Extensor carpi ulnaris muscle shows unexpected slow-to-fast fiber type switch in Duchenne muscular dystrophy dogs

Aged dystrophin-null canines are excellent models to study experimental therapies for Duchenne muscular dystrophy (DMD), a lethal muscle disease caused by dystrophin deficiency. To establish the baseline, we studied the extensor carpi ulnaris (ECU) muscle in 15 terminal age (3-year-old) male affected and 15 age/sex-matched normal dogs. Affected dogs showed histological and anatomical hallmarks of dystrophy, including muscle inflammation and fibrosis, myofiber size variation, centralized myonuclei, and a significant reduction of the muscle weight, muscle-to-body weight ratio, and muscle cross-sectional area. To rigorously characterize the contractile properties of the ECU muscle, we developed a novel in situ assay. Twitch and tetanic force, contraction and relaxation rate, and resistance to eccentric contraction-induced force loss were significantly decreased in affected dogs. Intriguingly, the time-to-peak tension and half-relaxation time were significantly shortened in affected dogs. Contractile kinetics predicted an unforeseen slow-to-fast myofiber type switch which we confirmed at the protein and transcript level. Our study established a foundation to study long-term and late-stage therapeutic interventions in dystrophic canines. The unexpected myofiber type switch highlights the complexity of muscle remodeling in dystrophic large mammals.