Longitudinal assessment of skeletal muscle functional mechanics in the DE50-MD dog model of Duchenne muscular dystrophy.

ABSTRACT

Duchenne muscular dystrophy (DMD), caused by mutations in the dystrophin (DMD) gene, is associated with fatal muscle degeneration and atrophy. Patients with DMD have progressive reductions in skeletal muscle strength and resistance to eccentric muscle stretch. Using the DE50-MD dog model of DMD, we assessed tibiotarsal joint (TTJ) flexor and extensor force dynamics, and the resistance of dystrophic muscle to eccentric stretch. Male DE50-MD and wild-type (WT) dogs were analysed every 3 months until 18 months of age. There was an age-associated decline in eccentric contraction resistance in DE50-MD TTJ flexors that discriminated, with high statistical power, WT from DE50-MD individuals. For isometric contraction, at the majority of timepoints, DE50-MD dogs had lower maximum absolute and relative TTJ flexor force, reduced TTJ muscle contraction times and prolonged relaxation compared to those in WT dogs. Cranial tibial muscles, the primary TTJ flexor, of 18-month-old DE50-MD dogs had significant numbers of regenerating fibres as expected, but also fewer type I fibres and more hybrid fibres than those in WT dogs. We conclude that these parameters, in particular, the eccentric contraction decrement, could be used as objective outcome measures for pre-clinical assessment in DE50-MD dogs.