Document Type : Research Paper
Author
Assistance Professor of Sport Physiology, Allameh Tabataba’i University
Abstract
The aim of present study was to investigate effect of six weeks of endurance training on NT-4/5 expression at sensory roots of sciatic nerve in male rats with diabetic neuropathy. To do this, a number of 20 Wistar male rats (eight weeks of age) with average weight of 250±20g were used. Then rats were classified randomly to four 5-rats groups including diabetic exercised group, diabetic control group, healthy exercised group, and healthy control group. Two weeks after inducing the diabetes, endurance exercise protocol was executed moderately (50-55% of VO2max) for five days a week. Speed and time of treadmill exercise was increased gradually. The Quantitative Real time-PCR technique was used to measure the mRNA NT-4/5 expression. In addition, for determining the difference among the groups, the One-way ANOVA were applied. The findings resulted from the research revealed that diabetes significantly increases the expression of NT-4/5 gene at sensory roots of sciatic nerve (P≤0.001). Also 6 weeks of endurance training significantly increases expression of NT-4/5 gene at sensory roots of sciatic nerve of healthy rats (P≤0.05). However, 6 weeks of endurance training has no effect on expression of NT-4/5 gene at sensory roots of sciatic nerve of diabetic neuropathic male rats (P=0.938). However, NT-4/5 expression in diabetic exercised group was significantly lower in comparison with diabetic control group (P≤0.001). Therefore, diabetic neuropathy and endurance training alone can increase the expression of NT-4 gene at sensory roots of sciatic nerve, however, these effects decrease together.
Keywords
Main Subjects
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6. Griesbeck O, Parsadanian AS, Sendtner M, Thoenen H. Expression of neurotrophins in skeletal muscle: Quantitative comparison and significance for motoneuron survival and maintenance of function. J Neurosci Res. 1995;42:21–33.
7. Yamamoto M, Sobue G, Yamamoto K, Terao S, Mitsuma T. Expression of mRNAs for neurotrophic factors (NGF, BDNF, NT-3, and GDNF) and their receptors (p75NGFR, trkA, trkB, and trkC) in the adult human peripheral nervous system and nonneural tissues. Neurochem Res. 1996;21:929–38.
8. Funakoshi H, Frisen J, Barbany G, Timmusk T, Zachrisson O, Verge VMK, et al. Differential expression of mRNAs for neurotrophins and their receptors after axotomy of the sciatic nerve. J Cell Biol. 1993;123:455–65.
9. Boucek P. Advanced diabetic neuropathy: A point of no return? Rev Diabet Stud, 2006, 3(3):143-150.
10. Yasuda H, Terada M, Maeda K, Kogawa S, Sanada M, Haneda M, et al. Diabetic neuropathy and nerve regeneration. Progress in Neurobiology. 2003; 69(4): 229-85.
11. Fernyhough P, Diemel LT, Brewster WJ, Tomlinson DR. Altered neurotrophin mRNA levels in peripheral nerve and skeletal muscle of experimentally diabetic rats. J N C, 1995;64:1231–7.
12. Fernyhough P, Maeda K, Tomlinson DR. Brain-derived neurotrophic factor mRNA levels are up-regulated in hindlimb skeletal muscle of diabetic rats: Effect of denervation. Exp Neurol. 1996;141:297–303.
13. Fernyhough P, Diemel LT, Tomlinson DR. Target tissue production and axonal transport of neurotrophin-3 are reduced in streptozotocindiabetic rats. Diabetologia. 1998;41:300–6.
14. Kust BM, Copray JC, Brouwer N, Troost D, Boddeke HW. Elevated levels of neurotrophins in human biceps brachii tissue of amyotrophic lateral sclerosis. Experimental Neurology. 2002;177:419–27.
15. Molteni R, Zheng JQ, Ying Z, Gomez-Pinilla F, Twiss JL. Voluntary exercise increases axonal regeneration from sensory neurons. Proc Natl Acad Sci. 2004;101, 8473–8.
16. Funakoshi H, Belluardo N, Arenas E, Yamamoto Y, Casabona A, Persson H, et al. Musclederived neurotrophin-4 as an activity-dependent trophic signal for adult motor neurons. Science. 1995;268:1495–9.
17. Poo MM. Neurotrophins as synaptic modulators. Nat Rev Neurosci. 2001; 2:24–32.
18. Lu B. BDNF and activity-dependent synaptic modulation. Learn Mem. 2003;10:86-98.
19. Cohen-Cory S. The developing synapse: Construction and modulation of synaptic structures and circuits. Science. 2002;298:770-6.
20. Dakhili A B., Gharakhanlou R., Movaheddin M., Khazani A., Keshavarz M. The effect of 6 weeks endurance training on gene expression of nerve growth factor in sensory spinal cord of rats with diabetic neuropathy. Iranian journal of Diabetes and Metabolism. 2014;13(3):263-71.
21. Eslami R, Gharakhanlou R, Kazemi A, Dakhili A B, Sorkhkamanzadeh G, Ayob Sheikhy A. Does endurance training compensate for neurotrophin deficiency following diabetic neuropathy? Iran Red Crescent Med J. 2016;18(10): 1-11.
22. Eslami R., Sorkhkamanzadeh G., Gharakhanlou R., Kazemi , A R, Banaifar A A.. The effects of diabetes and endurance training on BDNF gene expression in sensory spinal cord of rats with diabetic neuropathy. Exercise physiology, 2015; (26) 7: 131-46. (In Persian)
23. Calcutt N. Modeling Diabetic Sensory Neuropathy in Rats. In: Luo ZD, editor. Pain research: Methods in molecular medicine. Switzerland: Humana Press; 2004. p. 55-65.
24. Chae CH, Jung SL, An SH, Jung CK, Nam SN, Kim HT. Treadmill exercise suppresses muscle cell apoptosis by increasing nerve growth factor levels and stimulating p-phosphatidylinositol 3-kinase activation in the soleus of diabetic rats. J Physiol Biochem, 2011;67(2):235-41.
25. Hargreaves K, Dubner R, Brown F, Flores C, Joris J. A new and sensitive method for measuring thermal nociception in cutaneous hyperalgesia. Pain. 1988;32(1):77-88.
26. Talbot S, Théberge-Turmel P, Liazoghli D, Sénécal J, Gaudreau P, Couture R. Cellular localization of kinin B1 receptor in the spinal cord of streptozotocin-diabetic rats with a fluorescent. J neuroinflammation. 2009;6:11: 1-12.
27. Tal M, Bennett GJ. Extra-territorial pain in rats with a peripheral mononeuropathy: Mechano-hyperalgesia and mechano-allodynia in the territory of an uninjured nerve. Pain. 1994;57(3):375-82.
28. Wong CY, Byrne NM, O’Moore-Sullivan T, Hills AP, Prins JB, Marwick TH. Effect of weight loss due to lifestyle intervention on subclinical cardiovascular dysfunction in obesity (body mass index 30 kg/m2). Am J Cardiol. 2006;98:1593–8.
29. Christ-Roberts CY, Pratipanawatr T, Pratipanawatr W, Berria R, Belfort R, Kashyap S, et al. Exercise training increases glycogen synthase activity and GLUT4 expression but not insulin signaling in overweight nondiabetic and type 2 diabetic subjects. Metabolism. 2004;53:1233-42.
30. Sriwijitkamol A, Coletta D, Estela W, Gabriela B, Sara M, John B, et al. Effect of acute exercise on AMPK signaling in skeletal muscle of subjects with type 2 diabetes:A time-course and dose-response study. Diabetes. 2007;56:836-48.
31. Nojima H, Watanabe H, Yamane K, Kitahara Y, Sekikawa K, Yamamoto H, et al. Effect of aerobic exercise training on oxidative stress in patients with type 2 diabetes mellitus. Metabolism. 2008;57:170–6.
32. Sigal RJ, Kenny GP, Boulé NG, Wells GA, Prud’homme D, Fortier M, et al. Effects of aerobic training, resistance training, or both on glycemic control in type 2 diabetes: A randomized trial. Ann Intern Med. 2007;147:357–69.
33. Zochodne DW, Ramji N, Toth C. Neuronal targeting in diabetes mellitus: A story of sensory neurons and motor neurons. Neuroscientist.2008;14(4):311-8.
34. Huang EJ, Reichard LF. Neurotrophins: Role in neuronal development and function. Annu Rev Neurosci. 2001;24:677-736.
35. Cai F, Tomlinson DR, Fernyhough P. Elevated expression of neurotrophin-3 mRNA in sensory nerve of streptozotocin-diabetic rats. Neuroscience Letters. 1999;263(2-3):81-4.
36. Belluardo N, Westerblad H, Mudo G, Casabona A, Bruton J, Caniglia G, et al. Neuromuscular junction disassembly and muscle fatigue in mice lacking neurotrophin-4. Mol Cell Neurosci. 2001;18:56–67.
37. Salehi I, Farajnia S, Mohamadi M, Sabouri GM. The pattern of brainderived neurotrophic factor gene expression in the hippocampus of diabetic rats. Iran J Basic Med Sci. 2010;13:146-53.
38. Lee SS, Yoo JH, Kang S, Woo JH, Shin KO, et al. The effects of 12 weeks regular aerobic exercise on brain-derived neurotrophic factor and inflammatory factors in juvenile obesity and type 2 diabetes mellitus. Journal of PT S. 2014;26(8):1199-204.
39. Mizisin AP, Calcutt NA, Tomlinson DR, Gallagher A, Fernyhough P. Neurotrophin-3 reverses nerve conduction velocity deficits in streptozotocin-diabetic rats. JPNS. 1999;4:211–21.
40. Zochodne DW. Diabetes mellitus and the peripheral nervous system: manifestations and mechanisms. Muscle Nerve, 2007;36(2):144-66.
41. Chen YW, Hsieh PL, Chen YC, Hung CH, Cheng JT. Physical exercise induces excess hsp72 expression and delays the development of hyperalgesia and allodynia in painful diabetic neuropathy rats. Anesth Analg. 2013;116(2):482-90.
42. Chen YW, Li YT, Chen YC, Li ZY, Hung CH. Exercise training attenuates neuropathic pain and cytokine expression after chronic constriction injury of rat sciatic nerve. Anesth Analg. 2012;114:1330–7.
2. Thoenen H. The changing scene of neurotrophic factor. Trends Neurosci. 1991;14:165–70.
3. Verdi J M, Birren S J, Ibanez C F, Persson H, Kaplan D R, Benedetti M, Chao M V, Anderson D J. p75_LNGFR regulates Trk signal transduction and NGF-induced neuronal differentiation in MAH cells. Neuron. 1994;12:733–45.
4. Friedman B, Kleinfeld D, Ip N.Y, Verge V.M.K, Moulton R, Boland P, Zlotchenko E, Lindsay R.M, Liu L. BDNF and NT-4/5 exert neurotrophic influences on injured adult spinal motor neurons. J Neurosci. 1995;15:1044–56.
5. Sakuma K, Watanabe K, Sano M, Uramoto I, Nakano H, Li YJ, et al. 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. Brain Res. 2001;907:1–19.
6. Griesbeck O, Parsadanian AS, Sendtner M, Thoenen H. Expression of neurotrophins in skeletal muscle: Quantitative comparison and significance for motoneuron survival and maintenance of function. J Neurosci Res. 1995;42:21–33.
7. Yamamoto M, Sobue G, Yamamoto K, Terao S, Mitsuma T. Expression of mRNAs for neurotrophic factors (NGF, BDNF, NT-3, and GDNF) and their receptors (p75NGFR, trkA, trkB, and trkC) in the adult human peripheral nervous system and nonneural tissues. Neurochem Res. 1996;21:929–38.
8. Funakoshi H, Frisen J, Barbany G, Timmusk T, Zachrisson O, Verge VMK, et al. Differential expression of mRNAs for neurotrophins and their receptors after axotomy of the sciatic nerve. J Cell Biol. 1993;123:455–65.
9. Boucek P. Advanced diabetic neuropathy: A point of no return? Rev Diabet Stud, 2006, 3(3):143-150.
10. Yasuda H, Terada M, Maeda K, Kogawa S, Sanada M, Haneda M, et al. Diabetic neuropathy and nerve regeneration. Progress in Neurobiology. 2003; 69(4): 229-85.
11. Fernyhough P, Diemel LT, Brewster WJ, Tomlinson DR. Altered neurotrophin mRNA levels in peripheral nerve and skeletal muscle of experimentally diabetic rats. J N C, 1995;64:1231–7.
12. Fernyhough P, Maeda K, Tomlinson DR. Brain-derived neurotrophic factor mRNA levels are up-regulated in hindlimb skeletal muscle of diabetic rats: Effect of denervation. Exp Neurol. 1996;141:297–303.
13. Fernyhough P, Diemel LT, Tomlinson DR. Target tissue production and axonal transport of neurotrophin-3 are reduced in streptozotocindiabetic rats. Diabetologia. 1998;41:300–6.
14. Kust BM, Copray JC, Brouwer N, Troost D, Boddeke HW. Elevated levels of neurotrophins in human biceps brachii tissue of amyotrophic lateral sclerosis. Experimental Neurology. 2002;177:419–27.
15. Molteni R, Zheng JQ, Ying Z, Gomez-Pinilla F, Twiss JL. Voluntary exercise increases axonal regeneration from sensory neurons. Proc Natl Acad Sci. 2004;101, 8473–8.
16. Funakoshi H, Belluardo N, Arenas E, Yamamoto Y, Casabona A, Persson H, et al. Musclederived neurotrophin-4 as an activity-dependent trophic signal for adult motor neurons. Science. 1995;268:1495–9.
17. Poo MM. Neurotrophins as synaptic modulators. Nat Rev Neurosci. 2001; 2:24–32.
18. Lu B. BDNF and activity-dependent synaptic modulation. Learn Mem. 2003;10:86-98.
19. Cohen-Cory S. The developing synapse: Construction and modulation of synaptic structures and circuits. Science. 2002;298:770-6.
20. Dakhili A B., Gharakhanlou R., Movaheddin M., Khazani A., Keshavarz M. The effect of 6 weeks endurance training on gene expression of nerve growth factor in sensory spinal cord of rats with diabetic neuropathy. Iranian journal of Diabetes and Metabolism. 2014;13(3):263-71.
21. Eslami R, Gharakhanlou R, Kazemi A, Dakhili A B, Sorkhkamanzadeh G, Ayob Sheikhy A. Does endurance training compensate for neurotrophin deficiency following diabetic neuropathy? Iran Red Crescent Med J. 2016;18(10): 1-11.
22. Eslami R., Sorkhkamanzadeh G., Gharakhanlou R., Kazemi , A R, Banaifar A A.. The effects of diabetes and endurance training on BDNF gene expression in sensory spinal cord of rats with diabetic neuropathy. Exercise physiology, 2015; (26) 7: 131-46. (In Persian)
23. Calcutt N. Modeling Diabetic Sensory Neuropathy in Rats. In: Luo ZD, editor. Pain research: Methods in molecular medicine. Switzerland: Humana Press; 2004. p. 55-65.
24. Chae CH, Jung SL, An SH, Jung CK, Nam SN, Kim HT. Treadmill exercise suppresses muscle cell apoptosis by increasing nerve growth factor levels and stimulating p-phosphatidylinositol 3-kinase activation in the soleus of diabetic rats. J Physiol Biochem, 2011;67(2):235-41.
25. Hargreaves K, Dubner R, Brown F, Flores C, Joris J. A new and sensitive method for measuring thermal nociception in cutaneous hyperalgesia. Pain. 1988;32(1):77-88.
26. Talbot S, Théberge-Turmel P, Liazoghli D, Sénécal J, Gaudreau P, Couture R. Cellular localization of kinin B1 receptor in the spinal cord of streptozotocin-diabetic rats with a fluorescent. J neuroinflammation. 2009;6:11: 1-12.
27. Tal M, Bennett GJ. Extra-territorial pain in rats with a peripheral mononeuropathy: Mechano-hyperalgesia and mechano-allodynia in the territory of an uninjured nerve. Pain. 1994;57(3):375-82.
28. Wong CY, Byrne NM, O’Moore-Sullivan T, Hills AP, Prins JB, Marwick TH. Effect of weight loss due to lifestyle intervention on subclinical cardiovascular dysfunction in obesity (body mass index 30 kg/m2). Am J Cardiol. 2006;98:1593–8.
29. Christ-Roberts CY, Pratipanawatr T, Pratipanawatr W, Berria R, Belfort R, Kashyap S, et al. Exercise training increases glycogen synthase activity and GLUT4 expression but not insulin signaling in overweight nondiabetic and type 2 diabetic subjects. Metabolism. 2004;53:1233-42.
30. Sriwijitkamol A, Coletta D, Estela W, Gabriela B, Sara M, John B, et al. Effect of acute exercise on AMPK signaling in skeletal muscle of subjects with type 2 diabetes:A time-course and dose-response study. Diabetes. 2007;56:836-48.
31. Nojima H, Watanabe H, Yamane K, Kitahara Y, Sekikawa K, Yamamoto H, et al. Effect of aerobic exercise training on oxidative stress in patients with type 2 diabetes mellitus. Metabolism. 2008;57:170–6.
32. Sigal RJ, Kenny GP, Boulé NG, Wells GA, Prud’homme D, Fortier M, et al. Effects of aerobic training, resistance training, or both on glycemic control in type 2 diabetes: A randomized trial. Ann Intern Med. 2007;147:357–69.
33. Zochodne DW, Ramji N, Toth C. Neuronal targeting in diabetes mellitus: A story of sensory neurons and motor neurons. Neuroscientist.2008;14(4):311-8.
34. Huang EJ, Reichard LF. Neurotrophins: Role in neuronal development and function. Annu Rev Neurosci. 2001;24:677-736.
35. Cai F, Tomlinson DR, Fernyhough P. Elevated expression of neurotrophin-3 mRNA in sensory nerve of streptozotocin-diabetic rats. Neuroscience Letters. 1999;263(2-3):81-4.
36. Belluardo N, Westerblad H, Mudo G, Casabona A, Bruton J, Caniglia G, et al. Neuromuscular junction disassembly and muscle fatigue in mice lacking neurotrophin-4. Mol Cell Neurosci. 2001;18:56–67.
37. Salehi I, Farajnia S, Mohamadi M, Sabouri GM. The pattern of brainderived neurotrophic factor gene expression in the hippocampus of diabetic rats. Iran J Basic Med Sci. 2010;13:146-53.
38. Lee SS, Yoo JH, Kang S, Woo JH, Shin KO, et al. The effects of 12 weeks regular aerobic exercise on brain-derived neurotrophic factor and inflammatory factors in juvenile obesity and type 2 diabetes mellitus. Journal of PT S. 2014;26(8):1199-204.
39. Mizisin AP, Calcutt NA, Tomlinson DR, Gallagher A, Fernyhough P. Neurotrophin-3 reverses nerve conduction velocity deficits in streptozotocin-diabetic rats. JPNS. 1999;4:211–21.
40. Zochodne DW. Diabetes mellitus and the peripheral nervous system: manifestations and mechanisms. Muscle Nerve, 2007;36(2):144-66.
41. Chen YW, Hsieh PL, Chen YC, Hung CH, Cheng JT. Physical exercise induces excess hsp72 expression and delays the development of hyperalgesia and allodynia in painful diabetic neuropathy rats. Anesth Analg. 2013;116(2):482-90.
42. Chen YW, Li YT, Chen YC, Li ZY, Hung CH. Exercise training attenuates neuropathic pain and cytokine expression after chronic constriction injury of rat sciatic nerve. Anesth Analg. 2012;114:1330–7.
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