1Assistant Professor, Physical Education Department, Vali-Asr University, Rafsanjan, Iran
2Assistant Professor, Physical Education Department, Lorestan University, Khoram abad, Iran
Background & Aims: Diabetic neuropathy can lead to atrophy and weakness of distally located muscles and lack of neurotrophic support is believed to contribute to the development of these consequences. So, the aim of the present study was to investigate BDNF and TrKB gene expression in soleus muscle of Wistar male rats with diabetic neuropathy following endurance training. Methods: A total of 16 Wistar male rats were randomly assigned in 4 groups: diabetic trained (DT), diabetic Non-trained (DNT), normal trained (NT) and normal control (NC). Two weeks after STZ injection (45 mg/Kg), diabetic neuropathy was demonstrated with mechanical allodynia and thermal hyperalgesia tests. Then, moderate endurance training protocol was performed for 6 weeks and 48 hours after the final training session, rats were dissected and soleus muscle tissues were removed. BDNF and TrkB gene expression was determined with Real time- PCR methods. Results: Soleus muscle weight decreased in diabetic groups (p=0/001); even though, compared with DNT group, it was higher in DT group (p=0/001). BDNF and TrkB gene expression in DNT group was higher than NC group (p=0/001). Also, training significantly decreased BDNF and TrkB gene expression and blood glucose levels in DT group compared with DNT group (P=0/001 and P=0/0001, respectively). Conclusion: In soleus muscle of diabetic rats, BDNF and TrkB mRNA up-regulation is involved in the development of muscle atrophy and training as a non-pharmacotherapy strategy can modulate it. So, considering BDNF and TrkB as novel therapeutic targets in diabetes disease is suggested.
Edwards JL, Vincent AM, Cheng HT, Feldman EL. Diabetic neuropathy: mechanisms to management. Pharmacol Ther 2008; 120(1):1-34.
Frier BC, Noble EG, Locke M. Diabetes-induced atrophy is associated with a muscle-specific alteration in NF-κB activation and expression. Cell Stress and Chaperones 2008; 13(3): 287-296.
Ibanez C F, Ebendal T, Persson H. Chimeric molecules with multiple neurotrophic activities reveal structural elements determining the specificities of NGF and BDNF. EMBO J 1991; 10(8): 2105-10.
Barbacid M. The Trk family of neurotrophin receptors. J Neurobiol 1994; 25(11):1386-403.
Huang EJ, Reichard LF. Neurotrophins: role in neuronal development and function. Annu Rev Neurosci. 2001; 24:677-736.
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(1-2):1–19.
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(1): 21–33.
Yamamoto M, Sobue G, Yamamoto K, 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(8): 929-38.
Kust BM, Copray JC, Brouwer N, Troost D, Boddeke HW. Elevated levels of neurotrophins in human biceps brachii tissue of amyotrophic lateral sclerosis. Exp Neurol 2002; 177(2): 419–27.
Fernyhough P, Diemel LT, Brewster WJ, Tomlinson DR. Altered neurotrophin mRNA levels in peripheral nerve and skeletal muscle of experimentally diabetic rats. J Neurochem 1995; 64(3): 1231–7.
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(2): 297–303.
Fernyhough P, Diemel LT, Tomlinson DR. Target tissue production and axonal transport of neurotrophin-3 are reduced in streptozotocin diabetic rats. Diabetologia 1998; 41(3): 300–6.
Gomez-Pinilla F, Ying Z, Roy RR, Molteni R, Edgerton VR. Voluntary exercise induces a BDNF-mediated mechanism that promotes neuroplasticity. J Neurophysiol 2002; 88(5):2187-95.
Adlard PA, Perreau VM, Engesser-Cesar C, Cotman CW. The timecourse of induction of brain-derived neurotrophic factor mRNA and protein in the rat hippocampus following voluntary exercise. Neurosci Lett. 2004; 363(1):43-8.
Cuppini R, Sartini S, Agostini D, Guescini M, Ambrogini P, Betti M, et al. BDNF expression in rat skeletal muscle after acute or repeated exercise. Arch Ital Biol. 2007; 145(2): 99-110.
Gomez-Pinilla F, Ying Z, Opazo P, Roy RR, Edgerton VR. Differential regulation by exercise of BDNF and NT-3 in rat spinal cord and skeletal muscle. Eur J Neurosci 2001; 13(6):1078-84.
Andreassen CS, Jakobsen J, Ringgaard S, Ejskjaer N, Andersen H. Accelerated atrophy of lower leg and foot muscles-a follow-up study of long-term diabetic polyneuropathy using magnetic resonance imaging (MRI). Diabetologia. 2009; 52(6): 1182–91.
Calcutt N, Freshwater J, O'Brien J. Protection of sensory function and antihyperalgesic properties of prosaposin-derived peptide in diabetic rats. Anesthesiology 2000; 93(5): 1271-8.
Kuhad A, Chopra K. Tocotrienol attenuates oxidative-nitrosative stress and inflammatory cascade in experimental model of diabetic neuropathy. Neuropharmacology 2009 57(4):456-62.
Beyreuther B, Callizot N, Stohr T: Antinociceptive efficacy of lacosamide in a rat model for painful diabetic neuropathy. Eur J Pharmacol. 2006; 539(1-2): 64-70.
Chae C.H., Jung S.L., An S.H., Park B.Y., Wang S.W., Cho I.H., et al. Treadmill exercise improves cognitive function and facilitates nerve growth factor signaling by activating mitogen-activated protein kinase/ extracellular signalregulated kinase1/2 in the streptozotocin-induced diabetic rat hippocampus. Neuroscience 2009; 164(4): 1665–73.
Sharma NK, Ryals JM, Gajewski BJ, Wright DE. Aerobic Exercise Alters Analgesia and Neurotrophin-3 Synthesis in an Animal Model of Chronic Widespread Pain. Phys Ther. 2010; 90(5):714-25.
Calcutt NA, Jorge MC, Yaksh TL, Chaplan SR. Tactile allodynia and formalin hyperalgesia in streptozotocin-diabetic rats: effects of insulin, aldose reductase inhibition and lidocaine. Pain 1996; 68(2-3): 293-9.
Tal M, Bennett GJ. Extra–territorial pain in rat with a peripheral mononeuropathy: mechano–hyperalgesia and mechano – allodynia in the territory of an uninjerd nerve. Pain 1994; 57(3): 375-82.
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.
Farrell PA, Fedele J, Hernandez J, Fluckey JD, Miller JL, Lang CH, et al. Hypertrophy of skeletal muscle in diabetic rats in response to chronic resistance exercise. J Appl Physiol 1999; 87(3): 1075-82.
Pfaffl MW. A new mathematical model for relative quantification in real-time RT–PCR. Nucleic Acids Research 2001; 29(9): e45-e45.
Ernfors, P., Rosario C.M., Merlio J.P., Grant G., Aldskogius H., Persson H. Expression of mRNA for neurotrophin receptors in the dorsal root ganglion and spinal cord during development and following peripheral or central axotomy. Mol Res Mol Brain Res 1993; 17(3-4): 217-26.
Mizisin A.P., DiStefano P.S., Liu X., Garrett D.N., Tonra J.R.. Decreased accumulation of endogenous brain-derived neurotrophic factor against constricting sciatic nerve ligatures in streptozotocin-diabetic and galactose-fed rats. Neurosci Lett 1999; 263(1-2): 149-52.
Colberg SR, Sigal RJ, Fernhall B, Regensteiner JG, Blissmer BJ, Rubin RR, et al. Exercise and Type 2 Diabetes The American College of Sports Medicine and the American Diabetes Association: joint position statement executive summary. Diabetes care 2010; 33(12), 2692-6.
Sharma NK. Ryals JM. Gajewski BJ. Wright DE. Aerobic Exercise Alters Analgesia and Neurotrophin-3 Synthesis in an Animal Model of Chronic Widespread Pain. Phys Ther. 2010; 90(5): 714-25.
Colombo E., Bedogni F., Lorenzetti I., Landsberger N., Previtali S. C., Farina C. Autocrine and immune cell‐derived BDNF in human skeletal muscle: implications for myogenesis and tissue regeneration. J pathol 2013; 231(2): 190-8.
Lee JH, McCarty R. Glycemic control of pain threshold in diabetic and control rats. Physiol Behav 1990; 47(2): 225-30.
Lee JH, McCarty R. Pain threshold in diabetic rats: effects of good versus poor diabetic control. Pain 1992; 50(2): 231- 6.
Millan MJ. The induction of pain: an integrative review. Prog Neurobiol 1999; 57(1): 1-164.
Vaynman S., Ying Z., Gomez‐Pinilla F. Hippocampal BDNF mediates the efficacy of exercise on synaptic plasticity and cognition. European J Neurosci 2004; 20(10): 2580-90.
Van Hoomissen J. D., Chambliss H.O., Holmes P.V., Dishman R.K. Effects of chronic exercise and imipramine on mRNA for BDNF after olfactory bulbectomy in rat. Brain research 2003; 974(1-2), 228-35.
Ogborn D I, Gardiner P F. Effects of Exercise and Muscle Type on BDNF, NT-4/5, and TrkB Expression in Skeletal Muscle. Muscle and Nerve 2010; 41(3): 385-91.
Brandt C., Pedersen B.K. The role of exercise-induced myokines in muscle homeostasis and the defense against chronic diseases. J BioMed Biotechnol International 2010; 520258.