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Vector‐mediated expression of muscle specific kinase restores specific force to muscles in the mdx mouse model of Duchenne muscular dystrophy
Author(s) -
Ban Joanne,
Beqaj Besa,
Phillips William D.
Publication year - 2021
Publication title -
experimental physiology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.925
H-Index - 101
eISSN - 1469-445X
pISSN - 0958-0670
DOI - 10.1113/ep089439
Subject(s) - duchenne muscular dystrophy , mdx mouse , dystrophin , tibialis anterior muscle , muscular dystrophy , muscle hypertrophy , myocyte , utrophin , endocrinology , medicine , biology , muscle contraction , skeletal muscle , anatomy , chemistry , microbiology and biotechnology
New FindingsWhat is the central question of this study? The (dystrophin‐deficient) muscles of mdx mice generate less contractile force per cross‐sectional area (specific force) than those of healthy wild‐type mice: what is the influence of muscle specific kinase (MuSK) upon the properties of the tibialis anterior (TA) muscle in mdx mice?What is the main finding and its importance? Injection of adeno‐associated viral vector encoding MuSK into the TA muscle of young mdx mice increased the specific force of the muscle, suggesting the MuSK signalling system has the potential to restore healthy growth to dystrophin‐deficient muscles.Abstract In the mdx mouse model of Duchenne muscular dystrophy, muscle fibres are fragile and prone to injury and degeneration. Compared to wild‐type mice, muscles of mdx mice also develop less specific force (contractile force/cross‐sectional area). We recently reported that injecting adeno‐associated viral vector encoding muscle specific kinase (AAV‐MuSK) into muscles of mdx mice increased utrophin expression and made the muscles more resistant to acute stretch‐induced injury. Here we injected AAV‐MuSK unilaterally into the tibialis anterior muscle of mdx mice at a younger age (4 weeks), and recorded contraction force from the muscles in situ at 12 weeks of age. Compared to contralateral empty‐vector control muscles, muscles injected with AAV‐MuSK produced 28% greater specific force ( P = 0.0005). They did not undergo the compensatory hypertrophy that normally occurs in muscles of mdx mice. Injection of AAV encoding rapsyn (a downstream effector of MuSK signalling) caused no such improvement in muscle strength. Muscles injected with AAV‐MuSK displayed a 10% reduction in the number of fibres with centralized nuclei ( P = 0.0015). Our results in mdx mice suggest that elevating the expression of MuSK can reduce the incidence of muscle fibre regeneration and improve the strength of dystrophin‐deficient muscles.