Glucocorticoid Receptor Signaling Impairs Protein Turnover Regulation in Hypoxia-Induced Muscle Atrophy in Male Mice

Chiel C. Theije*, Annemie M. W. J. Schols, Wouter H. Lamers, Judith J. M. Ceelen, Rick H. van Gorp, J. J. Rob Hermans, S. Elonore Kohler, Ramon C. J. Langen

*Corresponding author for this work

Research output: Contribution to journalArticleAcademicpeer-review

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Abstract

Hypoxemia may contribute to muscle wasting in conditions such as chronic obstructive pulmonary disease. Muscle wasting develops when muscle proteolysis exceeds protein synthesis. Hypoxia induces skeletal muscle atrophy in mice, which can in part be attributed to reduced food intake. We hypothesized that hypoxia elevates circulating corticosterone concentrations by reduced food intake and enhances glucocorticoid receptor (GR) signaling in muscle, which causes elevated protein degradation signaling and dysregulates protein synthesis signaling during hypoxia-induced muscle atrophy. Muscle-specific GR knockout and control mice were subjected to normoxia, normobaric hypoxia (8% oxygen), or pair-feeding to the hypoxia group for 4 days. Plasma corticosterone and muscle GR signaling increased after hypoxia and pair-feeding. GR deficiency prevented muscle atrophy by pair-feeding but not by hypoxia. GR deficiency differentially affected activation of ubiquitin 26S-proteasome and autophagy proteolytic systems by pair-feeding and hypoxia. Reduced food intake suppressed mammalian target of rapamycin complex 1 (mTORC1) activity under normoxic but not hypoxic conditions, and this retained mTORC1 activity was mediated by GR. We conclude that GR signaling is required for muscle atrophy and increased expression of proteolysis-associated genes induced by decreased food intake under normoxic conditions. Under hypoxic conditions, muscle atrophy and elevated gene expression of the ubiquitin proteasomal system-associated E3 ligases Murf1 and Atrogin-1 are mostly independent of GR signaling. Furthermore, impaired inhibition of mTORC1 activity is GR-dependent in hypoxia-induced muscle atrophy.
Original languageEnglish
Pages (from-to)519-534
Number of pages16
JournalEndocrinology
Volume159
Issue number1
DOIs
Publication statusPublished - 1 Jan 2018

Keywords

  • OBSTRUCTIVE PULMONARY-DISEASE
  • SKELETAL-MUSCLE
  • GENE-EXPRESSION
  • GLUTAMINE-SYNTHETASE
  • MAMMALIAN TARGET
  • EPITHELIAL-CELLS
  • UP-REGULATION
  • WEIGHT-LOSS
  • MTOR
  • PATHWAY

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