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 sexdependent differences in gene expression are retained in vitro in cultured human skeletal muscle. In contrast, glucose and lipid metabolism did not show any sexdependent 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 βestradiol 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