NT-3 Gene Therapy Improves Muscle Function in Old Mice

It is hypothesized that degeneration of neuromuscular junctions is an important contributing cause of the characteristic loss of muscle mass and strength that takes place with age, leading to sarcopenia. Researchers here use a gene therapy to upregulate expression of a gene involved in neuromuscular junction maintenance, and find that it improves muscle function in old mice. The paper includes a fairly detailed discussion of the biochemistry involved, and the researchers consider this an approach that works through similar mechanisms to those involved in the effects of exercise.

Sarcopenia is progressive loss of muscle mass and strength, occurring during normal aging with significant consequences on the quality of life for elderly. Neurotrophin 3 (NT-3) is an important autocrine factor supporting Schwann cell survival and differentiation and stimulating axon regeneration and myelination. NT-3 is involved in the maintenance of neuromuscular junction (NMJ) integrity, restoration of impaired radial growth of muscle fibers through activation of the Akt/mTOR pathway.

We tested the efficacy of NT-3 gene transfer therapy in wild type (WT)-aged C57BL/6 mice, a model for natural aging and sarcopenia. In this study, we used a triple muscle-specific creatine kinase (tMCK) promoter to restrict NT-3 expression to the skeletal muscle and self-complimentary adeno-associated virus serotype 1 (scAAV1) as vector. The treatment efficacy was assessed at 6 months post-injection using run to exhaustion and rotarod tests, in vivo muscle contractility assay, and histopathological studies of the peripheral nervous system, including NMJ connectivity and muscle.

NT-3 gene therapy in WT-aged C57BL/6 mice resulted in functional and in vivo muscle physiology improvements, supported by quantitative histology from muscle, peripheral nerves, and NMJ. Hindlimb and forelimb muscles in the untreated cohort showed the presence of a muscle- and sex-dependent remodeling and fiber size decrease with aging, which was normalized toward values obtained from 10 months old WT mice with treatment. Considering the cost and quality of life to the individual, we believe our study has important implications for management of age-related sarcopenia.

Link: https://doi.org/10.18632/aging.204577