Molecular basis for skeletal muscle pathophysiology in Pompe's disease

描述(申请人提供)：酸性α-葡萄糖苷酶(GAA)缺乏症(Pompe病)是一种常染色体隐性遗传性疾病，由GAA基因突变导致阻止或减少溶酶体内糖原的正常分解。主要的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，包括快速致命性婴儿障碍、青少年和晚发型成人肌病。婴儿形式表现为骨骼肌和心肌糖原积聚的低张力，并死于心肺衰竭。此外，经典的婴儿起病形式由于肝脏内糖原沉积增加而导致肝肿大。进展缓慢的成年患者会出现严重的骨骼肌无力，最终导致呼吸衰竭。糖酵解II型肌肉纤维(白色)在庞贝氏病中主要受影响，而氧化I型肌肉纤维(红色)相对较少。最近的研究观察到，庞贝小鼠的骨骼肌巨噬功能存在缺陷。巨噬是细胞器(即线粒体)、大分子(即糖原)和细胞质成分被包裹到自噬小体中的复杂过程，自噬小体与溶酶体融合，从而分解和释放单个分子成分。糖酵解II型肌肉纤维(白色肌肉)在庞贝氏病中主要受影响，并积累自噬空泡，而氧化I型肌肉纤维(红色)受影响较小。观察到GGA缺乏导致自噬空泡堆积，这表明巨噬细胞的启动正常发生，但在巨噬细胞的晚期事件中存在缺陷，即溶酶体融合。这为肌肉萎缩的机制、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Pompe病的肌肉缺陷提出了几个新的假说。在这项提案中，我们将研究肌肉退化的机制(S)，以及溶酶体碱化对mTORC 1激活和宏自噬的影响。这些信息将被用来设计特定的营养、运动、药理和激素信号调节，以恢复溶酶体功能，并改善因GAA缺乏而发生的骨骼肌退化。

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.