PE methylation in skeletal muscle energy efficiency

项目摘要/摘要 在过去的二十年里，与肥胖相关的代谢性疾病的流行以惊人的速度增加。 生活方式的改变促进了长期体重管理的有限成功，而许多医生 干预措施有副作用。能源效率的降低可能会提供一种替代方法 促进减肥。由于骨骼肌是一个质量和代谢需求都很大的器官，能量 据预测，骨骼肌的低效将促进全身能量的大幅增加。 支出。对膜泡的研究表明，肌细胞/内质网的能量效率 (SR/ER)Ca~(2+)-ATPase(SERCA)泵可能受SR磷脂组成的调节。在这 应用，我们建议研究磷脂酰乙醇胺(PE)甲基化在调节 肌肉能量效率。PE甲基化由PE甲基转移酶(PEMT)催化，小鼠 由于PEMT基因的全身缺失，可以防止饮食诱导的肥胖。我们发现骨骼 来自PEMT基因敲除小鼠的肌肉代谢率提高，这可能是由减少 SERCA能效。我们假设PE甲基化缺陷会降低SERCA的能量效率 通过其对骨骼肌肌浆网磷脂组成的影响。目标1：通过组织特异性灭活 PEMT，我们将确定PE甲基化缺陷如何影响细胞内钙离子的处理以增加骨骼 肌肉能量消耗。目标2：在多个实验模型中，我们将确定 肌肉肌浆网磷脂足以引起静息代谢率和倾向的变化 饮食导致的肥胖。目标3：我们将得出使用PE收缩肌肉的机械效率(η 甲基化缺陷。我们还将研究灭活PEMT是否会增强抗肥胖作用 经常锻炼的效果。

Project Summary/Abstract A pandemic in obesity-related metabolic diseases has increased at an alarming rate over the last two decades. Lifestyle changes promote limited success for long-term weight management, while many medical interventions have side effects. Reduction in energy efficiency might provide an alternative approach to promote weight loss. As skeletal muscle is an organ with large mass and metabolic demand, energy inefficiency in skeletal muscle would be predicted to promote substantial increase in whole body energy expenditure. Studies in membrane vesicles suggest that energy efficiency of sarco/endoplasmic reticulum (SR/ER) Ca2+-ATPase (SERCA) pump may be modulated by composition of SR phospholipids. In this application, we propose to investigate the role of phosphatidylethanolamine (PE) methylation in regulating muscle energy efficiency. PE methylation is catalyzed by an enzyme PE methyltransferase (PEMT), and mice with whole body deletion of PEMT are protected from diet-induced obesity. We discovered that skeletal muscles from PEMT knockout mice have elevated metabolic rate, which was likely promoted by a reduction in SERCA energy efficiency. We hypothesize that PE methylation deficiency reduces SERCA energy efficiency through its effects on skeletal muscle SR phospholipid composition. Aim 1: With tissue-specific inactivation of PEMT, we will determine how PE methylation deficiency affects cellular Ca2+ handling to increase skeletal muscle energy expenditure. Aim 2: In multiple experimental models, we will determine whether alterations in muscle SR phospholipids would be sufficient to induce changes in resting metabolic rate and propensity for diet-induced obesity. Aim 3: We will derive mechanical efficiency (η) of contracting muscles with PE methylation deficiency. We will also examine whether inactivation of PEMT would augment the anti-obesogenic effect of regular exercise.