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: 10265345
• 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 2023-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10265345
• 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; 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; 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; Time; Training; VO2max; Veterans; Wistar Rats; Woman; Women' s Health; aged; clinically relevant; clinically significant; design; diabetic; energy balance; estrogen disruption; exercise capacity; experimental study; functional status; improved; in vivo; inhibitor/antagonist; insight; knowledge base; men; military veteran; mortality; pre-clinical; programs; reproductive; response; sex; 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 的一个主要健康优先事项。超过 24% 的退伍军人患有 T2D，两倍以上 全国平均水平。退伍军人管理局绝经前年龄的女性退伍军人人数不断增加 范围。与年龄匹配的女性相比，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。有氧功率预测 与 T2D 相关的不良健康相关结果的发生率。 T2D 对有氧运动能力产生负面影响 与患有 T2D 的男性相比，患有 T2D 的绝经前女性的程度更大。有氧力量部分是 依赖于骨骼肌生物能学。该提案旨在解决具有临床意义的 与患有 T2D 的女性相关的知识差距，以确定临床治疗的潜在目标，以改善 患有 T2D 的女性的健康状况，并提供几种具体方法的培训，帮助我做好准备 成功过渡到独立。 有氧力量部分取决于骨骼肌生物能学：与测量相关的信号传导 细胞能量平衡和线粒体生物合成/功能。据报道，雌激素 (E2) 信号传导 支持骨骼肌生物能学，然而，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背景很重要。我的试验数据揭示了意想不到的情况 E2 和糖尿病对骨骼肌生物能调节剂的不利相互作用。我的工作 假设糖尿病抑制 E2 介导的骨骼肌生物能支持 生殖年龄的雌性大鼠。我将通过两个具体目标来解决这个假设： 目标 1：测试糖尿病环境对骨骼肌 E2 信号传导和线粒体的影响 体外生物发生。该目标将确定糖尿病对 E2 介导的信号相关支持的影响 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 将生成数据来识别与糖尿病相关的机制，这些机制可以有针对性地恢复 T2D 女性线粒体生物能量学。 目标 2：了解糖尿病是否会破坏 E2 对体内骨骼肌生物能的支持 损害运动能力。这一目标将确定糖尿病相关的生物能后果 通过测量底物利用率、线粒体功能来破坏 E2 对骨骼肌的支持， 和有氧运动能力。 该提案解决了与功能状态下降相关的临床相关知识差距 患有 T2D 的绝经前妇女，可以确定临床治疗的潜在目标，以改善健康 患有 T2D 的女性。通过我的导师的培训、课程作业以及成功完成 项目特定目标，我将进一步发展我在原代细胞培养、细胞培养方面的知识基础和技能 信号转导、E2 操纵并得出新数据，这将使我走上实现我的目标的道路 成为一名成功的、独立的 VA 科学家的总体目标。