Dystrophin deficiency compromises force production of the extensor carpi ulnaris muscle in the canine model of Duchenne muscular dystrophy.

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. Unfortunately, equivalent assays have not been established in dystrophic dogs. To fill the gap, we developed a novel in situ protocol to measure force generated by the extensor carpi ulnaris (ECU) muscle of a dog. We also determined the muscle length to fiber length ratio and the pennation angle of the ECU muscle. Muscle pathology and contractility were compared between normal and affected dogs. Absence of dystrophin resulted in marked histological damage in the ECU muscle of affected dogs. Central nucleation was significantly increased and myofiber size distribution was altered in the dystrophic ECU muscle. Muscle weight and physiological cross sectional area (PCSA) showed a trend of reduction in affected dogs although the difference did not reach statistical significance. Force measurement revealed a significant decrease of absolute force, and the PCSA or muscle weight normalized specific forces. To further characterize the physiological defect in affected dog muscle, we conducted eccentric contraction. Dystrophin-null dogs showed a significantly greater force loss following eccentric contraction damage. 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 outcomes following innovative gene and/or cell therapies.