The Interaction of Diabetes and Estrogen on Skeletal Muscle Bioenergetics

糖尿病和雌激素对骨骼肌生物能学的相互作用

• 批准号: 10552615
• 负责人: Rebecca L Scalzo
• 金额: --
• 依托单位: VA EASTERN COLORADO HEALTH CARE SYSTEM
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-01-01 至 2024-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10552615
• 关键词: 3-Phosphoinositide Dependent Protein Kinase-1; 5' -AMP-activated protein kinase; Address; Aerobic; Aerobic Exercise; Affect; Age; Animal Model; Attenuated; Bioenergetics; Biogenesis; Biological; Cardiovascular Diseases; Cell Culture Techniques; Clinical; Cyclic AMP; Data; Diabetes Mellitus; Diet; Disparity; Environment; Estradiol; Estrogens; Exercise; Exposure to; Fat-Restricted Diet; Female; Goals; Health; Health Priorities; High Fat Diet; Impairment; In Vitro; Incidence; Knowledge; Measures; Mediating; Mentors; Methods; Mitochondria; Molecular Target; Mus; Muscle; Muscle Fibers; NOS3 gene; Non-Insulin-Dependent Diabetes Mellitus; Outcome; Oxygen; PIK3CG gene; PPAR gamma; Pathway interactions; Physiological; Population; Premenopause; Prevalence; Primary Cell Cultures; Process; Rattus; Reporting; Research Personnel; Respiration; Role; Scientist; Sex Differences; Signal Pathway; Signal Transduction; Skeletal Muscle; System; Testing; Training; VO2max; Veterans; Wistar Rats; Woman; Women' s Health; aged; antagonist; clinically relevant; clinically significant; design; diabetic; energy balance; estrogen disruption; exercise capacity; experimental study; functional status; improved; in vivo; inhibitor; insight; knowledge base; men; military veteran; mortality; pre-clinical; programs; reproductive; response; sex; skills; sugar; training opportunity; uptake

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.

2型糖尿病（T2D）是VA内的主要健康优先事项。超过24％的退伍军人有T2D，两次 全国平均水平。在绝经前的VA中，女性退伍军人人数越来越大 范围。与年龄匹配的T2D的绝经前女性与健康相关的结果较差 男人有T2D。 T2D中这种性别差异的机制尚不清楚。有氧力量预测 与T2D相关的与健康相关的结果不良的发生率。 T2D对有氧力量产生负面影响 与患有T2D的男性相比，年绝经前女性具有更高的程度。有氧力量部分是 取决于骨骼肌生物能力。该建议旨在解决临床意义的 与T2D女性有关的知识差距，以确定临床疗法的潜在靶标，以改善 具有T2D的女性的健康状况，并通过几种特定方法提供培训，这将使我做好准备 成功过渡到独立。 有氧力量部分取决于骨骼肌生物能源：与和措施相关的信号传导 细胞能量平衡和线粒体生物发生/功能。据报道雌激素（E2）信号传导 但是，支持骨骼肌生物能学，我令人惊讶的临床前数据表明 研究雌激素信号传导的生理环境很重要。我的飞行员数据显示出意外 E2和糖尿病在骨骼肌生物能力调节剂上的不良相互作用。我的工作 假设是糖尿病抑制了E2介导的对生物能学的支持 生殖老化的雌性大鼠。我将以两个具体的目的解决这一假设： 目标1：测试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。该目标将确定糖尿病对与信号相关的信号的支持的影响 与细胞能量平衡和线粒体生物发生的测量。通过复杂的信号研究 将生成数据以识别可以针对恢复的糖尿病相关机制 T2D女性的线粒体生物能学。 目的2：了解糖尿病中E2对体内骨骼肌生物能力的支持是否破坏 损害运动能力。这个目标将确定与糖尿病相关的生物能后果 通过底物利用率，线粒体功能的措施来破坏E2对骨骼肌的支持， 和有氧运动能力。 该提案解决了与降低功能状态有关的临床相关知识差距 绝经前女性T2D，可以识别临床疗法的潜在靶标，以改善健康状况 T2D的妇女。通过与我的导师的培训，课程和成功完成 特定于项目的目标，我将进一步发展我的知识库和在原发性细胞培养中的知识库和技能 信号转导，以及对E2的操纵并得出新数据，这将使我走上实现我的路径 成为成功的独立VA科学家的总体目标。