Long‐term delivery of FGF‐6 changes the fiber type and fatigability of muscle reinnervated from embryonic neurons transplanted into adult rat peripheral nerve

Abstract

Motoneuron death leads to muscle denervation and atrophy. Transplantation of embryonic neurons into peripheral nerves results in reinnervation and provides a strategy to rescue muscles from atrophy independent of neuron replacement in a damaged or diseased spinal cord. But the count of regenerating axons always exceeds the number of motor units in this model, so target-derived trophic factor levels may limit reinnervation. Our aim was to examine whether long-term infusion of fibroblast growth factor-6 (FGF-6) into denervated medial gastrocnemius muscles improved the function of muscles reinnervated from neurons transplanted into nerve of adult Fischer rats. Factor delivery (10 microg, 4 weeks) began after sciatic nerve transection. After a week of nerve degeneration, 1 million embryonic day 14-15 ventral spinal cord cells were transplanted into the distal tibial stump as a neuron source. Ten weeks later, neurons that expressed motoneuron markers survived in the nerves. More myelinated axons were in nerves to saline-treated muscles than in FGF-6-treated muscles. However, each group showed comparable reductions in muscle fiber atrophy because of reinnervation. Mean reinnervated fiber area was 43%-51% of non-denervated fibers. Denervated fiber area averaged 11%. FGF-6-treated muscles were more fatigable than other reinnervated muscles but had stronger motor units and fewer type I fibers than did saline-treated muscles. FGF-6 thus influenced function by changing the type of fiber reinnervated by transplanted neurons. Deficits in FGF-6 may also contribute to the increase in type I fibers in muscles reinnervated from peripheral axons, suggesting that the effects of FGF-6 on fiber type are independent of the neuron source used for reinnervation.

Transplanted Mouse Embryonic Stem-Cell-Derived Motoneurons Form Functional Motor Units and Reduce Muscle Atrophy

“…Animals implanted with ES-cell-derived MNs demonstrated significant attenuation of muscle atrophy when compared with surgical control muscles after 3 months of denervation. A similar reduction in whole muscle atrophy has been reported after transplantation of embryonic MNs into the rat tibial nerve (Thomas et al, 2000(Thomas et al, , 2003Grumbles et al, 2005Grumbles et al, , 2007.…”

Transplantation of Embryonic Spinal Cord Derived Cells Helps to Prevent Muscle Atrophy after Peripheral Nerve Injury

“…In order to avoid the differentiation concerns, we decided to also use fetal spinal cord cells directly as they have already differentiated into neurons at the isolation time. These few studies that have used fetal spinal cord cells have shown the cells to be able to both assist with the axonal regeneration and with preventing the muscle atrophy [46,50,51,52,53,54,55,56]. Our aim was to compare this kind of fetal cells with pure NPCs for their ability to survive in injured nerve and their ability to reinnervate the muscle and reduce the muscle atrophy.…”