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 a-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 lateonset patients display an interesting correlation among autophagy impairment, atrophy and disease progression. Moreover, reactivation of autophagy in vitro contributes to acid a-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.

Autophagy in Natural History and After ERT in Glycogenosis Type II

“…In infantile Pompe patients, the enormous build-up of glycogen-filled lysosomes appears to cause the muscle damage (Raben et al 2007). Recent studies showed that autophagy impairment contributes to both disease progression and fibre atrophy (Nascimbeni et al 2012). A residually functional autophagic flux is important for an efficient ERT delivery in muscle lysosomes, since mature GAA forms were found in our ERT-responsive juvenile case.…”

“…1). This patient had no detectable GAA mature forms and instead elevated levels of the inactive 110 kDa precursor (Nascimbeni et al 2012). ERT induced the appearance of mature 76 kDa GAA even if at very low level.…”

“…An important pathological feature is failure of autophagosomal turnover and massive autophagic build-up in fibres. This contributes to myofiber atrophy that increases during natural history in late-onset GSDII (Nascimbeni et al 2012).…”

“…We studied muscle autophagy markers and atrophy at different times of the disease progression. For immunohistochemical analysis, muscle sections were incubated with primary antibodies against caveolin-3, p62, LC3, according to methods previously reported (Nascimbeni et al 2008(Nascimbeni et al , 2012. The percentage of vacuolated fibres and p62-positive fibres was defined as those presenting either diffuse or scattered intracytoplasmic vacuoles or staining, respectively.…”

Vacuolar Myopathies: Ultrastructural Studies Benefit Diagnosis

“…Following a discussion of etiologic and diagnostic information on each entity, the original case study is returned to and concluded based on the findings. The selected entities covered from the differential diagnosis are summarized below:Glycogen Storage Disease Type II (Pompe Disease) This disease is caused by a mutation in the GAA gene which encodes the acid α-glucosidase (formerly known as acid maltase) enzyme necessary for breaking down glycogen into glucose, within lysosomes, for cellular recycling [1]. A decrease in functional acid α-glucosidase results in a build-up of lysosome-bound glycogen within various cell types in the body, including cardiac and skeletal muscle, and leads to cellular dysfunction.…”