Glucocorticoids and 11β-HSD1 are major regulators of intramyocellular protein metabolism

Morgan, S.A., Hassan-Smith, Z.K., Doig, C.L. ORCID: 0000-0001-9694-4230, Sherlock, M., Stewart, P.M. and Lavery, G.G., 2016. Glucocorticoids and 11β-HSD1 are major regulators of intramyocellular protein metabolism. Journal of Endocrinology, 229 (3), pp. 277-286. ISSN 0022-0795

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Abstract

The adverse metabolic effects of prescribed and endogenous glucocorticoid excess, ‘Cushing’s syndrome’, create a significant health burden. While skeletal muscle atrophy and resultant myopathy is a clinical feature, the molecular mechanisms underpinning these changes are not fully defined. We have characterized the impact of glucocorticoids upon key metabolic pathways and processes regulating muscle size and mass including: protein synthesis, protein degradation, and myoblast proliferation in both murine C2C12 and human primary myotube cultures. Furthermore, we have investigated the role of pre-receptor modulation of glucocorticoid availability by 11β-hydroxysteroid dehydrogenase type 1 (11β-HSD1) in these processes. Corticosterone (CORT) decreased myotube area, decreased protein synthesis, and increased protein degradation in murine myotubes. This was supported by decreased mRNA expression of insulin-like growth factor (IGF1), decreased activating phosphorylation of mammalian target of rapamycin (mTOR), decreased phosphorylation of 4E binding protein 1 (4E-BP1), and increased mRNA expression of key atrophy markers including: atrogin-1, forkhead box O3a (FOXO3a), myostatin (MSTN), and muscle-ring finger protein-1 (MuRF1). These findings were endorsed in human primary myotubes, where cortisol also decreased protein synthesis and increased protein degradation. The effects of 11-dehydrocorticosterone (11DHC) (in murine myotubes) and cortisone (in human myotubes) on protein metabolism were indistinguishable from that of CORT/cortisol treatments. Selective 11β-HSD1 inhibition blocked the decrease in protein synthesis, increase in protein degradation, and reduction in myotube area induced by 11DHC/cortisone. Furthermore, CORT/cortisol, but not 11DHC/cortisone, decreased murine and human myoblast proliferative capacity. Glucocorticoids are potent regulators of skeletal muscle protein homeostasis and myoblast proliferation. Our data underscores the potential use of selective 11β-HSD1 inhibitors to ameliorate muscle-wasting effects associated with glucocorticoid excess.

Item Type: Journal article
Publication Title: Journal of Endocrinology
Creators: Morgan, S.A., Hassan-Smith, Z.K., Doig, C.L., Sherlock, M., Stewart, P.M. and Lavery, G.G.
Publisher: BioScientifica
Date: June 2016
Volume: 229
Number: 3
ISSN: 0022-0795
Identifiers:
NumberType
10.1530/JOE-16-0011DOI
27048233PubMed ID
1069849Other
Rights: © 2016 Society for Endocrinology. This work is licensed under a Creative Commons Attribution 3.0 Unported License.
Divisions: Schools > School of Science and Technology
Record created by: Jonathan Gallacher
Date Added: 19 Jun 2019 08:44
Last Modified: 31 May 2021 15:09
URI: http://irep.ntu.ac.uk/id/eprint/36853

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