title: Activation of JNK1 contributes to dystrophic muscle pathogenesis.
abstract: Duchenne Muscular Dystrophy (DMD) originates from deleterious mutations in the dystrophin gene, with a complete loss of the protein product. Subsequently, the disease is manifested in severe striated muscle wasting and death in early adulthood. Dystrophin provides a structural base for the assembly of an integral membrane protein complex. As such, dystrophin deficiency leads to an altered mechanical integrity of the myofiber and a predisposition to contraction-induced damage. However, the development of myofiber degeneration prior to an observed mechanical defect has been documented in various dystrophic models. Although activation of a detrimental signal transduction pathway has been suggested as a probable cause, a specific cellular cascade has yet to be defined. Here, it is shown that murine models of DMD displayed a muscle-specific activation of JNK1. Independent activation of JNK1 resulted in defects in myotube viability and integrity in vitro, similar to a dystrophic phenotype. In addition, direct muscle injection of an adenoviral construct containing the JNK1 inhibitory protein, JIP1, dramatically attenuated the progression of dystrophic myofiber destruction. Taken together, these results suggest that a JNK1-mediated signal cascade is a conserved feature of dystrophic muscle and contributes to the progression of the disease pathogenesis.
authors.affiliation: Department of Cellular and Molecular Medicine, Neuromuscular Research Group, Ottawa Health Research Institute and the University of Ottawa, Ottawa, Ontario, Canada.
authors.forename: S M
authors.initials: SM
authors.lastname: Kolodziejczyk
authors.forename: G S
authors.initials: GS
authors.lastname: Walsh
authors.forename: K
authors.initials: K
authors.lastname: Balazsi
authors.forename: P
authors.initials: P
authors.lastname: Seale
authors.forename: J
authors.initials: J
authors.lastname: Sandoz
authors.forename: A M
authors.initials: AM
authors.lastname: Hierlihy
authors.forename: M A
authors.initials: MA
authors.lastname: Rudnicki
authors.forename: J S
authors.initials: JS
authors.lastname: Chamberlain
authors.forename: F D
authors.initials: FD
authors.lastname: Miller
authors.forename: L A
authors.initials: LA
authors.lastname: Megeney
mesh_terms: D000256:Adenoviridae / Q000235:genetics; D000818:Animals; D002478:Cells, Cultured; D004789:Enzyme Activation; D049452:Green Fluorescent Proteins; D006801:Humans; D007202:Indicators and Reagents / Q000378:metabolism; D008164:Luminescent Proteins / Q000378:metabolism; D020935:MAP Kinase Signaling System; D051379:Mice; D018101:Mice, Inbred mdx; D008822:Mice, Transgenic; D019950:Mitogen-Activated Protein Kinase 1 / Q000378:metabolism; D048052:Mitogen-Activated Protein Kinase 3; D048055:Mitogen-Activated Protein Kinase 8; D020928:Mitogen-Activated Protein Kinases / Q000235:genetics / Q000378:metabolism*; D018482:Muscle, Skeletal / Q000201:enzymology / Q000378:metabolism / Q000473:pathology*; D009137:Muscular Dystrophy, Animal / Q000201:enzymology / Q000235:genetics / Q000473:pathology; D020388:Muscular Dystrophy, Duchenne / Q000201:enzymology* / Q000235:genetics / Q000473:pathology*; D009206:Myocardium / Q000201:enzymology / Q000378:metabolism / Q000473:pathology; D010766:Phosphorylation; D014162:Transfection
chemical_list: D007202:Indicators and Reagents; D008164:Luminescent Proteins; D049452:Green Fluorescent Proteins; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3; D048055:Mitogen-Activated Protein Kinase 8; D020928:Mitogen-Activated Protein Kinases