Muscle atrophy in response to cytotoxic chemotherapy is dependent on intact glucocorticoid signaling in skeletal muscle

• Published in: PloS one Vol. 9; no. 9; p. e106489
• Main Authors: Braun, Theodore P, Szumowski, Marek, Levasseur, Peter R, Grossberg, Aaron J, Zhu, XinXia, Agarwal, Anupriya, Marks, Daniel L
• Format: Journal Article
• Language: English
• Published: United States Public Library of Science 25.09.2014; Public Library of Science (PLoS)
• Subjects: Animals; Antineoplastic Agents - adverse effects; Antineoplastic Agents - therapeutic use; Apoptosis - drug effects; Atrophy; Autophagy; Autophagy - drug effects; Biology and Life Sciences; Cachexia; Cachexia - chemically induced; Cancer; Chemotherapy; Corticosterone; Corticosterone - blood; Cytokines; Cytotoxicity; Female; Gene Knockout Techniques; Glucocorticoids; Glucocorticoids - metabolism; Health aspects; Hypothalamic-pituitary-adrenal axis; Hypothalamus; Inflammation; Inflammatory response; Laboratory animals; Lysosomes - metabolism; Male; Mice; Morbidity; Muscle, Skeletal - drug effects; Muscle, Skeletal - metabolism; Muscle, Skeletal - pathology; Muscles; Muscular Atrophy - blood; Muscular Atrophy - chemically induced; Muscular Atrophy - metabolism; Muscular Atrophy - pathology; Musculoskeletal system; Myocardium - metabolism; Myocardium - pathology; Neoplasms - drug therapy; Neoplasms - metabolism; Neoplasms - pathology; Organ Size - drug effects; Organ Specificity; Pediatrics; Phagocytosis; Pharmacology; Pituitary; Proteasome Endopeptidase Complex - metabolism; Proteasomes; Proteins; Receptors, Glucocorticoid - deficiency; Receptors, Glucocorticoid - genetics; Rodents; Science; Signal Transduction - drug effects; Signaling; Skeletal muscle; Steroids (Organic compounds); Ubiquitin; Ubiquitin - metabolism
• ISSN: 1932-6203; 1932-6203
• DOI: 10.1371/journal.pone.0106489

Cancer cachexia is a syndrome of weight loss that results from the selective depletion of skeletal muscle mass and contributes significantly to cancer morbidity and mortality. The driver of skeletal muscle atrophy in cancer cachexia is systemic inflammation arising from both the cancer and cancer treatment. While the importance of tumor derived inflammation is well described, the mechanism by which cytotoxic chemotherapy contributes to cancer cachexia is relatively unexplored. We found that the administration of chemotherapy to mice produces a rapid inflammatory response. This drives activation of the hypothalamic-pituitary-adrenal axis, which increases the circulating level of corticosterone, the predominant endogenous glucocorticoid in rodents. Additionally, chemotherapy administration results in a significant loss of skeletal muscle mass 18 hours after administration with a concurrent induction of genes involved with the ubiquitin proteasome and autophagy lysosome systems. However, in mice lacking glucocorticoid receptor expression in skeletal muscle, chemotherapy-induced muscle atrophy is completely blocked. This demonstrates that cytotoxic chemotherapy elicits significant muscle atrophy driven by the production of endogenous glucocorticoids. Further, it argues that pharmacotherapy targeting the glucocorticoid receptor, given in concert with chemotherapy, is a viable therapeutic strategy in the treatment of cancer cachexia.