Molecular basis for skeletal muscle pathophysiology in Pompe's disease

庞贝氏病骨骼肌病理生理学的分子基础

基本信息

批准号：
9233022
负责人：
JEFFREY E. PESSIN
金额：
$ 44.38万
依托单位：
ALBERT EINSTEIN COLLEGE OF MEDICINE, INC
依托单位国家：
美国
项目类别：
财政年份：
2013
资助国家：
美国
起止时间：
2013-03-07 至 2018-02-28
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9233022
关键词：
Adolescent Adult Aerobic Affect Anaerobic Bacteria Autophagocytosis Autophagosome Biological Case Study Cells Cessation of life Clinical Competence Complex Data Defect Deposition Diet Dietary Intervention Disease Effectiveness Environment Event Exercise FRAP1 gene Failure Fast-Twitch Muscle Fibers Fasting Functional disorder Genes Genetic Genetic Models Glucan 1,4-alpha-Glucosidase Glycogen Glycogen storage disease type II Growth Factor Hepatomegaly Hormonal Individual Inherited Intervention Lead Leucine Liver Lysosomal Function Inhibition Lysosomes Mammalian Cell Measures Microtubules Mitochondria Molecular Mus Muscle Muscle Fibers Muscle Weakness Muscle function Muscle hypotonia Muscular Atrophy Mutation Myoblasts Myocardium Myopathy Nutrient Organelles Other Genetics Pathology Pathway interactions Patients Pharmacology Phenotype Physiological Process Protein Biosynthesis Protein Synthesis Inhibition Proteins Regulation Reporting Residual state Respiratory Failure Signal Transduction Signaling Protein Skeletal Muscle Slow-Twitch Muscle Fibers Structure Testing Toxic effect Vacuole Vesicle alkalinity design exercise intervention glucosidase glycogen metabolism improved in vivo infancy inhibitor/antagonist knock-down macromolecule macrophage muscle degeneration muscle form muscle physiology mutant novel nutrition overexpression prevent protein degradation public health relevance skeletal muscle wasting tibialis anterior muscle

项目摘要

DESCRIPTION (provided by applicant): Acid alpha-glucosidase (GAA) deficiency (Pompe's disease) is an autosomal recessive inherited disease that results from mutations in the GAA gene preventing or reducing the normal breakdown of glycogen in lysosomes. The primary defect occurs in cardiac and skeletal muscle and depending upon the degree of residual GAA enzymatic activity results in a spectrum of phenotypes that include a rapid fatal infantile disorder, juvenile and a late-onset adult myopathy. The infantile form presents as hypotonia with accumulation of glycogen in skeletal and heart muscle, and death due to cardiorespiratory failure. In addition, the classical infantile-onset form results in hepatomegaly due to increased glycogen deposition within the liver. Adult individuals with the slowly progressive form develop severe skeletal muscle weakness and eventually respiratory failure. Glycolytic type II muscle fibers (white) are primarily affected in Pompe's disease whereas oxidative type I muscle fibers (red) are relatively spared. Recent studies have observed that Pompe mice display defective skeletal muscle macroautophagy. Macroautophagy is a complex process by which organelles (ie: mitochondria), macromolecules (ie: glycogen) and cytoplasmic components are entrapped into autophagosomes that fuse with the lysosome for breakdown and release of individual molecular components. Glycolytic type II muscle fibers (white muscle) are primarily affected in Pompe's disease and accumulate autophagic vacuoles whereas oxidative type I muscle fibers (red) are much less unaffected. The observation that GGA deficiency results in the accumulation of autophgic vacuoles suggests macroautophagy initiation occurs normally but with a defect in late macrophage events, ie: lysosomal fusion. This raises several novel hypotheses for the mechanism of muscle wasting, the physiologic and molecular basis for lysosomal glycogen metabolism and the exciting potential of using dietary, exercise and signal transduction regulation to reduce and/or reverse the muscle defects in Pompe's disease. In this proposal we will examine the mechanism(s) responsible for muscle degradation and the consequences of lysosomal alkalization on mTORC1 activation and macroautophagy. This information will then be used to design specific nutrition, exercise, pharmacologic, and hormonal signaling regulators to restore lysosome function and ameliorate the skeletal muscle degeneration that occurs in GAA deficiency.

描述（由申请人提供）：酸性α-葡萄糖苷酶（GAA）缺乏症（庞贝病）是一种常染色体隐性遗传病，由GAA基因突变导致，阻止或减少溶酶体中糖原的正常分解。主要缺陷发生在心肌和骨骼肌中，根据残留 GAA 酶活性的程度，会导致一系列表型，包括快速致命的婴儿疾病、青少年肌病和迟发性成人肌病。婴儿型表现为肌张力低下，骨骼和心肌中糖原积聚，并因心肺衰竭而死亡。此外，经典的婴儿发病形式由于肝脏内糖原沉积增加而导致肝肿大。患有缓慢进展型的成年个体会出现严重的骨骼肌无力，并最终出现呼吸衰竭。糖酵解型 II 型肌纤维（白色）主要受到庞贝氏病的影响，而氧化型 I 型肌纤维（红色）则相对较少受到影响。最近的研究观察到庞贝氏小鼠表现出骨骼肌巨自噬缺陷。巨自噬是一个复杂的过程，细胞器（即线粒体）、大分子（即糖原）和细胞质成分被捕获到自噬体中，自噬体与溶酶体融合以分解和释放单个分子成分。糖酵解 II 型肌纤维（白色肌肉）主要在庞贝氏病中受到影响并积聚自噬空泡，而氧化型 I 肌纤维（红色）则不太受影响。 GGA 缺乏导致自噬空泡积累的观察结果表明，巨自噬起始正常发生，但晚期巨噬细胞事件存在缺陷，即：溶酶体融合。这提出了一些关于肌肉萎缩机制、溶酶体糖原代谢的生理和分子基础以及利用饮食、运动和信号转导调节来减少和/或逆转庞贝病肌肉缺陷的令人兴奋的潜力的新假设。在本提案中，我们将研究导致肌肉降解的机制以及溶酶体碱化对 mTORC1 激活和巨自噬的影响。然后，这些信息将用于设计特定的营养、运动、药理学和激素信号调节剂，以恢复溶酶体功能并改善 GAA 缺乏时发生的骨骼肌退化。