title: The role of autophagy in the pathogenesis of glycogen storage disease type II (GSDII).
abstract: Regulated removal of proteins and organelles by autophagy-lysosome system is critical for muscle homeostasis. Excessive activation of autophagy-dependent degradation contributes to muscle atrophy and cachexia. Conversely, inhibition of autophagy causes accumulation of protein aggregates and abnormal organelles, leading to myofiber degeneration and myopathy. Defects in lysosomal function result in severe muscle disorders such as Pompe (glycogen storage disease type II (GSDII)) disease, characterized by an accumulation of autophagosomes. However, whether autophagy is detrimental or not in muscle function of Pompe patients is unclear. We studied infantile and late-onset GSDII patients and correlated impairment of autophagy with muscle wasting. We also monitored autophagy in patients who received recombinant α-glucosidase. Our data show that infantile and late-onset patients have different levels of autophagic flux, accumulation of p62-positive protein aggregates and expression of atrophy-related genes. Although the infantile patients show impaired autophagic function, the late-onset patients display an interesting correlation among autophagy impairment, atrophy and disease progression. Moreover, reactivation of autophagy in vitro contributes to acid α-glucosidase maturation in both healthy and diseased myotubes. Together, our data suggest that autophagy protects myofibers from disease progression and atrophy in late-onset patients.
authors.affiliation: Department of Neurosciences, University of Padova, Biomedical Campus 'Pietro d'Abano', Italy.
authors.forename: A C
authors.initials: AC
authors.lastname: Nascimbeni
authors.forename: M
authors.initials: M
authors.lastname: Fanin
authors.forename: E
authors.initials: E
authors.lastname: Masiero
authors.forename: C
authors.initials: C
authors.lastname: Angelini
authors.forename: M
authors.initials: M
authors.lastname: Sandri
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000378:metabolism; D000328:Adult; D001343:Autophagy; D002648:Child; D056947:Enzyme Replacement Therapy; D005260:Female; D006009:Glycogen Storage Disease Type II / Q000188:drug therapy / Q000378:metabolism* / Q000473:pathology; D006801:Humans; D008297:Male; D008869:Microtubule-Associated Proteins / Q000378:metabolism; D011485:Protein Binding; D011994:Recombinant Proteins / Q000235:genetics / Q000378:metabolism / Q000627:therapeutic use; D000071456:Sequestosome-1 Protein; D000520:alpha-Glucosidases / Q000235:genetics / Q000378:metabolism / Q000627:therapeutic use
chemical_list: D048868:Adaptor Proteins, Signal Transducing; C477012:MAP1LC3A protein, human; D008869:Microtubule-Associated Proteins; D011994:Recombinant Proteins; C099718:SQSTM1 protein, human; D000071456:Sequestosome-1 Protein; D000520:alpha-Glucosidases