Molecular basis for skeletal muscle pathophysiology in Pompe's disease

描述（由申请方提供）：酸性α-葡糖苷酶（GAA）缺乏症（庞贝氏病）是一种常染色体隐性遗传疾病，由GAA基因突变导致，阻止或减少溶酶体中糖原的正常分解。原发性缺陷发生在心肌和骨骼肌中，并且取决于残留GAA酶活性的程度，导致一系列表型，包括快速致死性婴儿疾病、青少年和迟发性成人肌病。婴儿型表现为肌张力减退，骨骼肌和心肌中糖原蓄积，并因心肺衰竭而死亡。此外，由于肝内糖原沉积增加，经典的肝肿大型会导致肝肿大。患有缓慢进展型的成年个体发展为严重的骨骼肌无力，最终呼吸衰竭。糖酵解II型肌纤维（白色）主要受庞贝氏病影响，而氧化I型肌纤维（红色）相对较少。最近的研究已经观察到庞贝氏症小鼠显示有缺陷的骨骼肌巨自噬。大自噬是一个复杂的过程，其中细胞器（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累自噬空泡，而氧化I型肌纤维（红色）受影响要小得多。GGA缺乏导致自噬空泡积累的观察结果表明，大自噬启动正常发生，但在晚期巨噬细胞事件中存在缺陷，即：溶酶体融合。这提出了几个新的假设，肌肉萎缩的机制，溶酶体糖原代谢的生理和分子基础，以及令人兴奋的潜力，使用饮食，运动和信号转导调节，以减少和/或逆转庞贝氏症的肌肉缺陷。在本提案中，我们将研究负责肌肉降解的机制以及溶酶体碱化对mTORC 1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缺乏症中发生的骨骼肌变性。

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.