DOK7 Gene Therapy Enhances Neuromuscular Junction Innervation and Motor Function in Aged Mice

Muscle denervation at the neuromuscular junction (NMJ), the essential synapse between motor neuron and skeletal muscle, is associated with age-related motor impairment. Therefore, improving muscle innervation at aged NMJs may be an effective therapeutic strategy for treating the impairment. We previously demonstrated that the muscle protein Dok-7 plays an essential role in NMJ formation, and, indeed, its forced expression in muscle enlarges NMJs. Moreover, therapeutic administration of an adeno-associated virus vector encoding human Dok-7 (DOK7 gene therapy) suppressed muscle denervation and enhanced motor activity in a mouse model of amyotrophic lateral sclerosis (ALS). Here, we show that DOK7 gene therapy significantly enhances motor function and muscle strength together with NMJ innervation in aged mice. Furthermore, the treated mice showed greatly increased compound muscle action potential (CMAP) amplitudes compared with the controls, suggesting enhanced neuromuscular transmission. Thus, therapies aimed at enhancing NMJ innervation have potential for treating age-related motor impairment. [Display omitted] •DOK7 gene therapy enhances motor function and muscle strength in aged (≥2 years) mice•DOK7 gene therapy enhances neuromuscular junction (NMJ) innervation in aged mice•DOK7 gene therapy increases compound muscle action potential amplitudes in aged mice•Enhancing NMJ innervation in the elderly may strengthen muscles and motor activities Clinical Genetics; Molecular Mechanism of Gene Regulation; Musculoskeletal Medicine