Splice modulation therapy has shown great clinical promise in Duchenne muscular dystrophy, resulting in the production of dystrophin protein. Despite this, the relationship between restoring dystrophin to established dystrophic muscle and its ability to induce clinically relevant changes in muscle function is poorly understood. In order to robustly evaluate functional improvement, this study used in situ protocols in the mdx mouse to measure muscle strength and resistance to eccentric contraction-induced damage. Here, the treatment of muscle was modelled with pre-existing dystrophic pathology using antisense oligonucleotides conjugated to a cell-penetrating peptide. This study reveals that 15 % homogeneous dystrophin expression is sufficient to protect against eccentric contraction-induced injury. In addition, a greater than 40% increase was demonstrated in specific isometric force following repeated administrations. Strikingly, it was shown that changes in muscle strength are proportional to dystrophin expression levels. These data define the dystrophin restoration levels required to slow down or prevent disease progression and improve overall muscle function once a dystrophic environment has been established in the mdx mouse model.
