Impaired muscular force production in a canine model of muscular dystrophin deficiency

Abstract

Loss of muscle force is a salient feature of Duchenne muscular dystrophy (DMD), a fatal disease caused by dystrophin deficiency. Assessment of force production from a single intact muscle has been considered as the gold standard for studying physiological consequences in murine models of DMD. A similar assay has not been established in dystrophic dogs. Therefore, we developed a novel in situ protocol to measure force generated by the extensor carpi ulnaris (ECU) muscle from Normal (n=4) and Affected dog (n=3). Absence of dystrophin resulted in marked histological damage in the ECU muscle. Peak tetanic force was significantly reduced in affected dogs (only 78% of Normal group, p<0.025). The ability to maintain the initial tension during continuous tetanic contractions was similar in both groups. Importantly, eccentric contractions by extending 5% of ECU muscle length while muscle was contracting, induced a much higher magnitude of force loss in the affected dogs (p<0.001). Our data showed that dystrophin‐deficient muscle is sensitive to damage by eccentric contraction. To our knowledge, this is the first convincing demonstration of force deficit in a single intact muscle in the canine DMD model. The method described here will be of great value to study physiological outcome following innovative gene and/or cell therapies.Supported by NIH AR‐49419, MDA, and Jesse's Journey‐the foundation for gene and cell therapy