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：
10242978
负责人：
Katsuhiko Funai
金额：
$ 3.62万
依托单位：
UNIVERSITY OF UTAH
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 2022-01-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10242978
关键词：
ATP Hydrolysis Affect Basal metabolic rate Body Weight decreased Ca(2+)-Transporting ATPase Choline Chronic Consumption Contracts Diet Endoplasmic Reticulum Energy Intake Energy Metabolism Enzymes Estrogen receptor positive 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 Wild Type Mouse Woman choline deficient diet comorbidity diet and exercise food consumption men metabolic rate mouse model novel therapeutic intervention obesity treatment obesogenic pandemic disease reconstitution respiratory side effect 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会产生副作用。能源效率的降低可能会提供一种替代方法。促进减肥，因为骨骼肌是一个质量大、代谢需求大的器官。预计骨骼肌的低效率会促进全身能量的大幅增加膜囊泡的研究表明肌浆/内质网的能量效率。 (SR/ER) Ca2+-ATPase (SERCA) 泵可能受 SR 磷脂组成的调节。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 PE 甲基化是由 PE 甲基转移酶 (PEMT) 催化的，并且小鼠。我们发现，全身删除 PEMT 可以预防饮食引起的肥胖。 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。我们认为 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：具有组织特异性灭活作用。 PEMT，我们将确定 PE 甲基化缺陷如何影响细胞 Ca2+ 处理以增加骨骼目标 2：在多个实验模型中，我们将确定肌肉能量消耗是否发生变化。肌肉 SR 磷脂足以引起静息代谢率和运动倾向的变化目标 3：我们将得出通过 PE 收缩肌肉的机械效率 (η)。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。