17) to E.C.H. D.S. and R.J.C. a grant from the Cancer Institute New South Wales, Australia (RG093633) to R.J.C. and D.S. an International Scholarship from the Brazilian Government (CAPES, process 10448/13-6) to N.M.L.A. and an International Postgraduate Research Scholarship from UNSW Sydney, Australia to S.D. D.S. E.C.H. A.K. N.M.L.A. and R.J.C. contributed to the conception and design of the study. N.M.L.A. A.K. C.L. S.B. S.D. J.M.W. N.A.M. J.B. N.T. and D.S. contributed to the acquisition of the data. N.M.L.A. A.K. A.C.F.C. C.L. S.B. S.D. J.M.W. N.A.M. J.B. P.J.M. R.J.C. N.T. E.C.H. and D.S. analysed and interpreted the data. D.S. drafted the manuscript and all authors critically revised the manuscript and contributed important intellectual content. All the authors approved the final version of the manuscript to be submitted. The authors declare no conflicts of interest. Publisher Copyright: {\textcopyright} 2019 Elsevier Inc.",
year = "2020",
month = feb,
doi = "10.1016/j.metabol.2019.154025",
language = "English",
volume = "103",
journal = "Metabolism: Clinical and Experimental",
issn = "0026-0495",
publisher = "Elsevier",
}