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Metabolic remodeling of skeletal muscle in mitochondrial myopathies

线粒体肌病中骨骼肌的代谢重塑

基本信息

批准号：
10341214
负责人：
Qiuying Chen
金额：
$ 54.47万
依托单位：
WEILL MEDICAL COLL OF CORNELL UNIV
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-04-01 至 2025-02-28
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10341214
关键词：
ATP Synthesis Pathway Affect Amino Acids Arginine Body Weight decreased Carbon Catabolism Cells Chronic Citric Acid Cycle Citrulline Clinical Coenzyme A DNA Defect Dependence Development Dietary Intervention Disease Disease Progression Disease model Disease stratification Evaluation Face Functional disorder Gene Mutation Genetic Genetic Diseases Glutamate Metabolism Pathway Glutamates Glutamine Glycolysis Goals Human Impairment Inherited Intervention Knockout Mice Knowledge Link Lipids Metabolic Metabolic Diseases Metabolic Pathway Metabolism Mitochondria Mitochondrial DNA Mitochondrial Diseases Mitochondrial Myopathies Mus Muscle Muscle Proteins Muscle function Muscular Atrophy Myoblasts Myopathy Naphthoquinones Neurologic Nuclear Oxidative Phosphorylation Oxides Pathogenesis Pathogenicity Pathway interactions Patients Pattern Phenotype Phosphorylation Plasma Process Proteins Proteolysis Proteomics Publishing Research Role Skeletal Muscle Specimen Starvation Supplementation Symptoms System Testing Therapeutic Tissues alpha ketoglutarate base biomarker panel biomarker signature effective therapy improved lipid metabolism man metabolic abnormality assessment metabolic phenotype metabolic profile mitochondrial DNA mutation mitochondrial metabolism mouse model neuromuscular novel oxidation profiles in patients response screening targeted treatment therapeutic target

项目摘要

Project Summary Mitochondrial diseases are heterogeneous genetic disorders caused by the impairment of the oxidative phosphorylation (OXPHOS) system, affecting tissues that are heavily energy dependent, and often manifesting with neuromuscular symptoms accompanied by a variety of additional clinical features. Although the energetic defects arising from genetic errors in mitochondrial and nuclear DNA are often known, many aspects of mitochondrial disease pathogenesis are yet to be elucidated. As a consequence, because of the lack of defined metabolic targets, no proven effective treatments or cures are available. Our recently published studies indicate that a dramatic metabolic remodeling occurs in the skeletal muscle of a mouse model of mitochondrial myopathy. We found that a starvation-like response promotes muscle protein breakdown and amino acid catabolism to support a compensatory energy-generating oxidative flux. In this flux, glutamate is oxidized through the TCA cycle and allows for OXPHOS- independent substrate-level ADP phosphorylation. However, this compensatory process results in muscle wasting and lipids accumulation. We hypothesize that in addition to ATP synthesis impairment, OXPHOS-defective tissues must face a number of dysmetabolic problems caused by altered pathways of the intermediary metabolism. Importantly, in preliminary studies leading to this application, we have discovered that skeletal muscle from human patients with mitochondrial myopathy show similar compensatory metabolic responses. Our findings suggest that this metabolic shift towards preferred utilization of amino acids over lipids for energetic purposes underlies maladaptive effects, contributing to disease pathogenesis. In aim 1 of this application, we will investigate in depth the mechanisms and roles of the metabolic rewiring in OXPHOS-defective muscle of a mouse model of mitochondrial myopathy. In aim 2 we will investigate the muscle metabolic remodeling in human mitochondrial myopathy. In aim 3 we will test metabolic supplementation therapy in the mitochondrial myopathy mouse. At the conclusion of this study we will have improved our knowledge on the pathogenic mechanisms of mitochondrial diseases, established a functional biomarker panel for human mitochondrial myopathy, and assessed if metabolic supplementation can improve the myopathic phenotype.

项目摘要线粒体疾病是异质性遗传性疾病，由线粒体功能受损引起。氧化磷酸化（OXPHOS）系统，影响组织，是大量的能量依赖性，经常表现为神经肌肉症状，伴有各种其他临床特征。虽然由于遗传错误而产生的能量缺陷，线粒体和核DNA通常是已知的，线粒体疾病的许多方面发病机制尚未阐明。由于缺乏明确的代谢目标，没有被证明有效的治疗或治愈是可用的。我们最近出版的研究表明，小鼠的骨骼肌中发生了显著的代谢重塑，线粒体肌病模型。我们发现类似饥饿的反应会促进肌肉蛋白质分解和氨基酸催化剂，以支持代偿性能量产生氧化通量在这种通量中，谷氨酸通过TCA循环被氧化，并允许OXPHOS- 独立底物水平ADP磷酸化。然而，这种补偿过程导致肌肉萎缩和脂肪堆积。我们假设除了ATP的合成损伤，OXPHOS缺陷组织必须面对许多代谢异常的问题，通过改变中间代谢途径。重要的是，在初步研究中，对于这种应用，我们已经发现，来自人类患者的骨骼肌线粒体肌病表现出相似的代偿性代谢反应。我们的研究结果表明这种代谢转变倾向于优先利用氨基酸而不是脂质，目的是适应不良效应的基础，有助于疾病的发病机制。在本申请的目的1中，我们将深入研究线粒体肌病小鼠模型的OXPHOS缺陷肌肉中的代谢重连。在目的2中，我们将研究人类线粒体肌病的肌肉代谢重建。在目标3中，我们将测试线粒体肌病小鼠的代谢补充疗法。在这项研究结束时，我们将提高我们对致病性线粒体疾病的机制，建立了一个功能性生物标志物小组，为人类线粒体肌病，并评估代谢补充剂是否可以改善肌病表型