The Interaction of Diabetes and Estrogen on Skeletal Muscle Bioenergetics

2型糖尿病(T2D)是退伍军人管理局的主要健康优先事项。超过24%的退伍军人患有T2D，两次 全国平均水平。退伍军人中有越来越多的女性处于绝经前年龄 射程。与年龄匹配的绝经前女性相比，患有T2D的绝经前女性的健康相关结果较差 患有T2D的男性。T2D中这种性别差异的机制尚不清楚。有氧能力预示着 与T2D相关的不良健康结局的发生率。T2D对有氧功率产生负面影响 绝经前女性T2D较男性T2D程度高。有氧能力部分地 依赖于骨骼肌生物能量学。这项建议旨在解决一种具有临床意义的 与女性T2D相关的知识差距，以确定临床治疗的潜在靶点，以改善 T2D妇女的健康，并提供几种具体方法的培训，这些方法将使我为 成功地过渡到独立。 有氧能力部分依赖于骨骼肌生物能量学：信号传递与测量 细胞能量平衡和线粒体的生物发生/功能。据报道，雌激素(E2)信号转导 然而，支持骨骼肌生物能量学的我令人惊讶的临床前数据表明， 研究雌激素信号的生理背景是重要的。我的飞行员数据揭示了一种意想不到的 雌激素和糖尿病对骨骼肌生物能量学调节的不利作用。我的工作 假说是糖尿病抑制了E_2介导的骨骼肌对生物能量的支持。 生殖年龄雌性大鼠。我将以两个具体目标来解释这一假设： 目的1：检测糖尿病环境对骨骼肌E2信号和线粒体的影响 体外生物发生。这一目标将决定糖尿病对E2介导的相关信号支持的影响 细胞能量平衡和线粒体生物发生的方法和措施。通过复杂的信号研究 将生成数据以确定糖尿病相关机制(S)，可以作为恢复的目标 患有T2D的女性的线粒体生物能量学。 目的2：了解糖尿病对体内骨骼肌生物能量学的支持是否受E2的干扰 有损运动能力。这一目标将决定糖尿病相关疾病的生物能量后果 通过底物利用、线粒体功能、 和有氧运动能力。 这项建议解决了与功能状态降低有关的临床相关知识差距 绝经前妇女患有T2D，可以确定临床治疗的潜在靶点，以改善健康 患有T2D的女性。通过与我的导师的培训，课程安排，以及成功完成 项目的具体目标，我将进一步发展我在原代细胞培养，细胞 信号转导和对E2的操纵，并获得新的数据，这些数据将使我走上实现我的 总体目标是成为一名成功的、独立的退伍军人事务部科学家。

Type 2 Diabetes (T2D) is a major health priority within the VA. More than 24% of Veterans have T2D, twice the national average. There is an increasing population of female veterans in the VA in the premenopausal age range. Premenopausal women with T2D have poorer health-related outcomes compared with age-matched men with T2D. The mechanisms for this sex difference in T2D are unknown. Aerobic power predicts the incidence of the poor health-related outcomes associated with T2D. T2D negatively impacts aerobic power to a greater degree in premenopausal women with T2D compared with men with T2D. Aerobic power is partially dependent on skeletal muscle bioenergetics. This proposal is designed to address a clinically significant knowledge gap related to women with T2D, to identify potential targets for clinical therapies to improve the health of women with T2D, and to provide training in several specific methods that will prepare me for a successful transition to independence. Aerobic power is partially dependent on skeletal muscle bioenergetics: signaling associated with and measures of cellular energy balance and mitochondrial biogenesis/function. Estrogen (E2) signaling is reported to be supportive of skeletal muscle bioenergetics, however, my surprising preclinical data suggest that the physiological context in which estrogen signaling is studied is important. My pilot data reveal an unexpected adverse interaction of E2 and diabetes on the regulators of skeletal muscle bioenergetics. My working hypothesis is that diabetes suppresses E2-mediated support of bioenergetics in skeletal muscle of reproductive aged female rats. I will address this hypothesis with two specific aims: Aim 1: To test the impact of the diabetic environment on skeletal muscle E2 signaling and mitochondrial biogenesis in vitro. This aim will determine impact of diabetes on E2-mediated support of signaling associated with and measures of cellular energy balance and mitochondrial biogenesis. Through intricate signaling studies data will be generated to identify the diabetes-associated mechanism(s) that could be targeted to restore mitochondrial bioenergetics in women with T2D. Aim 2: To understand whether the disruption of E2 support of skeletal muscle bioenergetics in vivo by diabetes impairs exercise capacity. This aim will determine the bioenergetic consequences of the diabetes-associated disruption of E2 support of skeletal muscle through measures of substrate utilization, mitochondrial function, and aerobic exercise capacity. This proposal addresses the clinically relevant knowledge gap related to decreased functional status of premenopausal women with T2D and could identify potential targets for clinical therapies to improve the health of women with T2D. Through training with my mentors, coursework, and the successful completion of the project specific aims, I will further develop my knowledge base and skillset in primary cell culture, cellular signal transduction, and manipulation of E2 and derive new data that will set me on the path to achieve my overall goal of becoming a successful, independent VA scientist.