Long-term delivery of FGF-6 changes the fiber type and fatigability of muscle reinnervated from embryonic neurons transplanted into adult rat peripheral nerve.
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.
Grumbles
Robert M
RM
The Miami Project to Cure Paralysis, Department of Neurological Surgery, University of Miami Miller School of Medicine, Miami, Florida 33136-2104, USA.
Casella
Gizelda T B
GT
Rudinsky
Michelle J
MJ
Wood
Patrick M
PM
Sesodia
Sanjay
S
Bent
Melissa
M
Thomas
Christine K
CK
D000818:Animals; D001284:Atrophy; D001369:Axons / Q000502:physiology; D002452:Cell Count; D002470:Cell Survival / Q000502:physiology; D017690:Cell Transplantation; D005260:Female; D051522:Fibroblast Growth Factor 6 / Q000494:pharmacology*; D007150:Immunohistochemistry; D009046:Motor Neurons / Q000502:physiology; D018763:Muscle Fatigue / Q000502:physiology*; D018485:Muscle Fibers, Skeletal / Q000187:drug effects*; D018657:Muscle Fibers, Slow-Twitch / Q000502:physiology; D018482:Muscle, Skeletal / Q000166:cytology / Q000196:embryology* / Q000294:innervation*; D009413:Nerve Fibers, Myelinated / Q000502:physiology; D009416:Nerve Regeneration / Q000502:physiology; D009469:Neuromuscular Junction / Q000502:physiology; D009474:Neurons / Q000637:transplantation*; D010525:Peripheral Nerves / Q000196:embryology* / Q000502:physiology*; D011518:Proto-Oncogene Proteins / Q000494:pharmacology*; D051381:Rats; D011916:Rats, Inbred F344
C486116:Fgf6 protein, rat; D051522:Fibroblast Growth Factor 6; D011518:Proto-Oncogene Proteins