Exercise activates the phosphatidylinositol 3-kinase pathway

Brain Res Mol Brain Res. 2005 Apr 27;135(1-2):181-93. doi: 10.1016/j.molbrainres.2004.12.001. Epub 2005 Jan 26.


Physical exercise is known to enhance psychological well-being and coping capacity. Voluntary physical exercise in rats also robustly and rapidly up-regulates hippocampal brain-derived neurotrophic factor (BDNF) mRNA levels, which are potentiated following a regimen of chronic antidepressant treatment. Increased BDNF levels are associated with enhanced activity of cyclic AMP response element binding protein (CREB). So far, relatively little is known about the intracellular signaling mechanisms mediating this effect of exercise. We wished to explore the possibility that exercise and/or antidepressant treatment activate the hippocampal phosphatidylinositol-3 (PI-3) kinase pathway, which mediates cellular survival. In young male Sprague-Dawley rats, we examined the effects of 2 weeks of daily voluntary wheel-running activity and/or tranylcypromine (n = 7 per group) on the levels of the active forms of protein-dependent kinase-1 (PDK-1), PI-3 kinase, phospho-thr308-Akt, phospho-ser473-Akt, and phospho-glycogen synthase kinase-3beta (GSK3beta; inactive form), as well as BDNF, activated CREB, and the phospho-Trk receptor, in the rat hippocampus, and compared these with sedentary saline-treated controls. Immunoblotting analyses revealed that in exercising rats, there was a significant increase in PI-3 kinase expression (4.61 times that of controls, P = 0.0161) and phosphorylation of PDK-1 (2.73 times that of controls, P = 0.0454), thr308-Akt (2.857 times that of controls, P = 0.0082), CREB (60.27 times that of controls, P = 0.05), and Trk (35.3 times that of controls, P < 0.0001) in the hippocampi of exercising animals; BDNF was also increased (3.2 times that of controls), but this was not statistically significant. In rats receiving both exercise and tranylcypromine, BDNF (4.51 times that of controls, P = 0.0068) and PI-3 kinase (4.88 times that of controls, P = 0.0103), and the phospho- forms of Trk (13.67 times that of controls, P = 0.0278), thr308-Akt (3.644 times that of controls, P = 0.0004), GSK-3beta (2.93 times that of controls, P = 0.026), and CREB (88.97 times that of controls, P = 0.0053) were significantly increased. These results suggest that the exercise-induced expression of BDNF is associated with the increased expression of several key intermediates of the PI-3 kinase/Akt pathway, which is known for its role in enhancing neuronal survival.

Publication types

  • Comparative Study
  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Analysis of Variance
  • Animals
  • Antidepressive Agents / pharmacology
  • Behavior, Animal
  • Blotting, Western / methods
  • Brain-Derived Neurotrophic Factor / metabolism
  • Cyclic AMP Response Element-Binding Protein / metabolism
  • DNA-Binding Proteins / metabolism
  • Enzyme Activation / drug effects
  • Enzyme Activation / physiology
  • Forkhead Transcription Factors
  • Hippocampus / drug effects
  • Hippocampus / enzymology*
  • Male
  • Models, Biological
  • Nerve Tissue Proteins / metabolism
  • Oligopeptides / metabolism
  • Phosphatidylinositol 3-Kinases / metabolism*
  • Phosphorylation
  • Physical Conditioning, Animal / physiology*
  • Protein Serine-Threonine Kinases
  • Proto-Oncogene Proteins
  • Proto-Oncogene Proteins c-akt
  • Rats
  • Rats, Sprague-Dawley
  • Receptor, trkA / metabolism
  • Signal Transduction / drug effects
  • Signal Transduction / physiology*
  • Tranylcypromine / pharmacology


  • Antidepressive Agents
  • Brain-Derived Neurotrophic Factor
  • Cyclic AMP Response Element-Binding Protein
  • DNA-Binding Proteins
  • Forkhead Transcription Factors
  • Nerve Tissue Proteins
  • Oligopeptides
  • Proto-Oncogene Proteins
  • Foxo1 protein, rat
  • Tranylcypromine
  • GSK peptide
  • Receptor, trkA
  • Akt1 protein, rat
  • Protein Serine-Threonine Kinases
  • Proto-Oncogene Proteins c-akt