A possible role for BDNF, NT-4 and TrkB in the spinal cord and muscle of rat subjected to mechanical overload, bupivacaine injection and axotomy

Neurotrophins play a crucial role in the regulation of survival and the mai ntenance of specific functions for various populations of neurons. Neurotro phin-4 (NT-4) is most abundant in skeletal muscle, and is thought to promot e sciatic nerve sprouting, inhibit agrin-induced acetylcholine receptor (AC hR) clustering, evoke postsynaptic potentiation and induce mitochondrial pr oliferation. Using Western blot analysis, immunoprecipitation and immunohis tochemistry, we investigated the distribution of NT-4 in slow- and fast-typ e muscles. We also tested the adaptive response of this protein in the mech anically overloaded muscle, in the regenerating muscle following bupivacain e injection and in the denervated muscle. Additionally, we investigated whe ther TrkB phosphorylation in the spinal cord and in the sciatic nerve occur s through the interaction with BDNF or NT-4 when the innervating muscle is damaged. Markedly more NT-4 was expressed in fast-type muscles compared wit h the slow types. TrkB protein was more frequently observed around the edge of myofibers (neuromuscular junction) of the soleus muscle compared with t he gastrocnemius muscle. TrkB tyrosine phosphorylation occurred in the spin al cord but not in the sciatic nerve 24 h after bupivacaine injection of th e innervating muscle. At the same time, the amount of TrkB co-precipitating with BDNF was markedly increased in the spinal cord. A rapid activation of TrkB (1-8 h)was also observed in the spinal cord after axotomy,while the a mount of TrkB co-precipitating with NT-4 was markedly lower after axotomy. These results indicate that NT-4 is preferentially distributed in fast-type muscles. Furthermore. by interacting with BDNF and NT-4, the TrkB in the s pinal cord may be important for the survival of motoneurons and outgrowth o f injured peripheral axons following muscle damage. (C) 2001 Elsevier Scien ce B.V. All rights reserved.