title: P38α MAPK underlies muscular dystrophy and myofiber death through a Bax-dependent mechanism.
abstract: Muscular dystrophies are a group of genetic diseases that lead to muscle wasting and, in most cases, premature death. Cytokines and inflammatory factors are released during the disease process where they promote deleterious signaling events that directly participate in myofiber death. Here, we show that p38α, a kinase in the greater mitogen-activated protein kinase (MAPK)-signaling network, serves as a nodal regulator of disease signaling in dystrophic muscle. Deletion of Mapk14 (p38α-encoding gene) in the skeletal muscle of mdx- (lacking dystrophin) or sgcd- (δ-sarcoglycan-encoding gene) null mice resulted in a significant reduction in pathology up to 6 months of age. We also generated MAPK kinase 6 (MKK6) muscle-specific transgenic mice to model heightened p38α disease signaling that occurs in dystrophic muscle, which resulted in severe myofiber necrosis and many hallmarks of muscular dystrophy. Mechanistically, we show that p38α directly induces myofiber death through a mitochondrial-dependent pathway involving direct phosphorylation and activation of the pro-death Bcl-2 family member Bax. Indeed, muscle-specific deletion of Bax, but not the apoptosis regulatory gene Tp53 (encoding p53), significantly reduced dystrophic pathology in the muscles of MKK6 transgenic mice. Moreover, use of a p38 MAPK pharmacologic inhibitor reduced dystrophic disease in Sgcd(-/-) mice suggesting a future therapeutic approach to delay disease.
authors.affiliation: Department of Pediatrics, Cincinnati Children's Hospital Medical Center, University of Cincinnati, Cincinnati, 240 Albert Sabin Way, Cincinnati, OH 45229, USA.
authors.forename: Erin R
authors.initials: ER
authors.lastname: Wissing
authors.affiliation: Department of Pediatrics, Cincinnati Children's Hospital Medical Center, University of Cincinnati, Cincinnati, 240 Albert Sabin Way, Cincinnati, OH 45229, USA.
authors.forename: Justin G
authors.initials: JG
authors.lastname: Boyer
authors.affiliation: Department of Pediatrics, Cincinnati Children's Hospital Medical Center, University of Cincinnati, Cincinnati, 240 Albert Sabin Way, Cincinnati, OH 45229, USA.
authors.forename: Jennifer Q
authors.initials: JQ
authors.lastname: Kwong
authors.affiliation: Department of Pediatrics, Cincinnati Children's Hospital Medical Center, University of Cincinnati, Cincinnati, 240 Albert Sabin Way, Cincinnati, OH 45229, USA.
authors.forename: Michelle A
authors.initials: MA
authors.lastname: Sargent
authors.affiliation: Department of Pediatrics, Cincinnati Children's Hospital Medical Center, University of Cincinnati, Cincinnati, 240 Albert Sabin Way, Cincinnati, OH 45229, USA.
authors.forename: Jason
authors.initials: J
authors.lastname: Karch
authors.affiliation: Department of Medicine, Section of Cardiology, University of Chicago, 5841 S. Maryland, MC 6088, Chicago, IL 60637, USA.
authors.forename: Elizabeth M
authors.initials: EM
authors.lastname: McNally
authors.affiliation: Cardiovascular Division, King's College London, 125 Coldharbour Lane, London SE5 9NU, UK and.
authors.forename: Kinya
authors.initials: K
authors.lastname: Otsu
authors.affiliation: Department of Pediatrics, Cincinnati Children's Hospital Medical Center, University of Cincinnati, Cincinnati, 240 Albert Sabin Way, Cincinnati, OH 45229, USA, Howard Hughes Medical Institute, Cincinnati Children's Hospital Medical Center, Cincinnati, 240 Albert Sabin Way, Cincinnati, OH 45229, USA jeff.molkentin@cchmc.org.
authors.forename: Jeffery D
authors.initials: JD
authors.lastname: Molkentin
mesh_terms: D000818:Animals; D004195:Disease Models, Animal; D016189:Dystrophin / Q000235:genetics; D005786:Gene Expression Regulation; D006801:Humans; D051379:Mice; D018101:Mice, Inbred mdx; D008822:Mice, Transgenic; D008928:Mitochondria / Q000378:metabolism; D048308:Mitogen-Activated Protein Kinase 14 / Q000235:genetics* / Q000378:metabolism*; D018482:Muscle, Skeletal / Q000378:metabolism / Q000473:pathology*; D009136:Muscular Dystrophies / Q000378:metabolism / Q000473:pathology*; D049031:Sarcoglycans / Q000235:genetics; D015398:Signal Transduction; D051028:bcl-2-Associated X Protein / Q000235:genetics / Q000378:metabolism*
chemical_list: C494827:Bax protein, mouse; D016189:Dystrophin; D049031:Sarcoglycans; D051028:bcl-2-Associated X Protein; D048308:Mitogen-Activated Protein Kinase 14