The role of steroid hormones in skeletal muscle metabolism

Steroid hormones play important roles in the regulation of whole body metabolism. Skeletal muscle is an insulin-responsive organ with a key role in overall substrate metabolism. Disturbances in skeletal muscle metabolism, as a result of hormonal imbalance may be an underlying defect in metabolic disease. Reduced insulin-responsive glucose disposal in skeletal muscle is a characteristic feature of metabolic syndrome.

The overall aim of this thesis work is to identify the role of steroid hormones on glucose and lipid metabolism; and to dissect the impact of sex steroid hormones on insulin signaling pathways in human skeletal muscle. A further goal is to understand how sex differences impact on skeletal muscle metabolism.

Whole body metabolism differs between men and women, and sex-dependent differences in gene expression are evident in skeletal muscle biopsies. Some sex- dependent differences in gene expression are retained in vitro in cultured human skeletal muscle. In contrast, glucose and lipid metabolism did not show any sex- dependent differences. Chronic exposure of muscle cell cultures to physiological doses of testosterone or 17 β-estradiol resulted in sex-dependent responses. Exposure to testosterone enhanced palmitate oxidation, AMP dependent protein kinase phosphorylation and IRS2 gene expression in myotubes from both sexes, while 17 β-estradiol exposure increased palmitate oxidation in myotubes from male donors only and PDK4 gene expression from female donors only. Testosterone or 17 β-estradiol treatment enhanced insulin-stimulated glucose incorporation into glycogen and AKT phosphorylation only in myotubes from female donors. Acute supra-physiological doses of testosterone or 17 β-estradiol reduced glucose metabolism, independent of sex origin of the cells. Moreover, acute testosterone treatment increased basal palmitate oxidation and disrupted the insulin-suppressive effect on palmitate oxidation.

Increased glucocorticoid action leads to reduced whole body insulin action and may predispose to type 2 diabetes. Local conversion of cortisone to active cortisol by the enzyme 11β-hydroxysteroid dehydrogenase in target tissues may regulate tissue-specific roles of glucocorticoids in patho-physiological states. Chronic high dose exposure to cortisol or cortisone reduced glucose metabolism, and enhanced palmitate oxidation, via induction of PDK4 expression in myotubes. siRNA-mediated reduction or pharmacological inhibition of HSD1 prevented the effects of cortisone, but not cortisol, on metabolic responses.

In conclusion, steroid hormones exert diverse effects in a dose and time dependent manner. Modulation of steroid hormone actions at specific regulatory steps may provide potential therapeutic entry points for metabolic disease and Type 2 diabetes. Moreover, attention should be focused on understanding sex-dependent differences in metabolic disease, and sex-origin of cells is important to consider when assessing hormonal responses in culture.

List of scientific papers

I. Rune A, Salehzadeh F, Szekeres F, Kuhn I, Osler ME, and Al-Khalili L. (2009). Evidence against a sexual dimorphism in glucose and fatty acid metabolism in skeletal muscle cultures from age-matched men and post-menopausal women. Acta Physiol. (197), 207-15.
https://doi.org/10.1111/j.1748-1716.2009.02010.x

II. Salehzadeh F, Rune A, Osler M, Al-Khalili L. (2011). Testosterone or 17 β-estradiol exposure reveals sex-specific effects on glucose and lipid metabolism in human myotubes. [Submitted]

III. Salehzadeh F, Guimaraes D, Al-Khalili L. (2011). Regulation of glucose uptake by endothelin-1 in human skeletal muscle in vivo and in vitro. [Manuscript]

IV. Salehzadeh F, Al-Khalili L, Kulkarni SS, Wang M, Lönnqvist F, Krook A. (2009). Glucocorticoid-mediated effects on metabolism are reversed by targeting 11 beta hydroxysteroid dehydrogenase type 1 in human skeletal muscle. Diabetes Metab Res Rev. (2009), 250–8.
https://doi.org/10.1002/dmrr.944