Raben, N., Hill, V., Shea, L., Takikita, S., Baum, R., Mizushima, N. et al. Suppression of autophagy in skeletal muscle uncovers the accumulation of ubiquitinated proteins and their potential role in muscle damage in Pompe disease. Hum. Mol. Genet. 17, 3897-3908

Arthritis and Rheumatism Branch, National Institute of Arthritis and Musculoskeletal and Skin Diseases, National Institutes of Health, Bethesda, MD 20892-1820, USA.
Human Molecular Genetics (Impact Factor: 6.39). 10/2008; 17(24):3897-908. DOI: 10.1093/hmg/ddn292
Source: PubMed


The role of autophagy, a catabolic lysosome-dependent pathway, has recently been recognized in a variety of disorders, including Pompe disease, the genetic deficiency of the glycogen-degrading lysosomal enzyme acid-alpha glucosidase. Accumulation of lysosomal glycogen, presumably transported from the cytoplasm by the autophagic pathway, occurs in multiple tissues, but pathology is most severe in skeletal and cardiac muscle. Skeletal muscle pathology also involves massive autophagic buildup in the core of myofibers. To determine if glycogen reaches the lysosome via autophagy and to ascertain whether autophagic buildup in Pompe disease is a consequence of induction of autophagy and/or reduced turnover due to defective fusion with lysosomes, we generated muscle-specific autophagy-deficient Pompe mice. We have demonstrated that autophagy is not required for glycogen transport to lysosomes in skeletal muscle. We have also found that Pompe disease involves induction of autophagy but manifests as a functional deficiency of autophagy because of impaired autophagosomal-lysosomal fusion. As a result, autophagic substrates, including potentially toxic aggregate-prone ubiquitinated proteins, accumulate in Pompe myofibers and may cause profound muscle damage.

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    • "Inhibition/alteration of autophagy contributes to myofiber degeneration leading to accumulation of abnormal (dysfunctional) organelles and of unfolded and aggregation-prone proteins (Masiero et al., 2009; Sandri, 2010), which are typical features of several myopathies (Grumati et al., 2010; Nogalska et al., 2010). Generation of Atg5 and Atg7 muscle-specific knockout mice confirmed the physiological importance of the autophagy system in muscle mass maintenance (Raben et al., 2008; Masiero et al., 2009). The muscle-specific Atg7 knockout mice are characterized by the presence of abnormal mitochondria, oxidative stress, accumulation of polyubiquitinated proteins, and consequent sarcomere disorganization (Masiero et al., 2009). "
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    • "In general, the blocking of basal autophagy in muscle enhanced the accumulation of damaged and dysfunctional mitochondria, suggesting that mitophagy was impaired and critical to maintain muscle homeostasis (Masiero et al., 2009). Further, muscle-specific Atg5−/− mice displayed an atrophic phenotype in the fibers of the fast type, associated to accumulation of autophagic substrates, for instance, ubiquitinated proteins (Raben et al., 2008). In particular, in fast muscles of Atg5−/− mice, the size and density of lysosomes were increased and their distribution on the microtubules altered. "
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    • "The accumulation of Ub-proteins in the GAA-KO muscle, particularly in the non-soluble fraction, preceded the development of clinical symptoms and increased with age. In addition, immunostaining of isolated muscle fibers showed that both the Ub-proteins and p62/SQSTM1 were seen within the autophagic areas, again indicating that the recycling process is inefficient in Pompe skeletal muscle (Raben et al., 2008; Shea and Raben, 2009 "
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    ABSTRACT: Pompe disease is a lysosomal storage disorder in which acid alpha-glucosidase is deficient or absent. Deficiency of this lysosomal enzyme results in progressive expansion of glycogen-filled lysosomes in multiple tissues, with cardiac and skeletal muscle being the most severely affected. The clinical spectrum ranges from fatal hypertrophic cardiomyopathy and skeletal muscle myopathy in infants to relatively attenuated forms, which manifest as a progressive myopathy without cardiac involvement. The currently available enzyme replacement therapy proved to be successful in reversing cardiac but not skeletal muscle abnormalities. Although the overall understanding of the disease has progressed, the pathophysiology of muscle damage remains poorly understood. Lysosomal enlargement/rupture has long been considered a mechanism of relentless muscle damage in Pompe disease. In past years, it became clear that this simple view of the pathology is inadequate; the pathological cascade involves dysfunctional autophagy, a major lysosome-dependent intracellular degradative pathway. The autophagic process in Pompe skeletal muscle is affected at the termination stage - impaired autophagosomal-lysosomal fusion. Yet another abnormality in the diseased muscle is the accelerated production of large, unrelated to ageing, lipofuscin deposits - a marker of cellular oxidative damage and a sign of mitochondrial dysfunction. The massive autophagic buildup and lipofuscin inclusions appear to cause a greater effect on muscle architecture than the enlarged lysosomes outside the autophagic regions. Furthermore, the dysfunctional autophagy affects the trafficking of the replacement enzyme and interferes with its delivery to the lysosomes. Several new therapeutic approaches have been tested in Pompe mouse models: substrate reduction therapy, lysosomal exocytosis following the overexpression of transcription factor EB and a closely related but distinct factor E3, and genetic manipulation of autophagy.
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