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，以心磷脂代谢异常、线粒体功能障碍、肌肉萎缩和心力衰竭为特征。BTHS是一种特别重要的疾病，因为它通常在儿童时期是致命的，除了心力衰竭的标准治疗外，还没有批准的BTHS治疗方法。因此，迫切需要新的研究领域和测试新疗法的平台。通过最新的和创新的方法，这个项目将专注于骨骼肌和心脏营养(葡萄糖、脂肪酸和氨基酸)代谢在BTHS发病机制中的新作用。有关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表型信息是缺乏的，并且具有重要意义，因为这可能会促进我们对BTHS潜在发病机制的理解。有了这一认识，就可以针对BTHS进行安全有效的治疗。我们的总体假设是，骨骼肌和心脏的脂肪酸代谢受损会导致这些器官的燃料短缺，导致能量产生受损、运动不耐受和心力衰竭。此外，由于骨骼肌和心脏的脂肪酸新陈代谢受损，骨骼肌和心脏中的蛋白质分解(消耗)提供氨基酸作为对这种不足的脂肪酸能量供应的补偿，从而使BTHS的心脏和骨骼肌功能恶化。我们的目标是在30名患有BTHS的年轻人和儿童以及30名8-30岁的健康、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：1)表征骨骼肌和心脏的营养代谢；2)研究骨骼肌和心脏的营养代谢、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，我们将研究从成人和儿童BTHS和成人对照组获得的可诱导多能干细胞(来自皮肤成纤维细胞)来源的人心肌细胞中营养代谢的机械性分子途径；特别是蛋白质分解、线粒体功能和脂肪酸代谢。骨骼肌营养代谢将通过稳定同位素示踪法和质谱仪进行量化，心脏营养代谢将使用放射性同位素示踪法和PET成像进行量化，骨骼肌和心脏能量产生将通过磁共振波谱进行量化，骨骼肌功能将通过分级运动试验和间接量热法进行量化，心脏功能将通过超声心动图进行量化，心肌细胞营养途径的机制将通过多能干细胞诱导和蛋白质和RNA表达分析进行检测。 公共卫生相关性： Barth综合征(BTHS)是一种由心磷脂代谢异常引起的X连锁疾病，以骨骼和心肌病为特征，死亡率高。通过临床代谢和成像研究，以及皮肤活检样本的多能干细胞诱导和分子技术，该项目将产生关于BTHS发病机制的新的翻译信息，揭示潜在的干预靶点，并提供关于营养代谢和异常心磷脂和线粒体功能的独特数据。该项目有可能提供可以显著改善儿童和年轻人BTHS发病率和死亡率的信息，并可能与其他与BTHS无关的疾病，如衰老和成人心力衰竭相关。

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. PUBLIC HEALTH RELEVANCE: Barth syndrome (BTHS) is an X-linked disorder caused by abnormal cardiolipin metabolism and is characterized by skeletal and cardiomyopathy and high mortality rates. Through clinical metabolism and imaging studies and pluripotent stem cell induction and molecular techniques on skin biopsy samples, this project will produce novel translational information regarding the pathogenesis of BTHS, reveal potential targets for interventions and provide unique data regarding nutrient metabolism and abnormal cardiolipin and mitochondrial function. This project has the potential to provide information that could significantly improve morbidity and mortality i children and young adults with BTHS and may have relevance to other non-BTHS related conditions such as aging and adult heart failure.