Unravelling the mechanisms of menopause-induced insulin resistance: novel roles for estradiol in skeletal muscle mitochondrial function
Torres, Maria Jose
Menopause results in a progressive decline in ovarian production of 17[beta]-estradiol (E2), increased adiposity and a higher risk for type-2 diabetes, but hormone replacement therapies containing E2 reverse most of these effects. However, we still lack a comprehensive understanding of the mechanism(s) by which E2 modulates insulin sensitivity (IS) and susceptibility to metabolic disease. By using a short-term ovariectomized mouse (surgical removal of ovaries, OVX) and pharmacological replacement of E2, here we have developed a model to study the short-term effects of menopause and E2 replacement therapies on mitochondrial function and IS, within a simplified context (i.e. in the absence of obesity). Given the primary role that skeletal muscle and liver play in glucose homeostasis, the aims of this work are two-fold. First, to determine whether decreased mitochondrial and cellular redox function represent the underlying molecular mechanisms for menopause-induced insulin resistance, and how E2 replacement can reverse these effects. Second, to determine the effects of ovarian E2 depletion and replacement on liver mitochondrial and redox functions, with a specific emphasis on NADH:ubiquinone oxidoreductase (mitochondrial complex I) kinetics and its associated H2O2 emitting potential. The studies herein provide evidence that E2 protects mitochondrial function and redox homeostasis in skeletal muscle by increasing complex I and IIII activities, enhancing electron transfer supercomplex assembly, preventing free radical leak, and decreasing lipid packing of mitochondrial membranes. We report, for the first time, the detection of E2 in skeletal muscle mitochondria, thus providing compelling evidence that E2 localizes to mitochondrial membranes and regulates mitochondrial function through the "fine-tuning" of electron transfer efficiency. Finally, while OVX by itself did not induce major changes on mitochondrial function in the liver (at least in a short-term OVX model), E2 treatment had detrimental effects on mitochondrial function, particularly targeted to complex I. This highlights the remarkably opposite effects E2 can exert on such critical organelles as the mitochondria across tissues with a different "bioenergetics signature", as well as at physiological versus pharmacological concentrations. Collectively, this study offers insights into novel molecular mechanisms by which menopause sets, and E2 replacement reverses, a pro-diabetogenic state, and further advances our knowledge on the mechanisms behind tissue-specific effects of estrogens. The present findings reveal new horizons in the development of novel pharmacological interventions to prevent metabolic dysfunction in naturally or surgically-induced post-menopausal women.
Torres, Maria Jose. (November 2016). Unravelling the mechanisms of menopause-induced insulin resistance: novel roles for estradiol in skeletal muscle mitochondrial function (Doctoral Dissertation, East Carolina University). Retrieved from the Scholarship. (http://hdl.handle.net/10342/6006.)
Torres, Maria Jose. Unravelling the mechanisms of menopause-induced insulin resistance: novel roles for estradiol in skeletal muscle mitochondrial function. Doctoral Dissertation. East Carolina University, November 2016. The Scholarship. http://hdl.handle.net/10342/6006. October 19, 2018.
Torres, Maria Jose, “Unravelling the mechanisms of menopause-induced insulin resistance: novel roles for estradiol in skeletal muscle mitochondrial function” (Doctoral Dissertation., East Carolina University, November 2016).
Torres, Maria Jose. Unravelling the mechanisms of menopause-induced insulin resistance: novel roles for estradiol in skeletal muscle mitochondrial function [Doctoral Dissertation]. Greenville, NC: East Carolina University; November 2016.
East Carolina University