Treatment of Dystrophic mdx Mice with an ADAMTS-5 Specific Monoclonal Antibody Increases the Ex Vivo Strength of Isolated Fast Twitch Hindlimb Muscles

• Published in: Biomolecules (Basel, Switzerland) Switzerland), 2020-03, Vol.10 (3), p.416
• Main Authors: Addinsall, Alex B, Forgan, Leonard G, McRae, Natasha L, Kelly, Rhys W, McDonald, Penny L, McNeill, Bryony, McCulloch, Daniel R, Stupka, Nicole
• Format: Article
• Language: English
• Subjects: adamts-5; ADAMTS5 Protein - antagonists & inhibitors; ADAMTS5 Protein - metabolism; Animals; Antibodies, Monoclonal - pharmacology; contractile function; desmin; Disease Models, Animal; Duchenne muscular dystrophy; Extracellular matrix; Health aspects; Hindlimb - metabolism; Hindlimb - pathology; mdx mouse; Medicin och hälsovetenskap; Mice; Mice, Inbred mdx; Monoclonal antibodies; Muscle Fibers, Fast-Twitch - metabolism; Muscle Fibers, Fast-Twitch - pathology; Muscle Strength - drug effects; Muscular Dystrophy, Duchenne - metabolism; Muscular Dystrophy, Duchenne - pathology; myogenesis; Physiological aspects; skeletal muscle; versican; versikine
• ISSN: 2218-273X; 2218-273X
• DOI: 10.3390/biom10030416

Aberrant 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 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 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 mice. Nonetheless, ADAMTS-5 blockade improved ex vivo strength of isolated fast , but not slow , 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 makers 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.