Suppression of autophagy in skeletal muscle uncovers the accumulation of ubiquitinated proteins and their potential role in muscle damage in Pompe disease

Abstract

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.

Autophagy at the crossroads of catabolism and anabolism

“…A secondary phenotype of impaired GAA activity is defective autophagosome-lysosome fusion in the muscle fibres of patients with Pompe disease. This defect might interfere with the delivery of GAA into the lysosomal compartment, which has important implications for disease pathogenesis and the efficacy of recombinant enzymatic therapy in patients with Pompe disease [97][98][99] . Overall, despite the profound accumulation of glycogen-containing autophagic and lysosomal vesicles in skeletal myopathies, it remains uncertain whether impaired glycophagy functionally contributes to muscle dysfunction.…”

Heat shock response and autophagy—cooperation and control

“…33,34 Similarly, reduced autophagy in col6a ¡/ ¡ /collagen VI-deficient mice results in the accumulation of dysfunctional organelles and promotes apoptosis and muscle atrophy. 35 Mutant mice with normal levels of basal autophagy but deficient in exercise-or starvation-induced autophagy show lower endurance, impaired glucose metabolism, and inhibited glucose uptake by skeletal muscle after a single bout of exercise.…”

Chaperone-assisted degradation: multiple paths to destruction

“…It is tempting to speculate, e.g., that the progressive muscle weakness frequently observed among elderly people might be caused at least in part by an age-dependent decline in the activity of the proteostasis machinery. Furthermore, deregulated autophagy was shown to contribute to the pathology of Pompe disease and was recognized as a primary cause of Danon disease, centronuclear myopathy, and Xlinked myopathy with excessive autophagy (Nishino et al, 2000;Tanaka et al, 2000;Malicdan et al, 2008;Raben et al, 2008;Ramachandran et al, 2009;Vergne et al, 2009). The different diseases involve a progressively developing muscle weakness, which again illustrates the importance of autophagy for muscle maintenance.…”