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

描述（由申请人提供）： Barth综合征（BTHS）是一种X连锁疾病，其特征是心磷脂代谢异常、线粒体功能障碍、肌肉萎缩和心力衰竭。BTHS是一种特别重要的疾病，因为它在儿童时期通常是致命的，除了心力衰竭的标准治疗外，没有批准的BTHS治疗方法。因此，非常需要新的研究领域和平台来测试新的疗法。通过国家的最先进的和创新的方法，该项目将集中在骨骼肌和心脏营养（葡萄糖，脂肪酸和氨基酸）代谢的BTHS的发病机制中的新作用。关于BTHS中骨骼肌和心脏营养代谢的表型信息以及它如何与这些器官的能量产生和功能相关的信息是缺乏的，并且是重要的，因为这可能会促进我们对BTHS潜在发病机制的理解。有了这种理解，安全有效的治疗方法可以针对BTHS。我们的总体假设是骨骼肌和心脏中脂肪酸代谢受损导致这些器官中的燃料不足，导致能量产生受损，运动不耐受和心力衰竭。此外，作为骨骼肌和心脏中脂肪酸代谢受损的结果，骨骼肌和心脏中发生蛋白质分解（消耗）以提供氨基酸作为对这种不足的脂肪酸能量供应的补偿，从而恶化BTHS中的心脏和骨骼肌功能。我们的目的是在30名患有BTHS的年轻成人和儿童以及30名年龄、青春期阶段和活动水平匹配的健康对照组中解决这一假设，年龄为8-30岁：1）表征骨骼肌和心脏营养代谢和2）检查骨骼肌和心脏营养代谢、能量产生和功能（运动耐量和心脏功能）之间的关系。作为一个探索性的目标，我们将研究营养代谢的机制分子途径，特别是蛋白质分解，线粒体功能和脂肪酸代谢，在人肌细胞来源于诱导性多能干细胞（从皮肤成纤维细胞）从成人和儿童BTHS和成人对照。骨骼肌营养代谢将通过稳定同位素示踪方法和质谱法进行定量，心脏营养代谢使用放射性同位素示踪方法和PET成像，骨骼肌和心脏能量产生使用磁共振光谱法，骨骼肌功能通过分级运动试验和间接热量测定法进行定量，心脏功能通过超声心动图进行定量，以及通过多能干细胞诱导和蛋白质和RNA表达分析的肌细胞营养途径机制检查。

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.