Pompe disease is accompanied by the deficiency of the lysoso

Pompe disease is accompanied by the deficiency of the lysosomal α-1,4-glucosidase that makes the GSK343 unable to hydrolyze glycogen to glucose, thereby resulting in the accumulation of glycogen in lysosomes, especially in skeletal muscles and cardiac tissues. This accumulation results in the structural disorganization of the cells, cellular dysfunction, and an impaired autophagy. The impairment of autophagy is a consequence of enlarged glycogen-filled lysosomes and their inability to fuse with the autophagosome, thereby causing an accumulation of autophagic debris. This becomes one of the major hindrances in the enzyme replacement therapy (ERT) [71]. A recent experiment on α-glucosidase knockout (GAA KO) mice model with Atg7 deficient established successful ERT to clear the lysosomal glycogen in expanding muscle fibers [72]. Yet in another interesting experiment where autophagic debris was avoided through the transfection of shRNA-TSC2 in GAA KO mice, the mTOR activity was activated, thereby providing a successful outcome for ERT [73]. Gaucher disease is caused due to a mutation in GBA1 gene and is associated with defective glucocerebrosidase, an enzyme involved in the degradation of glucosylceramide and glucosylsphingosine [74]. Therefore, it results in the toxic accumulation of glycolipids in the neuronal cells. The autophagy-lysosome pathway, responsible for the clearance of aggregated materials, is defective in GBA1-mutant cells. In an experiment, GBA1-mutant neuronal stem cells showed a decrease in transcription factor EB (TFEB), leading to a decrease in the number of lysosomes and promoting autophagic block. Additionally, TFEB is regulated by mTORC1 at the surface of lysosomes. It has been witnessed that the activity of mTORC1 is elevated in GBA1 mutants, thus regulating TFEB and hence deteriorating the autophagic flux [75].
Muscular disorders and heart disease: fatigue: the autophagic hesitation The role of autophagy in maintaining muscle homeostasis has recently been studied. Autophagy, with its vast array of functions, plays an interesting and dual role in protecting and damaging the myofibrils. Similar to neuronal cells, muscle cells are also non-proliferative that causes excess accumulation of damaged materials within them. Therefore, an increase in the levels of autophagic vesicles serves as the diagnostic marker in any muscular atrophy. Autophagy-related genes that are up-regulated/down-regulated in different muscular disorders belong to the class of “atrogenes” or atrophy-related genes [76]. The protective role of autophagy has been validated in many publications. The muscle protein, myotubularin, regulates the concentration of phosphatidylinositol that is required for vesicular trafficking during autophagy. Myopathy is manifested by a defect in the muscle protein demonstrating the dysregulation of autophagy [77]. In an experiment where lysosomal membrane protein (LAMP2) was knocked out during myopathy showed an impairment in autophagy. Despite the accumulation of autophagic vacuoles in liver and heart cells, the protein degradation was not achieved owing to the reduced fusion of autophagosomes with lysosomes [78]. The administration of autophagic drugs further validates the role of autophagy in muscular disorders. For instance, chloroquine, a lysosomotropic agent, resulted in the induction of myopathy in cultured cells. Chloroquine is responsible for the elevation of lysosomal pH that disrupts the fusion of autophagosome with the lysosome and consequently reduced protein degradation [79]. Conversely, it has been demonstrated that chloroquine treatment results in the increase in expression of Atg5-Atg12 and Beclin1 protein of rat pulmonary artery smooth muscle cells [80]. Hence, the accumulation of autophagic vacuoles in myopathy may be due to reduced autophagy. In accordance with the context, a decline in ULK1 in skeletal muscles during fasting has been shown to accumulate LC3-I causing muscle atrophy, suggesting impairment in the conversion of LC3-I–LC3-II, which is indispensable for the autophagic process. Whereas knockdown of Ulk-2 did not cause any change in LC3, it resulted in the accumulation of p62 protein [81].