Aging
Navigate
Submit an Article
Research Paper|Volume 15, Issue 5|pp 1306—1329

AAV1.NT-3 gene therapy prevents age-related sarcopenia

Burcak Ozes1, Lingying Tong1, Morgan Myers1, Kyle Moss1, Alicia Ridgley1, Zarife Sahenk1,2,3
  • 1Center for Gene Therapy, The Abigail Wexner Research Institute, Nationwide Children’s Hospital, Columbus, OH 43205, USA
  • 2Department of Pediatrics and Neurology, Nationwide Children’s Hospital and The Ohio State University, Columbus, OH 43205, USA
  • 3Department of Pathology and Laboratory Medicine, Nationwide Children’s Hospital, Columbus, OH 43205, USA
Received: October 22, 2022Accepted: March 2, 2023Published: March 9, 2023
https://doi.org/10.18632/aging.204577

Copyright: © 2023 Ozes et al. This is an open access article distributed under the terms of the Creative Commons Attribution License (CC BY 3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

Abstract

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, via intramuscular injection 1 × 1011 vg AAV1.tMCK.NT-3, at 18 months of age. 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. AAV1.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. The molecular studies assessing the NT-3 effect on the oxidative state of distal hindlimb muscles, accompanied by western blot analyses for mTORC1 activation were in accordance with the histological findings. Considering the cost and quality of life to the individual, we believe our study has important implications for management of age-related sarcopenia.