Treadmill exercise reduces spinal cord injury‑induced apoptosis by activating the PI3K/Akt pathway in rats

Jung,Sun‑Young; Kim,Dae‑Young; Yune,Tae Young; Shin,Dong‑Hoon; Baek,Sang‑Bin; Kim,Chang‑Ju

doi:10.3892/etm.2013.1451

Treadmill exercise reduces spinal cord injury‑induced apoptosis by activating the PI3K/Akt pathway in rats

Authors:
- Sun‑Young Jung
- Dae‑Young Kim
- Tae Young Yune
- Dong‑Hoon Shin
- Sang‑Bin Baek
- Chang‑Ju Kim
View Affiliations

Affiliations: Department of Physiology, College of Medicine, Kyung Hee University, Seoul 136‑701, Republic of Korea, Department of Biochemistry and Molecular Biology, Age‑Related and Brain Diseases Research Centre, College of Medicine, Kyung Hee University, Seoul 136‑701, Republic of Korea, Department of Food and Biotechnology, Graduate School of Life Sciences and Biotechnology, Korea University, Seoul 136‑701, Republic of Korea, Department of Psychiatry, Gangneung Asan Hospital, Ulsan University, Gangneung 210‑711, Republic of Korea
Published online on: December 17, 2013 https://doi.org/10.3892/etm.2013.1451
Pages: 587-593

Metrics: Total Views: 0 (Spandidos Publications: | PMC Statistics: )

Metrics: Total PDF Downloads: 0 (Spandidos Publications: | PMC Statistics: )

Cited By (CrossRef): 0 citations Loading Articles...

Abstract

Apoptosis occurring secondary to spinal cord injury (SCI) causes further neural damage and functional loss. In this study, a rat model was used to investigate the effect of treadmill exercise on SCI‑induced apoptosis and expression of neurotrophic factors. To produce SCI, a contusion injury (10 g x 25 mm) was applied subsequent to laminectomy at the T9‑T10 level. Following SCI, treadmill exercise was performed for six weeks. Hindlimb motor function was evaluated with a grid‑walking test. The expression of neurotrophic factors and the level of apoptosis at the site of SCI were determined by western blotting. SCI reduced hindlimb motor function and suppressed expression of neurotrophin (NT)‑3 and insulin‑like growth factor (IGF)‑1. Expression of phosphatidylinositol 3‑kinase (PI3K), the ratio of phosphorylated Akt to Akt (pAkt/Akt) and the ratio of B-cell lymphoma 2 (Bcl‑2) to Bax (Bcl‑2/Bax) were decreased, and cleaved caspase‑3 expression was increased by SCI. Treadmill exercise enhanced hindlimb motor function and increased expression of nerve growth factor (NGF), NT‑3 and IGF‑1 in the SCI rats. Treadmill exercise increased PI3K expression, the pAkt/Akt and the Bcl‑2/Bax ratios, and suppressed cleaved caspase‑3 expression in the injured spinal cord. This study demonstrated that treadmill exercise promotes the recovery of motor function by suppressing apoptosis in the injured spinal cord. The beneficial effect of exercise may be attributed to the increase in expression of neurotrophic factors via activation of the PI3K/Akt pathway.

View Figures

View References

1	Tator CH and Fehlings MG: Review of the secondary injury theory of acute spinal cord trauma with emphasis on vascular mechanisms. J Neurosurg. 75:15–26. 1991. View Article : Google Scholar : PubMed/NCBI
2	Hwang L, Choi IY, Kim SE, Ko IG, Shin MS, Kim CJ, Kim SH, Jin JJ, Chung JY and Yi JW: Dexmedetomidine ameliorates intracerebral hemorrhage-induced memory impairment by inhibiting apoptosis and enhancing brain-derived neurotrophic factor expression in the rat hippocampus. Int J Mol Med. 31:1047–1056. 2013.
3	Kim DH, Ko IG, Kim BK, Kim TW, Kim SE, Shin MS, Kim CJ, Kim H, Kim KM and Baek SS: Treadmill exercise inhibits traumatic brain injury-induced hippocampal apoptosis. Physiol Behav. 101:660–665. 2010. View Article : Google Scholar : PubMed/NCBI
4	Savitz SI and Rosenbaum DM: Apoptosis in neurological disease. Neurosurgery. 42:555–574. 1998. View Article : Google Scholar
5	Sung YH, Kim SC, Hong HP, Park CY, Shin MS, Kim CJ, Seo JH, Kim DY, Kim DJ and Cho HJ: Treadmill exercise ameliorates dopaminergic neuronal loss through suppressing microglial activation in Parkinson’s disease mice. Life Sci. 91:1309–1316. 2012.PubMed/NCBI
6	Crowe MJ, Bresnahan JC, Shuman SL, Masters JN and Beattie MS: Apoptosis and delayed degeneration after spinal cord injury in rats and monkeys. Nat Med. 3:73–76. 1997. View Article : Google Scholar : PubMed/NCBI
7	Li GL, Brodin G, Farooque M, Funa K, Holtz A, Wang WL and Olsson Y: Apoptosis and expression of Bcl-2 after compression trauma to rat spinal cord. J Neuropathol Exp Neurol. 55:280–289. 1996. View Article : Google Scholar : PubMed/NCBI
8	Yong C, Arnold PM, Zoubine MN, Citron BA, Watanabe I, Berman NE and Festoff BW: Apoptosis in cellular compartments of rat spinal cord after severe contusion injury. J Neurotrauma. 15:459–472. 1998. View Article : Google Scholar : PubMed/NCBI
9	Emery E, Aldana P, Bunge MB, Puckett W, Srinivasan A, Keane RW, Bethea J and Levi AD: Apoptosis after traumatic human spinal cord injury. J Neurosurg. 89:911–920. 1998. View Article : Google Scholar : PubMed/NCBI
10	Youle RJ and Strasser A: The BCL-2 protein family: opposing activities that mediate cell death. Nat Rev Mol Cell Biol. 9:47–59. 2008. View Article : Google Scholar : PubMed/NCBI
11	Nathoo N, Narotam PK, Agrawal DK, Connolly CA, van Dellen JR, Barnett GH and Chetty R: Influence of apoptosis on neurological outcome following traumatic cerebral contusion. J Neurosurg. 101:233–240. 2004. View Article : Google Scholar : PubMed/NCBI
12	Tsuchiya D, Hong S, Matsumori Y, Kayama T, Swanson RA, Dillman WH, Liu J, Panter SS and Weinstein PR: Overexpression of rat heat shock protein 70 reduces neuronal injury after transient focal ischemia, transient global ischemia, or kainic acid-induced seizures. Neurosurgery. 53:1179–1188. 2003. View Article : Google Scholar
13	Elmore S: Apoptosis: a review of programmed cell death. Toxicol Pathol. 35:495–516. 2007. View Article : Google Scholar : PubMed/NCBI
14	Jin Z and El-Deiry WS: Overview of cell death signaling pathways. Cancer Biol Ther. 4:139–163. 2005.PubMed/NCBI
15	Schorey JS and Cooper AM: Macrophage signaling upon mycobacterial infection: the MAP kinases lead the way. Cell Microbiol. 5:133–142. 2003. View Article : Google Scholar : PubMed/NCBI
16	Cardone MH, Roy N, Stennicke HR, Salvesen GS, Franke TF, Stanbridge E, Frisch S and Reed JC: Regulation of cell death protease caspase-9 by phosphorylation. Science. 282:1318–1321. 1998. View Article : Google Scholar : PubMed/NCBI
17	Datta SR, Dudek H, Tao X, Masters S, Fu H, Gotoh Y and Greenberg ME: Akt phosphorylation of BAD couples survival signals to the cell-intrinsic death machinery. Cell. 91:231–241. 1997. View Article : Google Scholar : PubMed/NCBI
18	Shin DY, Kim GY, Lee JH, Choi BT, Yoo YH and Choi YH: Apoptosis induction of human prostate carcinoma DU145 cells by diallyl disulfide via modulation of JNK and PI3K/AKT signaling pathways. Int J Mol Sci. 13:14158–14171. 2012. View Article : Google Scholar : PubMed/NCBI
19	Fresno Vara JA, Casado E, de Castro J, Cejas P, Belda-Iniesta C and González-Barón M: PI3K/Akt signalling pathway and cancer. Cancer Treat Rev. 30:193–204. 2004.PubMed/NCBI
20	Li Y, Jiang Y, Wan Y, Zhang L, Tang W, Ma J, Wu S and Cheng W: Medroxyprogestogen enhances apoptosis of SKOV-3 cells via inhibition of the PI3K/Akt signaling pathway. Biomed Res. 27:43–50. 2013. View Article : Google Scholar : PubMed/NCBI
21	Barber AJ, Nakamura M, Wolpert EB, Reiter CE, Seigel GM, Antonetti DA and Gardner TW: Insulin rescues retinal neurons from apoptosis by a phosphatidylinositol 3-kinase/Akt-mediated mechanism that reduces the activation of caspase-3. J Biol Chem. 276:32814–32821. 2001. View Article : Google Scholar : PubMed/NCBI
22	Lobner D and Ali C: Mechanisms of bFGF and NT-4 potentiation of necrotic neuronal death. Brain Res. 954:42–50. 2002. View Article : Google Scholar : PubMed/NCBI
23	Zhou L and Shine HD: Neurotrophic factors expressed in both cortex and spinal cord induce axonal plasticity after spinal cord injury. J Neurosci Res. 74:221–226. 2003. View Article : Google Scholar : PubMed/NCBI
24	Guan J, Bennet L, Gluckman PD and Gunn AJ: Insulin-like growth factor-1 and post-ischemic brain injury. Prog Neurobiol. 70:443–462. 2003. View Article : Google Scholar : PubMed/NCBI
25	Pierchala BA, Ahrens RC, Paden AJ and Johnson EM Jr: Nerve growth factor promotes the survival of sympathetic neurons through the cooperative function of the protein kinase C and phosphatidylinositol 3-kinase pathways. J Biol Chem. 279:27986–27993. 2004. View Article : Google Scholar : PubMed/NCBI
26	Cotman CW, Berchtold NC and Christie LA: Exercise builds brain health: key roles of growth factor cascades and inflammation. Trends Neurosci. 30:464–472. 2007. View Article : Google Scholar : PubMed/NCBI
27	Tillerson JL, Caudle WM, Reverón ME and Miller GW: Exercise induces behavioral recovery and attenuates neurochemical deficits in rodent models of Parkinson’s disease. Neuroscience. 119:899–911. 2003.PubMed/NCBI
28	Griesbach GS, Hovda DA, Molteni R, Wu A and Gomez-Pinilla F: Voluntary exercise following traumatic brain injury: brain-derived neurotrophic factor upregulation and recovery of function. Neuroscience. 125:129–139. 2004. View Article : Google Scholar
29	Goldshmit Y, Lythgo N, Galea MP and Turnley AM: Treadmill training after spinal cord hemisection in mice promotes axonal sprouting and synapse formation and improves motor recovery. J Neurotrauma. 25:449–465. 2008. View Article : Google Scholar : PubMed/NCBI
30	Ying Z, Roy RR, Zhong H, Zdunowski S, Edgerton VR and Gomez-Pinilla F: BDNF-exercise interactions in the recovery of symmetrical stepping after a cervical hemisection in rats. Neuroscience. 155:1070–1078. 2008. View Article : Google Scholar : PubMed/NCBI
31	Yune TY, Lee JY, Jung GY, Kim SJ, Jiang MH, Kim YC, Oh YJ, Markelonis GJ and Oh TH: Minocycline alleviates death of oligodendrocytes by inhibiting pro-nerve growth factor production in microglia after spinal cord injury. J Neurosci. 27:7751–7761. 2007. View Article : Google Scholar : PubMed/NCBI
32	Chao OY, Pum ME, Li JS and Huston JP: The grid-walking test: assessment of sensorimotor deficits after moderate or severe dopamine depletion by 6-hydroxydopamine lesions in the dorsal striatum and medial forebrain bundle. Neuroscience. 202:318–325. 2012. View Article : Google Scholar
33	de Leon RD and Acosta CN: Effect of robotic-assisted treadmill training and chronic quipazine treatment on hindlimb stepping in spinally transected rats. J Neurotrauma. 23:1147–1163. 2006.PubMed/NCBI
34	Hennigan A, O’Callaghan RM and Kelly AM: Neurotrophins and their receptors: roles in plasticity, neurodegeneration and neuroprotection. Biochem Soc Trans. 35:424–427. 2007. View Article : Google Scholar : PubMed/NCBI
35	Yang D, Han Y, Zhang J, Chopp M and Seyfried DM: Statins enhance expression of growth factors and activate the PI3K/Akt-mediated signaling pathway after experimental intracerebral hemorrhage. World J Neurosci. 2:74–80. 2012. View Article : Google Scholar
36	Yao RQ, Qi DS, Yu HL, Liu J, Yang LH and Wu XX: Quercetin attenuates cell apoptosis in focal cerebral ischemia rat brain via activation of BDNF-TrkB-PI3K/Akt signaling pathway. Neurochem Res. 37:2777–2786. 2012. View Article : Google Scholar : PubMed/NCBI
37	Ying Z, Roy RR, Edgerton VR and Gómez-Pinilla F: Voluntary exercise increases neurotrophin-3 and its receptor TrkC in the spinal cord. Brain Res. 987:93–99. 2003. View Article : Google Scholar : PubMed/NCBI
38	Tait SW and Green DR: Mitochondria and cell death: outer membrane permeabilization and beyond. Nat Rev Mol Cell Biol. 11:621–632. 2010. View Article : Google Scholar : PubMed/NCBI
39	Taylor RC, Cullen SP and Martin SJ: Apoptosis: controlled demolition at the cellular level. Nat Rev Mol Cell Biol. 9:231–241. 2008. View Article : Google Scholar : PubMed/NCBI
40	Chan G, Nogalski MT, Bentz GL, Smith MS, Parmater A and Yurochko AD: Pi3k-dependent upregulation of Mcl-1 by human cytomegalovirus is mediated by epidermal growth factor receptor and inhibits apoptosis in short-lived monocytes. J Immunol. 184:3213–3222. 2010. View Article : Google Scholar : PubMed/NCBI
41	Chen M and Russo-Neustadt AA: Exercise activates the phosphatidylinositol 3-kinase pathway. Mol Brain Res. 135:181–193. 2005. View Article : Google Scholar : PubMed/NCBI
42	Cory S, Huang DC and Adams JM: The Bcl-2 family: roles in cell survival and oncogenesis. Oncogene. 22:8590–8607. 2003. View Article : Google Scholar : PubMed/NCBI
43	Liu G, Keeler BE, Zhukareva V and Houlé JD: Cycling exercise affects the expression of apoptosis-associated microRNAs after spinal cord injury in rats. Exp Neurol. 226:200–206. 2010. View Article : Google Scholar : PubMed/NCBI
44	Upadhyay D, Panduri V, Ghio A and Kamp DW: Particulate matter induces alveolar epithelial cell DNA damage and apoptosis: role of free radicals and the mitochondria. Am J Respir Cell Mol Biol. 29:180–187. 2003. View Article : Google Scholar : PubMed/NCBI