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

Theodore P. Braun, Marek Szumowski, Peter R. Levasseur, Aaron Grossberg, Xinxia Zhu, Anupriya Agarwal, Daniel Marks

Research output: Contribution to journalArticle

30 Citations (Scopus)

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.

Original languageEnglish (US)
Article numbere106489
JournalPLoS One
Volume9
Issue number9
DOIs
StatePublished - Sep 25 2014

Fingerprint

muscular atrophy
Chemotherapy
Muscular Atrophy
glucocorticoids
Glucocorticoids
drug therapy
Muscle
skeletal muscle
Skeletal Muscle
Drug Therapy
cachexia
Cachexia
neoplasms
Neoplasms
Glucocorticoid Receptors
inflammation
Drug therapy
Oncology
Proteasome Endopeptidase Complex
Corticosterone

ASJC Scopus subject areas

  • Agricultural and Biological Sciences(all)
  • Biochemistry, Genetics and Molecular Biology(all)
  • Medicine(all)

Cite this

Muscle atrophy in response to cytotoxic chemotherapy is dependent on intact glucocorticoid signaling in skeletal muscle. / Braun, Theodore P.; Szumowski, Marek; Levasseur, Peter R.; Grossberg, Aaron; Zhu, Xinxia; Agarwal, Anupriya; Marks, Daniel.

In: PLoS One, Vol. 9, No. 9, e106489, 25.09.2014.

Research output: Contribution to journalArticle

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