Brain Research 987 (2003) 93–99 www.elsevier.com / locate / brainres Research report V oluntary exercise increases neurotrophin-3 and its receptor TrkC in the spinal cord a c a,c a,b,c, * ´ Zhe Ying , Roland R. Roy ,V. Reggie Edgerton , Fernando Gomez-Pinilla a Department of Physiological Science, UCLA, 621 Charles E. Young Dr., Los Angeles, CA 90095, USA b Division of Neurosurgery, UCLA Brain Injury Research Center, Los Angeles, CA 90095, USA c Brain Research Institute, UCLA, Los Angeles, CA 90095, USA Accepted 3 July 2003 Abstract We have evaluated changes in the expression of neurotrophin-3 (NT-3) and its tyrosine kinase C (TrkC) receptor in the neuromuscular system as a result of voluntary physical activity. We assessed changes in the mRNAs and proteins for NT-3 and TrkC in the lumbar spinal cord and associated soleus muscle following 3 and 7 days of voluntary wheel running. We used quantitative Taqman RT-PCR to measure mRNA and ELISA to assess protein levels. NT-3 mRNA and protein levels increased in the spinal cord to reach statistical significance after 7 days of exercise compared to sedentary control rats. Immunohistochemical analyses localized the elevated NT-3 to the substantia gelatinosa (SG) and nucleus of the dorsal horn. TrkC mRNA levels were significantly elevated in the spinal cord after 3 and 7 days of running. In the soleus muscle, NT-3 mRNA levels and its receptor TrkC were elevated after 3 days, while NT-3 protein levels remained unaffected. The results demonstrate that voluntary exercise has a differential effect on NT-3 as well as its receptor TrkC in the neural and muscular components of the neuromuscular system, and emphasize the role of voluntary activity on the spinal cord and muscle.  2003 Elsevier B.V. All rights reserved. Theme: Development and regeneration Topic: Neurotrophic factors: expression and regulation Keywords: Neuromuscular activity; Neurotrophin; Skeletal muscle; Spinal cord; NT-3; TrkC 1. Introduction likely that exercise orchestrates the action of different trophic factors [20] with resulting effects on neural plas- Physical activity is considered beneficial for overall ticity and regeneration. Therefore, it is critical to determine neural function. In particular, a large volume of evidence how exercise affects the expression of select neurotrophins has demonstrated the role of locomotor training in allevi- that have recognized roles on CNS plasticity. ating motor and sensory impairments in the injured spinal NT-3 plays a central role in mediating CNS plasticity cord [5]. The mechanisms by which activity translates into and regeneration in the spinal cord and muscle. The spinal structural and functional changes in the CNS, however, are cord expresses NT-3 and its trkC receptor [4,19,27]. NT-3 poorly understood. Recent studies showing that neuro- plays an important role in the survival and function of trophins are regulated in an activity-dependent fashion [23] sensory neurons, such that mice lacking the NT-3 gene indicate that select neurotrophins may play an important show a severe loss of sensory neurons and concomitant role in these exercise-induced effects on the CNS. For gait abnormalities [7,8,31]. Application of NT-3 into the example, an increasing body of evidence shows that spinal cord of rodents can compensate for induced damage neuromuscular activity induces brain-derived neurotrophic as shown by increased axonal regeneration, reduced atro- factor (BDNF) in the brain [20] and spinal cord [11]. It is phy, and increased functional recovery [2,12,21,24,29,30]. The action of NT-3 is also important for the regulation of synaptic transmission, such that NT-3 added to muscle *Corresponding author. Tel. / fax: 11-310-206-9693. ´ E-mail address: fgomezpi@ucla.edu (F. Gomez-Pinilla). culture potentiates synaptic transmission and promotes the 0006-8993 / 03 / $ – see front matter  2003 Elsevier B.V. All rights reserved. doi:10.1016 / S0006-8993(03)03258-X