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性遗传疾病，是由GAA基因突变导致的，从而预防或减少溶酶体中糖原正常崩溃的损伤。主要缺陷发生在心脏和骨骼肌中，取决于残留的GAA酶活性的程度，导致一系列表型，包括快速致命的婴儿疾病，少年和晚期成年肌病。婴儿形式表现为肌肉和心肌中糖原的积累，以及由于心脏呼吸衰竭而导致的死亡。此外，由于肝内糖原沉积增加，经典的婴儿发作形式导致肝肿大。缓慢进行的成年人会出现严重的骨骼肌无力和最终的呼吸衰竭。糖酵解II型肌肉纤维（白色）主要在庞贝病中受到影响，而I型氧化肌肉纤维（红色）相对幸免。最近的研究观察到，庞贝小鼠表现出有缺陷的骨骼肌大噬菌物。大量噬菌体是一个复杂的过程，通过该过程，细胞器（IE：线粒体），大分子（IE：糖原）和细胞质成分被掺入自噬体中，它们与溶酶体融合在一起，以分解和释放单个分子成分。糖酵解II型肌肉纤维（白色肌肉）主要在庞贝氏病中受到影响，并积累自噬液泡，而I型I型肌肉纤维（红色）的影响较小得多。 GGA缺乏导致自噬液泡积累的观察结果表明大噬菌学起始正常发生，但在晚期巨噬细胞事件中存在缺陷，即：溶酶体融合。这为肌肉浪费的机制，溶酶体糖原代谢的生理和分子基础提出了几种新的假设，以及使用饮食，运动和信号转导调节调节以减少和/或逆转庞贝病中肌肉缺陷的令人兴奋的潜力。在此提案中，我们将研究负责肌肉降解的机制以及溶酶体碱化对MTORC1激活和大噬菌的后果。然后，这些信息将用于设计特定的营养，运动，药物和激素信号调节剂，以恢复溶酶体功能并改善GAA缺乏症中发生的骨骼肌变性。