Deconstructing pompe disease by analyzing single muscle fibers: To see a world in a grain of sand...
Journal
Autophagy
Journal Volume
3
Journal Issue
6
Pages
546-552
Date Issued
2007
Author(s)
Raben N.
Takikita S.
Pittis M.G.
Bembi B.
Marie S.K.N.
Roberts A.
Page L.
Kishnani P.S.
Schoser B.G.H.
Ralston E.
Nagaraju K.
Plotz P.H.
Abstract
Autophagy is a major pathway for delivery of proteins and organelles to lysosomes where they are degraded and recycled. We have previously shown excessive autophagy in a mouse model of Pompe disease (glycogen storage disease type II), a devastating myopathy caused by a deficiency of the glycogen-degrading lysosomal enzyme acid α-glucosidase. The autophagic buildup constituted a major pathological component in skeletal muscle and interfered with delivery of the therapeutic enzyme. To assess the role of autophagy in the pathogenesis of the human disease, we have analyzed vesicles of the lysosomal-degradative pathway in isolated single muscle fibers from Pompe patients. Human myofibers showed abundant autophagosome formation and areas of autophagic buildup of a wide range of sizes. In patients, as in the mouse model, the enormous autophagic buildup causes greater skeletal muscle damage than the enlarged, glycogen-filled lysosomes outside the autophagic regions. Clearing or preventing autophagic buildup seems, therefore, a necessary target of Pompe disease therapy. ?2007 Landes Bioscience.
Subjects
Autophagosome; Glycogen storage; Lysosomal storage disorder; Lysosome; Metabolic disorder; Myopathy; Skeletal muscle
SDGs
Other Subjects
alpha glucosidase; animal experiment; animal model; article; autophagy; cell organelle; controlled study; glycogen storage disease type 2; glycogen storage disease type 3; lysosome; mouse; muscle cell; muscle injury; myopathy; nonhuman; pathogenesis; phagosome; protein degradation; skeletal muscle
Publisher
Taylor and Francis Inc.
Type
journal article