(From the May 2018 issue of Research Now)
Tests on mouse models suggest potential to treat a host of muscle-wasting conditions
A gene known to repair damaged nerves also repairs damaged muscle, a team of investigators at Nationwide Children’s Hospital discovered.
The gene neurotrophin 3, or NT-3, increases muscle fiber diameter and induces remodeling of fiber types, the researchers found. The result is the size and composition of muscle fibers in a mouse model of diseased neurogenic muscle change to mirror the size and composition found in healthy wild-type mice.
The gene triggers the mTORC1 cell signaling pathway promoting muscle survival and growth, in vivo and in vitro experiments showed. Delivered to healthy muscle, NT-3 had no observable effect, indicating the gene is geared toward repair, the researchers say. They report their findings in Gene Therapy.
The findings suggest NT-3 has the potential to treat not only neuropathies to benefit nerves and muscles, the research team says, but also treat muscles in muscle-wasting conditions such as aging, cancer cachexia, certain types of muscle atrophy and genetic or acquired autoimmune primary muscle disorders.
Simply put, “When muscle fiber diameter increases, force generation improves,” says Zarife Sahenk, MD, PhD, a principal investigator in the Center for Gene Therapy in The Research Institute at Nationwide Children’s and leader of the research.
Dr. Sahenk’s lab has been studying NT-3 for more than a decade, and its recent gene therapy experiments treating mouse models of neuropathy showed the treatment improved nerve regeneration and myelination and increased muscle fiber diameter.
In this study, 16 weeks after delivering NT-3 to muscle via adeno-associated virus 1, the muscle diameter increases were greatest in fast-twitch glycolytic (FTC), also called the type IIb muscle fiber subtype, and now equaled the diameter in healthy mice. Prior to delivery, the mouse model had fewer FTC fibers, proportionally, than wild-type mice. But measurements taken at 16 weeks showed fiber remodeling had normalized the proportion.
The changes in muscle were accompanied by significant increases in the levels of phosphorylated 4E binding protein and S6 protein in the treated muscle compared to the untreated — evidence of mTORC1 activation, the researchers say.
Initially, the lab thought the muscle may be responding to reinnervation. Dr. Sahenk’s team tested the effect of NT-3 protein on muscle cultures without nerves. Through a series of experiments, they found direct evidence that NT-3 protein triggered protein synthesis by inducing the Akt/mTOR pathway in myotubes (a stage of muscle fiber development) and more evidence the gene was improving muscle and reversing the pathology.
Because of its versatility, Dr. Sahenk believes NT-3 therapy could be ideal for restoring damaged nerves and muscles in children who suffer chemotherapy-induced peripheral neuropathies, and a host of neural and muscle pathologies.
“These type II fibers are the first fibers to shrink due to inactivity,” she says. “NT-3 could potentially counter the effects of aging on muscle, or be used in paraplegia of hemiplegia.”
Citation: Yalvac ME, Amornvit J, Chen L, Shontz KM, Lewis S, Sahenk Z. AAV1.NT3 gene therapy increases muscle fiber diameter through activation of mTOR pathway and metabolic remodeling in a CMT mouse model. Gene Therapy. 2018 Mar 9. doi: 10.1038/s41434-018-0009-8. [Epub ahead of print]