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Heart and Skeletal Muscle Metabolism, Energetics and Function in Barth Syndrome

巴特综合征中的心脏和骨骼肌代谢、能量和功能

基本信息

批准号：
8675917
负责人：
WILLIAM Todd CADE
金额：
$ 48.92万
依托单位：
WASHINGTON UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2012
资助国家：
美国
起止时间：
2012-06-01 至 2017-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8675917
关键词：
3-Methylglutaconic aciduria type 2 Acute Address Adult Aerobic Exercise Age Aging Amino Acids Area Biopsy Specimen Cardiolipins Cardiomyopathies Catabolism Cells Child Childhood Clinical Data Defect Disease Echocardiography Energy Supply Exercise Exercise Tolerance Exercise stress test Fatigue Fatty Acids Fibroblasts Financial compensation Genes Genetic Genetic Transcription Glucose Heart Heart failure Hepatic Human Image Immunoblotting Indirect Calorimetry Intervention Isotopes Left Ventricular Dysfunction Left Ventricular Function Link Magnetic Resonance Spectroscopy Mass Spectrum Analysis Mediating Metabolism Methodology Mitochondria Modeling Molecular Morbidity - disease rate Mus Muscle Muscle Cells Muscle Fatigue Muscle function Mutation Myocardial Myocardial Ischemia Myocardium Myopathy Neutropenia Nutrient Nutritional Organ Oxidative Phosphorylation Participant Pathogenesis Pathology Pathway interactions Patients Physiological Pluripotent Stem Cells Polymerase Chain Reaction Positron-Emission Tomography Production Proteins Proteolysis Puberty Radio Recovery Research Rest Role Skeletal Muscle Skin Staging Structure Techniques Testing Time Tissues Tracer effective therapy falls fatty acid metabolism fatty acid oxidation glucose disposal glucose metabolism glucose production heart function improved induced pluripotent stem cell infancy innovation insight mitochondrial dysfunction mortality muscle metabolism novel nutrient metabolism oxidation protein expression skeletal stable isotope standard care wasting young adult

项目摘要

DESCRIPTION (provided by applicant): Barth syndrome (BTHS) is an X-linked disorder characterized by abnormal cardiolipin metabolism, mitochondrial dysfunction, muscle wasting and heart failure. BTHS is a particularly significant disease as it is often fatal in childhood and there are no approved therapies for BTHS other than the standard treatment of heart failure. Therefore novel areas of research and platforms in which to test new therapies are highly needed. Through state-of-the-art and innovative methodologies, this project will focus on the novel role of skeletal muscle and heart nutrient (glucose, fatty acid, and amino acid) metabolism in the pathogenesis of BTHS. Phenotypic information regarding skeletal muscle and heart nutrient metabolism in BTHS and how it may relate to energy production and function of these organs is lacking and is significant as this may advance our understanding of the underlying pathogenesis of BTHS. With this understanding, safe and efficacious therapies can be targeted for BTHS. Our overall hypothesis is that impaired fatty acid metabolism in skeletal muscle and the heart produces a fuel deficit in these organs leading to impaired energy production, exercise intolerance and heart failure. Further, as a consequence of impaired fatty acid metabolism in skeletal muscle and the heart, protein breakdown (wasting) in skeletal muscle and the heart occurs to provide amino acids as compensation for this inadequate fatty acid energy supply, thereby worsening heart and skeletal muscle function in BTHS. Our aims to address this hypothesis in 30 young adults and children with BTHS and 30 healthy, age, puberty stage and activity level matched controls ages 8-30 years are: 1) To characterize skeletal muscle and heart nutrient metabolism and 2) To examine the relationship between skeletal muscle and heart nutrient metabolism, energy production and function (exercise tolerance and heart function). As an exploratory aim, we will examine mechanistic molecular pathways of nutrient metabolism; specifically protein breakdown, mitochondrial function and fatty acid metabolism, in human myocytes derived from inducible pluripotent stem cells (from skin fibroblasts) obtained from adults and children with BTHS and from adult controls. Skeletal muscle nutrient metabolism will be quantified by stable-isotope tracer methodology and mass spectrometry, heart nutrient metabolism using radio-isotope tracer methodology and PET imaging, skeletal muscle and heart energy production using magnetic resonance spectroscopy, skeletal muscle function by graded exercise testing and indirect calorimetry, heart function by echocardiography, and myocyte nutrient pathway mechanism examination by pluripotent stem cell induction and protein and RNA expression analyses.

描述（由申请人提供）：