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：
10576797
负责人：
Qiuying Chen
金额：
$ 55.02万
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/10576797
关键词：
ATP Synthesis Pathway Acceleration 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 Oxidative Phosphorylation Deficiency 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 biomarker panel biomarker signature effective therapy efficacy evaluation 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.

项目概要线粒体疾病是由线粒体损伤引起的异质性遗传性疾病。氧化磷酸化（OXPHOS）系统，影响能量消耗严重的组织依赖性，常表现为神经肌肉症状，并伴有各种症状额外的临床特征。尽管遗传错误引起的能量缺陷线粒体和核 DNA 众所周知，线粒体疾病的许多方面发病机制尚未阐明。结果，由于缺乏明确的代谢目标，没有经过证实的有效治疗或治愈方法。我们最近发布的研究表明小鼠骨骼肌发生了显着的代谢重塑线粒体肌病模型。我们发现类似饥饿的反应可以促进肌肉蛋白质分解和氨基酸分解代谢以支持补偿性能量生成氧化通量。在此通量中，谷氨酸通过 TCA 循环被氧化，并允许 OXPHOS- 独立的底物水平 ADP 磷酸化。然而，这个补偿过程会导致肌肉消耗和脂质积累。我们假设除了 ATP 合成 OXPHOS 缺陷的组织必须面临许多引起的代谢障碍问题通过改变中间代谢途径。重要的是，在初步研究中领先在这个应用中，我们发现人类患者的骨骼肌线粒体肌病表现出类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来获取能量目的是适应不良效应的基础，导致疾病发病机制。在本应用的目标 1 中，我们将深入研究线粒体肌病小鼠模型中 OXPHOS 缺陷肌肉的代谢重新布线。在目标 2 中，我们将研究人类线粒体肌病中的肌肉代谢重塑。在目标 3 中，我们将在线粒体肌病小鼠中测试代谢补充疗法。在这项研究结束时，我们将提高对致病菌的认识线粒体疾病的机制，建立了人类功能性生物标志物组线粒体肌病，并评估代谢补充剂是否可以改善肌病表型。