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PE methylation in skeletal muscle energy efficiency

PE甲基化对骨骼肌能量效率的影响

基本信息

批准号：
9237338
负责人：
Katsuhiko Funai
金额：
$ 33.84万
依托单位：
EAST CAROLINA UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2017
资助国家：
美国
起止时间：
2017-02-01 至 2017-10-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9237338
关键词：
ATP Hydrolysis Adverse effects Affect Basal metabolic rate Body Weight decreased Ca(2+)-Transporting ATPase Choline Chronic Comorbidity Consumption Contracts Diet Endoplasmic Reticulum Energy Intake Energy Metabolism Enzymes Ethanolamines Exercise Exhibits Experimental Models Integral Membrane Protein Intervention Kinetics Knock-in Knock-out Knockout Mice Lead Lecithin Life Style Locomotion Mechanics Medical Membrane Metabolic Metabolic Diseases Methylation Mitochondria Modeling Mus Muscle Muscle Contraction Muscle Fibers Obese Mice Obesity Obesity associated disease Organ Overweight Phenotype Phosphatidylethanolamine Phosphatidylethanolamine N-Methyltransferase Phospholipids Phosphotransferases Predisposition Production Property Public Health Pump Reaction Role Skeletal Muscle Tamoxifen Testing Tissues United States Vesicle Weight Weight maintenance regimen Woman choline deficient diet diet and exercise food consumption men metabolic rate mouse model novel therapeutic intervention obesity treatment obesogenic pandemic disease reconstitution respiratory stoichiometry success uptake

项目摘要

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.

项目概要/摘要过去二十年来，与肥胖相关的代谢疾病的流行以惊人的速度增加。生活方式的改变对长期体重管理的成功有限，而许多医疗方法干预措施有副作用。降低能源效率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大、代谢需求大的器官，因此需要能量预计骨骼肌的低效率会促进全身能量的大幅增加支出。膜囊泡的研究表明肌浆/内质网的能量效率 (SR/ER) Ca2+-ATPase (SERCA) 泵可通过 SR 磷脂的成分进行调节。在这个应用中，我们建议研究磷脂酰乙醇胺（PE）甲基化在调节中的作用肌肉能量效率。 PE 甲基化由 PE 甲基转移酶 (PEMT) 催化，小鼠全身删除 PEMT 可以防止饮食引起的肥胖。我们发现骨骼 PEMT 基因敲除小鼠的肌肉代谢率升高，这可能是由于 SERCA 能源效率。我们假设 PE 甲基化缺陷会降低 SERCA 能源效率通过其对骨骼肌 SR 磷脂成分的影响。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 Ca2+ 处理以增加骨骼肌肉能量消耗。目标 2：在多个实验模型中，我们将确定是否发生了改变肌肉 SR 磷脂足以引起静息代谢率和运动倾向的变化饮食引起的肥胖。目标 3：我们将通过 PE 导出肌肉收缩的机械效率 (η) 甲基化缺陷。我们还将研究 PEMT 失活是否会增强抗肥胖作用经常锻炼的效果。