title: When more is less: excess and deficiency of autophagy coexist in skeletal muscle 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, which results from a deficiency of the glycogen-degrading lysosomal hydrolase acid-alpha glucosidase (GAA). Skeletal and cardiac muscle are most severely affected by the progressive expansion of glycogen-filled lysosomes. In both humans and an animal model of the disease (GAA KO), skeletal muscle pathology also involves massive accumulation of autophagic vesicles and autophagic buildup in the core of myofibers, suggesting an induction of autophagy. Only when we suppressed autophagy in the skeletal muscle of the GAA KO mice did we realize that the excess of autophagy manifests as a functional deficiency. This failure of productive autophagy is responsible for the accumulation of potentially toxic aggregate-prone ubiquitinated proteins, which likely cause profound muscle damage in Pompe mice. Also, by generating muscle-specific autophagy-deficient wild-type mice, we were able to analyze the role of autophagy in healthy skeletal muscle.
authors.affiliation: Arthritis and Rheumatism Branch, NIAMS, NIH, Bethesda, MD 20892-1820, USA. rabenn@arb.niams.nih.gov
authors.forename: Nina
authors.initials: N
authors.lastname: Raben
authors.forename: Rebecca
authors.initials: R
authors.lastname: Baum
authors.forename: Cynthia
authors.initials: C
authors.lastname: Schreiner
authors.forename: Shoichi
authors.initials: S
authors.lastname: Takikita
authors.forename: Noboru
authors.initials: N
authors.lastname: Mizushima
authors.forename: Evelyn
authors.initials: E
authors.lastname: Ralston
authors.forename: Paul
authors.initials: P
authors.lastname: Plotz
mesh_terms: D000818:Animals; D001343:Autophagy; D006009:Glycogen Storage Disease Type II / Q000201:enzymology / Q000473:pathology*; D006801:Humans; D051379:Mice; D018345:Mice, Knockout; D018482:Muscle, Skeletal / Q000201:enzymology / Q000473:pathology* / Q000648:ultrastructure; D009928:Organ Specificity; D000520:alpha-Glucosidases / Q000172:deficiency / Q000378:metabolism
chemical_list: D000520:alpha-Glucosidases