title: Muscle atrophy in response to cytotoxic chemotherapy is dependent on intact glucocorticoid signaling in skeletal muscle.
abstract: 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.
authors.affiliation: Papé Family Pediatric Research Institute, Oregon Health & Science University, Portland, Oregon, United States of America; MD/PhD Program, Oregon Health & Science University, Portland, Oregon, United States of America.
authors.forename: Theodore P
authors.initials: TP
authors.lastname: Braun
authors.affiliation: Papé Family Pediatric Research Institute, Oregon Health & Science University, Portland, Oregon, United States of America.
authors.forename: Marek
authors.initials: M
authors.lastname: Szumowski
authors.affiliation: Papé Family Pediatric Research Institute, Oregon Health & Science University, Portland, Oregon, United States of America.
authors.forename: Peter R
authors.initials: PR
authors.lastname: Levasseur
authors.affiliation: Department of Internal Medicine, Providence St. Vincent Medical Center, Portland, Oregon, United States of America.
authors.forename: Aaron J
authors.initials: AJ
authors.lastname: Grossberg
authors.affiliation: Papé Family Pediatric Research Institute, Oregon Health & Science University, Portland, Oregon, United States of America.
authors.forename: XinXia
authors.initials: X
authors.lastname: Zhu
authors.affiliation: Knight Cancer Institute, Oregon Health & Science University, Portland, Oregon, United States of America; Division of Hematology & Medical Oncology, Oregon Health & Science University, Portland, Oregon, United States of America.
authors.forename: Anupriya
authors.initials: A
authors.lastname: Agarwal
authors.affiliation: Papé Family Pediatric Research Institute, Oregon Health & Science University, Portland, Oregon, United States of America.
authors.forename: Daniel L
authors.initials: DL
authors.lastname: Marks
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000009:adverse effects* / Q000627:therapeutic use; D017209:Apoptosis / Q000187:drug effects; D001343:Autophagy / Q000187:drug effects; D002100:Cachexia / Q000139:chemically induced; D003345:Corticosterone / Q000097:blood; D005260:Female; D055786:Gene Knockout Techniques; D005938:Glucocorticoids / Q000378:metabolism*; D008247:Lysosomes / Q000378:metabolism; D008297:Male; D051379:Mice; D018482:Muscle, Skeletal / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology*; D009133:Muscular Atrophy / Q000097:blood / Q000139:chemically induced* / Q000378:metabolism / Q000473:pathology*; D009206:Myocardium / Q000378:metabolism / Q000473:pathology; D009369:Neoplasms / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology; D009929:Organ Size / Q000187:drug effects; D009928:Organ Specificity; D046988:Proteasome Endopeptidase Complex / Q000378:metabolism; D011965:Receptors, Glucocorticoid / Q000172:deficiency / Q000235:genetics; D015398:Signal Transduction / Q000187:drug effects*; D025801:Ubiquitin / Q000378:metabolism
chemical_list: D000970:Antineoplastic Agents; D005938:Glucocorticoids; D011965:Receptors, Glucocorticoid; D025801:Ubiquitin; D046988:Proteasome Endopeptidase Complex; D003345:Corticosterone