PhD Studentship: The role of pre-receptor glucocorticoid metabolism in atrophy signaling in COPD as

Chronic obstructive pulmonary disease (COPD) is a lung disorder with progressive airflow obstruction which often includes development of emphysema. COPD is increasingly acknowledged as a systemic disease due to its clinically significant extrapulmonary consequences, including skeletal muscle wasting with a prevalence of 20-40%. Importantly, muscle wasting contributes to a diminished muscle function, exercise capacity and health status, but is also a determinant of mortality in COPD . However, at present therapeutic strategies to prevent or reverse muscle atrophyremain to be developed.

Factors implicated as potential triggers of muscle wasting in COPD include disuse, hypoxemia, malnutrition, inflammation, and glucocorticoids (GCs). Synthetic GCs are frequently applied in COPD. Endogenously produced GCs also represent a potent signal for muscle catabolism. Interestingly, with the exception of disuse, all other COPD-related factors implicated in muscle atrophy outlined above are accompanied by increased circulating GC levels and correlated with muscle GC signalling and GC receptor (GR)-dependent atrophy. Combined, these studies implicate muscle GC signalling as a critical and potentially common process in COPD-associated muscle wasting.

The physiological and pathological effects of GCs on skeletal muscle are mainly conveyed by the GC receptor (GR). Inactive GR undergoes a conformational change upon ligand binding, resulting in its translocation to the nucleus. Genomic actions of activated GR in skeletal muscle include the transcription of specific target genes required for muscle proteolysis, by binding to GC response elements (GREs) of these GCresponsive genes. Expression of rate limiting enzymes of proteolysis, including ubiquitin E3 ligases such as atrogin-1 and MuRF1 controlling 26S-proteasomemediated protein degradation, as well as regulatory molecules of proteolysis signalling including KLF-15 and FoXO1/3a, was shown to be under control of GR genomic actions in GC-induced muscle wasting. The genomic actions of the GR have also been implicated in the suppression of protein synthesis in skeletal muscle, and rely on repression of mammalian target of rapamycin complex 1 (mTORC1) signalling through enhanced transcription of REDD1 by GCs. Consequently, GR activation shifts muscle protein turnover towards proteolysis, resulting in muscle atrophy. Despite the growing understanding of the actions of activated GR, the importance of Glucocorticoid metabolism in COPD-associated muscle wasting.

Starvation-, inflammation-, and hypoxia-induced muscle atrophy are all in part GC-driven, suggesting modulation of pre-receptor GC availability via 11b-HSD as a therapeutic approach to prevent or reverse muscle atrophy. Moreover, hypoxia-induced muscle atrophy may involve amplification of GC action, as Glucocorticoid metabolism in COPD-associated muscle wasting. 11b-HSD1 expression is increased by hypoxia and our preliminary data reveal potentiating effects of hypoxia on GR-regulated gene expression induced by GC. On a similar note, physical inactivity may result in increased 11b-HSD expression, with subsequent sensitization to GC-induced muscle atrophy in COPD. Based on this information, and preliminary findings, we hypothesize that 11-HSD1 modulates muscle GC and atrophy in COPD associated muscle wasting.

Using mouse models of COPD-associated muscle wasting we aim to:

1) Determine the expression and activity 11b-HSD1 in skeletal muscle and relate this to GR- and muscle atrophy .
2) Investigate sensitization to muscle atrophy induced by exogenously administered GCs.
3) Evaluate whether inhibition of 11b-HSD1 prevents or reverses skeletal muscle
atrophy.

To apply, please send:

• A Detailed CV, including your nationality and country of birth;
• Names and addresses of two referees;
• A covering letter highlighting your research experience/capabilities;
• Copies of your degree transcripts;
• Evidence of your proficiency in the English language, if applicable.

Funding Notes

This PhD Studentship is jointly supported by University of Birmingham (UK) and the Maastricht University (Netherlands) and provides a three year stipend and consumables costs.