Evaluation of 11β-hydroxysteroid dehydrogenase type 1 as a therapeutic target to treat sarcopenia in chronic kidney disease

Sagmeister, Michael Simon ORCID: 0000-0002-6166-6784 (2024). Evaluation of 11β-hydroxysteroid dehydrogenase type 1 as a therapeutic target to treat sarcopenia in chronic kidney disease. University of Birmingham. Ph.D.

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Abstract

The decline of muscle mass and strength, termed sarcopenia, is common in people with chronic kidney disease (CKD). Even though coexisting sarcopenia profoundly increases mortality and morbidity in CKD, no targeted treatments to correct the underlying disturbances in skeletal muscle metabolism are currently available.

This PhD thesis examines the hypothesis that excessive peripheral production of the hormone cortisol within skeletal muscle tissue by the enzyme 11beta hydroxysteroid dehydrogenase type 1 (11βHSD1) contributes to loss of muscle mass and strength in CKD, and that inhibition of 11βHSD1 has potential as a novel therapy to mitigate sarcopenia in CKD.

The scientific approach to explore this hypothesis comprises a range of preclinical and clinical research methodologies. The role of 11βHSD1 for muscle atrophy and consequences of its suppression are evaluated in vivo using a mouse model of persistent renal impairment. Complementary in vitro experiments using human muscle cells are conducted to elucidate regulation of 11βHSD1 by factors associated with CKD. Finally, 11βHSD1 activity is quantified directly in skeletal muscle biopsies in a case-control study involving volunteers with and without CKD to detect associations with kidney disease and muscle phenotype.

The data from independent preclinical and clinical lines of investigations indicate that 11βHSD1 activity in skeletal muscle tissue in conditions of CKD is unchanged compared to control conditions. Interestingly, the observational data from humans reveals that muscle 11βHSD1 activity is positively correlated with age and negatively correlated with muscle performance markers (grip strength, gait speed), regardless of CKD status. Nevertheless, genetic silencing of 11βHSD1 did not alter the muscle atrophy phenotype in mice with renal impairment. Compensatory elevation of circulating glucocorticoid levels is observed in mice without 11βHSD1 function, which may undermine the therapeutic efficacy of 11βHSD1 suppression.

In summary, the evidence gathered as part of this PhD thesis does not support significant upregulation of 11βHSD1 in skeletal muscle in response to reduction of kidney function or a major contribution to CKD-related sarcopenia risk. The upregulation of 11βHSD1 activity in skeletal muscle with age is consistent with previous reports and poses the question of its functional significance for age-related changes in skeletal muscle. The thesis concludes with a discussion of potential therapeutic niches for 11βHSD1 inhibitors that remain for future exploration.

Type of Work:

Thesis (Doctorates > Ph.D.)

Award Type:

Doctorates > Ph.D.

Supervisor(s):