PUBLICATION

NAD+ biosynthesis ameliorates a zebrafish model of muscular dystrophy

Authors
Goody, M.F., Kelly, M.W., Reynolds, C.J., Khalil, A., Crawford, B.D., and Henry, C.A.
ID
ZDB-PUB-121120-13
Date
2012
Source
PLoS Biology   10(10): e1001409 (Journal)
Registered Authors
Crawford, Bryan D., Henry, Clarissa A., Reynolds, Christine
Keywords
Embryos, Zebrafish, Integrins, Muscle fibers, Morphogenesis, Muscle regeneration, Muscle proteins, Muscle tissue
MeSH Terms
  • Paxillin/genetics
  • Paxillin/metabolism
  • Extracellular Matrix/metabolism
  • Dystrophin/metabolism
  • Zebrafish Proteins/genetics
  • Zebrafish Proteins/metabolism
  • Integrin alpha Chains/genetics
  • Integrin alpha Chains/metabolism
  • Animals
  • NAD/biosynthesis*
  • Disease Models, Animal
  • Antigens, CD/genetics
  • Antigens, CD/metabolism
  • Zebrafish/metabolism*
  • Laminin/metabolism
  • Cell Adhesion
  • Muscle, Skeletal/metabolism
  • Integrin alpha6/genetics
  • Integrin alpha6/metabolism
  • Muscular Dystrophies/genetics
  • Muscular Dystrophies/metabolism*
  • Dystroglycans/genetics
  • Dystroglycans/metabolism
(all 23)
PubMed
23109907 Full text @ PLoS Biol.
Abstract

Muscular dystrophies are common, currently incurable diseases. A subset of dystrophies result from genetic disruptions in complexes that attach muscle fibers to their surrounding extracellular matrix microenvironment. Cell-matrix adhesions are exquisite sensors of physiological conditions and mediate responses that allow cells to adapt to changing conditions. Thus, one approach towards finding targets for future therapeutic applications is to identify cell adhesion pathways that mediate these dynamic, adaptive responses in vivo. We find that nicotinamide riboside kinase 2b-mediated NAD+ biosynthesis, which functions as a small molecule agonist of muscle fiber-extracellular matrix adhesion, corrects dystrophic phenotypes in zebrafish lacking either a primary component of the dystrophin-glycoprotein complex or integrin alpha7. Exogenous NAD+ or a vitamin precursor to NAD+ reduces muscle fiber degeneration and results in significantly faster escape responses in dystrophic embryos. Overexpression of paxillin, a cell adhesion protein downstream of NAD+ in this novel cell adhesion pathway, reduces muscle degeneration in zebrafish with intact integrin receptors but does not improve motility. Activation of this pathway significantly increases organization of laminin, a major component of the extracellular matrix basement membrane. Our results indicate that the primary protective effects of NAD+ result from changes to the basement membrane, as a wild-type basement membrane is sufficient to increase resilience of dystrophic muscle fibers to damage. The surprising result that NAD+ supplementation ameliorates dystrophy in dystrophin-glycoprotein complex– or integrin alpha7–deficient zebrafish suggests the existence of an additional laminin receptor complex that anchors muscle fibers to the basement membrane. We find that integrin alpha6 participates in this pathway, but either integrin alpha7 or the dystrophin-glycoprotein complex is required in conjunction with integrin alpha6 to reduce muscle degeneration. Taken together, these results define a novel cell adhesion pathway that may have future therapeutic relevance for a broad spectrum of muscular dystrophies.

Genes / Markers
Figures
Figure Gallery (8 images)
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Expression
Phenotype
Mutations / Transgenics
Allele Construct Type Affected Genomic Region
mai1TgTransgenic Insertion
    wi390TgTransgenic Insertion
    1 - 2 of 2
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    Human Disease / Model
    1 - 1 of 1
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    Sequence Targeting Reagents
    Target Reagent Reagent Type
    dag1MO1-dag1MRPHLNO
    itga6aMO1-itga6aMRPHLNO
    itga6aMO2-itga6aMRPHLNO
    itga7MO2-itga7MRPHLNO
    tp53MO9-tp53MRPHLNO
    1 - 5 of 5
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    Fish
    Antibodies
    Name Type Antigen Genes Isotypes Host Organism
    Ab1-ptk2polyclonalIgGRabbit
    Ab1-pxnmonoclonalIgG1Mouse
    Ab3-lampolyclonal
      Rabbit
      1 - 3 of 3
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      Orthology
      No data available
      Engineered Foreign Genes
      Marker Marker Type Name
      EGFPEFGEGFP
      1 - 1 of 1
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      Mapping
      No data available