forgan-treatmentofdystrophic-2020.pdf (5.83 MB)
Treatment of dystrophic mdx mice with an adamts-5 specific monoclonal antibody increases the ex vivo strength of isolated fast twitch hindlimb muscles
journal contribution
posted on 2020-03-01, 00:00 authored by A B Addinsall, Len ForganLen Forgan, N L McRae, R W Kelly, P L McDonald, B McNeil, D R McCulloch, Nicole StupkaAberrant extracellular matrix synthesis and remodeling contributes to muscle degeneration and weakness in Duchenne muscular dystrophy (DMD). ADAMTS-5, a secreted metalloproteinase with catalytic activity against versican, is implicated in myogenesis and inflammation. Here, using the mdx mouse model of DMD, we report increased ADAMTS-5 expression in dystrophic hindlimb muscles, localized to regions of regeneration and inflammation. To investigate the pathophysiological significance of this, 4-week-old mdx mice were treated with an ADAMTS-5 monoclonal antibody (mAb) or IgG2c (IgG) isotype control for 3 weeks. ADAMTS-5 mAb treatment did not reduce versican processing, as protein levels of the cleaved versikine fragment did not differ between hindlimb muscles from ADAMTS-5 mAb or IgG treated mdx mice. Nonetheless, ADAMTS-5 blockade improved ex vivo strength of isolated fast extensor digitorum longus, but not slow soleus, muscles. The underpinning mechanism may include modulation of regenerative myogenesis, as ADAMTS-5 blockade reduced the number of recently repaired desmin positive myofibers without affecting the number of desmin positive muscle progenitor cells. Treatment with the ADAMTS-5 mAb did not significantly affect markers of muscle damage, inflammation, nor fiber size. Altogether, the positive effects of ADAMTS-5 blockade in dystrophic muscles are fiber-type-specific and independent of versican processing.
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Journal
BiomoleculesVolume
10Issue
3Article number
ARTN 416Publisher
MDPILocation
SwitzerlandPublisher DOI
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2218-273XeISSN
2218-273XLanguage
EnglishPublication classification
C1 Refereed article in a scholarly journalUsage metrics
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Science & TechnologyLife Sciences & BiomedicineBiochemistry & Molecular BiologyADAMTS-5contractile functiondesminDuchenne muscular dystrophymdx mousemyogenesisskeletal muscleversicanversikineMETALLOPROTEINASE DOMAINEXTRACELLULAR-MATRIXDISINTEGRIN-LIKESKELETAL-MUSCLEIN-VIVOEXPRESSIONCELLREGENERATIONTURNOVER
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