DOK7 Gene Therapy Regrows Neuromuscular Junctions to Improve Aged Muscle Function
One of the numerous possible contributing causes to sarcopenia, the name given to the characteristic age-related decline in muscle mass and strength, is the dysfunction and loss of neuromuscular junctions. These structures link muscles and nerves, but how much of the lost strength of sarcopenia is due to this cause versus, say, declining muscle stem cell activity. The best way to assess the contribution of any given form of damage to any specific age-related condition is to repair that damage, and only that damage, and then observe the results. With that in mind, researchers here report on their implementation of a gene therapy approach to force the regrowth of neuromuscular junctions in aged mice. The treated mice exhibit increased strength in comparison to their untreated peers, which is a promising step towards an eventual therapy for humans.
Age-related decline in motor function has a major impact on quality of human life. The motor impairment involves age-related changes at least in the nerve and muscle systems, including a pathogenic loss of skeletal muscle mass and strength, known as sarcopenia. Accumulating evidence raises the possibility that the age-related decline in motor function is caused, at least in part, by functional impairment of the neuromuscular junction (NMJ), a cholinergic synapse essential for motoneural control of skeletal muscle contraction. Many studies with rodents have shown age-related denervation at NMJs in addition to degeneration of the presynaptic motor nerve terminals, where the neurotransmitter acetylcholine is released, and the postsynaptic endplate, where acetylcholine receptors (AChRs) densely cluster, suggesting an impaired neuromuscular transmission with aging.
In humans, electrophysiological and muscle fiber-type studies suggested age-related denervation at NMJs. Indeed, it is reported that the denervation rate at NMJs increases upon aging, although age-related morphological changes at NMJs remain controversial. Moreover, a recent study suggests that the increased rate of NMJ denervation contributes to the reduction in muscle strength in patients with sarcopenia, supporting the idea that the NMJ is a possible therapeutic target for treating age-related motor dysfunction.
We previously generated AAV-D7, a recombinant muscle-tropic adeno-associated virus (AAV) serotype 9 vector carrying the human DOK7 gene under the control of the cytomegalovirus promoter, and demonstrated that therapeutic administration of AAV-D7 - DOK7 gene therapy - enlarges NMJs and improves impaired motor activity in a mouse model of familial amyotrophic lateral sclerosis (ALS). Given that NMJ denervation appears to play a crucial role in age-related decline in motor function, DOK7 gene therapy might also ameliorate age-related motor impairment by suppressing denervation at NMJs. Thus, in the present study, we examined whether DOK7 gene therapy improves the motor function in aged mice.
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.