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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：
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.

项目总结/文摘