title: Conditional knockout of pik3c3 causes a murine muscular dystrophy.
abstract: Abnormalities in phosphoinositide metabolism are an emerging theme in human neurodegenerative disease. Myotubular myopathy is a prototypical disorder of phosphoinositide dysregulation that is characterized by profound muscle pathology and weakness and that is caused by mutations in MTM1, which encodes a phosphatase that targets 3-position phosphoinositides, including phosphatidylinositol 3-phosphate. Although the association between MTM1 and muscle disease has become increasingly clarified, the normal role(s) of phosphatidylinositol 3-phosphate metabolism in muscle development and homeostasis remain poorly understood. To begin to address the function of phosphatidylinositol 3-phosphate in skeletal muscle, we focused on the primary kinase responsible for its production, and created a muscle-specific conditional knockout of the class III phosphatidylinositol 3-kinase, Pik3c3. Muscle-specific deletion of Pik3c3 did not disturb embryogenesis or early postnatal development, but resulted in progressive disease characterized by reduced activity and death by 2 months of age. Histopathological analysis demonstrated changes consistent with a murine muscular dystrophy. Examination for cellular mechanism(s) responsible for the dystrophic phenotype revealed significant alterations in the autophagolysosomal pathway with mislocation of known dystrophy proteins to the lysosomal compartment. In all, we present the first analysis of Pik3c3 in skeletal muscle, and report a novel association between deletion of Pik3c3 and muscular dystrophy.
authors.affiliation: Department of Pediatrics, University of Michigan Medical Center, Ann Arbor, Michigan; Neuroscience Graduate Program, University of Michigan Medical Center, Ann Arbor, Michigan.
authors.forename: Aaron
authors.initials: A
authors.lastname: Reifler
authors.affiliation: Department of Pediatrics, University of Michigan Medical Center, Ann Arbor, Michigan.
authors.forename: Xingli
authors.initials: X
authors.lastname: Li
authors.affiliation: Department of Molecular and Integrative Physiology, University of Michigan Medical Center, Ann Arbor, Michigan.
authors.forename: Ashley J
authors.initials: AJ
authors.lastname: Archambeau
authors.affiliation: Department of Molecular and Integrative Physiology, University of Michigan Medical Center, Ann Arbor, Michigan.
authors.forename: Joel R
authors.initials: JR
authors.lastname: McDade
authors.affiliation: Department of Neurology and Program of Genetics and Genome Biology, Hospital for Sick Children, Toronto, Ontario, Canada.
authors.forename: Nesrin
authors.initials: N
authors.lastname: Sabha
authors.affiliation: Department of Molecular and Integrative Physiology, University of Michigan Medical Center, Ann Arbor, Michigan.
authors.forename: Daniel E
authors.initials: DE
authors.lastname: Michele
authors.affiliation: Department of Pediatrics, University of Michigan Medical Center, Ann Arbor, Michigan; Department of Neurology and Program of Genetics and Genome Biology, Hospital for Sick Children, Toronto, Ontario, Canada; Departments of Paediatrics and Molecular Genetics, University of Toronto, Toronto, Ontario, Canada. Electronic address: james.dowling@sickkids.ca.
authors.forename: James J
authors.initials: JJ
authors.lastname: Dowling
mesh_terms: D000818:Animals; D001343:Autophagy; D058546:Class III Phosphatidylinositol 3-Kinases / Q000235:genetics / Q000378:metabolism*; D008247:Lysosomes / Q000378:metabolism / Q000473:pathology; D051379:Mice; D018345:Mice, Knockout; D009124:Muscle Proteins / Q000235:genetics / Q000378:metabolism*; D018482:Muscle, Skeletal / Q000201:enzymology* / Q000473:pathology; D009137:Muscular Dystrophy, Animal / Q000201:enzymology* / Q000235:genetics / Q000473:pathology; D018129:Phosphatidylinositol Phosphates / Q000235:genetics / Q000378:metabolism*
chemical_list: D009124:Muscle Proteins; D018129:Phosphatidylinositol Phosphates; D058546:Class III Phosphatidylinositol 3-Kinases
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