Frontiers in Biology

, Volume 8, Issue 1, pp 101–108 | Cite as

Exercise-dependent regulation of glial cell line-derived neurotrophic factor (GDNF) expression in skeletal muscle and its importance for the neuromuscular system

  • John-Mary Vianney
  • Monica J. Mccullough
  • Amy M. Gyorkos
  • John M. Spitsbergen


The focus of this review is to highlight the importance of glial cell line-derived neurotrophic factor (GDNF) for the motor nervous system. GDNF is the most potent survival factor for motor neurons, where it enhances maintenance and survival of both developing and mature motor neurons in vivo and in vitro. GDNF aids in neuromuscular junction formation, maintenance, and plasticity, where skeletal muscle-derived GDNF may be responsible for this phenomenon. Increased levels of physical activity can increase GDNF protein levels in skeletal muscle, where alterations in acetylcholine and acetylcholine receptor activation may be involved in regulation of these changes observed. With inactivity and disuse, GDNF expression shows different patterns of regulation in the central and peripheral nervous systems. Due to its potent effects for motor neurons, GDNF is being extensively studied in neuromuscular diseases.


glial cell line-derived neurotrophic factor neuromuscular junction motor neurons skeletal muscle 


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  1. Adlard P A, Cotman C W (2004). Voluntary exercise protects against stress-induced decreases in brain-derived neurotrophic factor protein expression. Neuroscience, 124(4): 985–992CrossRefPubMedGoogle Scholar
  2. Airaksinen M S, Saarma M (2002). The GDNF family: signalling, biological functions and therapeutic value. Nat Rev Neurosci, 3(5): 383–394CrossRefPubMedGoogle Scholar
  3. Allen S J, Dawbarn D (2006). Clinical relevance of the neurotrophins and their receptors. Clin Sci (Lond), 110(2): 175–191CrossRefGoogle Scholar
  4. Andonian M H, Fahim M A (1987). Effects of endurance exercise on the morphology of mouse neuromuscular junctions during ageing. J Neurocytol, 16(5): 589–599CrossRefPubMedGoogle Scholar
  5. Angka H E, Geddes A J, Kablar B (2008). Differential survival response of neurons to exogenous GDNF depends on the presence of skeletal muscle. Dev Dyn, 237(11): 3169–3178CrossRefPubMedGoogle Scholar
  6. Bergman E, Kullberg S, Ming Y, Ulfhake B (1999). Upregulation of GFRalpha-1 and c-ret in primary sensory neurons and spinal motoneurons of aged rats. J Neurosci Res, 57(2): 153–165CrossRefPubMedGoogle Scholar
  7. Blum M, Weickert C S (1995). GDNF mRNA expression in normal postnatal development, aging, and inWeaver mutant mice. Neurobiol Aging, 16(6): 925–929CrossRefPubMedGoogle Scholar
  8. Boger H A, Middaugh L D, Huang P, Zaman V, Smith A C, Hoffer B J, Tomac A C, Granholm A Ch (2006). A partial GDNF depletion leads to earlier age-related deterioration of motor function and tyrosine hydroxylase expression in the substantia nigra. Exp Neurol, 202(2): 336–347CrossRefPubMedGoogle Scholar
  9. Caumont A S, Octave J N, Hermans E (2006). Amantadine and memantine induce the expression of the glial cell line-derived neurotrophic factor in C6 glioma cells. Neurosci Lett, 394(3):196–201CrossRefPubMedGoogle Scholar
  10. Chen B M, Grinnell A D (1997). Kinetics, Ca2+ dependence, and biophysical properties of integrin-mediated mechanical modulation of transmitter release from frog motor nerve terminals. J Neurosci, 17(3): 904–916PubMedGoogle Scholar
  11. Clemow D B, Spitsbergen J M, McCarty R, Steers W D, Tuttle J B (1999). Altered NGF regulation may link a genetic predisposition for hypertension with hyperactive voiding. J Urol, 161(4): 1372–1377CrossRefPubMedGoogle Scholar
  12. Connor B, Dragunow M (1998). The role of neuronal growth factors in neurodegenerative disorders of the human brain. Brain Res Brain Res Rev, 27(1): 1–39CrossRefPubMedGoogle Scholar
  13. Cote M P, Azzam G A, Lemay M A, Zhukareva V, Houlé J D (2011). Activity-dependent increase in neurotrophic factors is associated with an enhanced modulation of spinal reflexes after spinal cord injury. J Neurotrauma, 28(2): 299–309CrossRefPubMedGoogle Scholar
  14. Deschenes M R, Maresh C M, Crivello J F, Armstrong L E, Kraemer W J, Covault J (1993). The effects of exercise training of different intensities on neuromuscular junction morphology. J Neurocytol, 22(8): 603–615CrossRefPubMedGoogle Scholar
  15. Dorlöchter M, Irintchev A, Brinkers M, Wernig A (1991). Effects of enhanced activity on synaptic transmission in mouse extensor digitorum longus muscle. J Physiol, 436: 283–292PubMedGoogle Scholar
  16. Dudanova I, Gatto G, Klein R (2010). GDNF acts as a chemoattractant to support ephrin A-induced repulsion of limb motor axons. Curr Biol, 20(23): 2150–2156CrossRefPubMedGoogle Scholar
  17. Dupont-Versteegden E E, Houlé J D, Dennis R A, Zhang J, Knox M, Wagoner G, Peterson C A (2004). Exercise-induced gene expression in soleus muscle is dependent on time after spinal cord injury in rats. Muscle Nerve, 29(1): 73–81CrossRefPubMedGoogle Scholar
  18. Ebert A D, Barber A E, Heins B M, Svendsen C N (2010). Ex vivo delivery of GDNF maintains motor function and prevents neuronal loss in a transgenic mouse model of Huntington’s disease. Exp Neurol, 224: 155–162CrossRefPubMedGoogle Scholar
  19. Edström E, Altun M, Bergman E, Johnson H, Kullberg S, Ramírez-León V, Ulfhake B (2007). Factors contributing to neuromuscular impairment and sarcopenia during aging. Physiol Behav, 92(1–2): 129–135CrossRefPubMedGoogle Scholar
  20. Fabel K, Fabel K, Tam B, Kaufer D, Baiker A, Simmons N, Kuo C J, Palmer T D (2003). VEGF is necessary for exercise-induced adult hippocampal neurogenesis. Eur J Neurosci, 18(10): 2803–2812CrossRefPubMedGoogle Scholar
  21. Frostick S P, Yin Q, Kemp G J (1998). Schwann cells, neurotrophic factors, and peripheral nerve regeneration. Microsurgery, 18(7): 397–405CrossRefPubMedGoogle Scholar
  22. Fu S Y, Gordon T (1997). The cellular and molecular basis of peripheral nerve regeneration. Mole Neurobiol 14(1–2): 67–116CrossRefGoogle Scholar
  23. Funakoshi H, Belluardo N, Arenas E, Yamamoto Y, Casabona A, Persson H, Ibáñez C F (1995). Muscle-derived neurotrophin-4 as an activity-dependent trophic signal for adult motor neurons. Science, 268(5216): 1495–1499CrossRefPubMedGoogle Scholar
  24. Gómez-Pinilla F, Ying Z, Opazo P, Roy R R, Edgerton V R (2001). Differential regulation by exercise of BDNF and NT-3 in rat spinal cord and skeletal muscle. Eur J Neurosci, 13(6): 1078–1084CrossRefPubMedGoogle Scholar
  25. Gómez-Pinilla F, Ying Z, Roy R R, Molteni R, Edgerton V R (2002). Voluntary exercise induces a BDNF-mediated mechanism that promotes neuroplasticity. J Neurophysiol, 88(5): 2187–2195CrossRefPubMedGoogle Scholar
  26. Hashimoto M, Nitta A, Fukumitsu H, Nomoto H, Shen L, Furukawa S (2005). Involvement of glial cell line-derived neurotrophic factor in activation processes of rodent macrophages. J Neurosci Res, 79(4): 476–487CrossRefPubMedGoogle Scholar
  27. Henderson C E, Phillips H S, Pollock R A, Davies A M, Lemeulle C, Armanini M, Simpson L C, Moffet B, Vandlen R A, Koliatsos V E, Rosenthal A (1994). GDNF: a potent survival factor for motoneurons present in peripheral nerve and muscle. Science, 266: 1062–1064CrossRefPubMedGoogle Scholar
  28. Houenou L J, Oppenheim R W, Li L, Lo A C, Prevette D (1996). Regulation of spinal motoneuron survival by GDNF during development and following injury. Cell Tissue Res, 286(2): 219–223CrossRefPubMedGoogle Scholar
  29. Jacob J M (1998). Lumbar motor neuron size and number is affected by age in male F344 rats. Mech Ageing Dev, 106(1–2): 205–216CrossRefPubMedGoogle Scholar
  30. Johnson F B, Sinclair D A, Guarente L (1999). Molecular biology of aging. Cell, 96(2): 291–302CrossRefPubMedGoogle Scholar
  31. Kanning K C, Kaplan A, Henderson C E (2010). Motor neuron diversity in development and disease. Annu Rev Neurosci, 33(1): 409–440CrossRefPubMedGoogle Scholar
  32. Kaplan D R, Miller F D (2000). Neurotrophin signal transduction in the nervous system. Curr Opin Neurobiol, 10(3): 381–391CrossRefPubMedGoogle Scholar
  33. Keller-Peck C R, Feng G, Sanes J R, Yan Q, Lichtman J W, Snider W D (2001). Glial cell line-derived neurotrophic factor administration in postnatal life results in motor unit enlargement and continuous synaptic remodeling at the neuromuscular junction. J Neurosci, 21(16): 6136–6146PubMedGoogle Scholar
  34. Kramer E R, Knott L, Su F, Dessaud E, Krull C E, Helmbacher F, Klein R (2006). Cooperation between GDNF/Ret and ephrinA/EphA4 signals for motor-axon pathway selection in the limb. Neuron, 50(1): 35–47CrossRefPubMedGoogle Scholar
  35. Kullberg S, Ramírez-León V, Johnson H, Ulfhake B (1998). Decreased axosomatic input to motoneurons and astrogliosis in the spinal cord of aged rats. J Gerontol A Biol Sci Med Sci, 53A(5): B369–B379CrossRefGoogle Scholar
  36. Lee R, Kermani P, Teng K K, Hempstead B L (2001). Regulation of cell survival by secreted proneurotrophins. Science, 294(5548): 1945–1948CrossRefPubMedGoogle Scholar
  37. Li W, Brakefield D, Pan Y C, Hunter D, Myckatyn T M, Parsadanian A (2007). Muscle-derived but not centrally derived transgene GDNF is neuroprotective in G93A-SOD1 mouse model of ALS. Exp Neurol, 203(2): 457–471CrossRefPubMedGoogle Scholar
  38. Lie D C, Weis J (1998). GDNF expression is increased in denervated human skeletal muscle. Neurosci Lett, 250(2): 87–90CrossRefPubMedGoogle Scholar
  39. Lin L F, Doherty D H, Lile J D, Bektesh S, Collins F (1993). GDNF: a glial cell line-derived neurotrophic factor for midbrain dopaminergic neurons. Science, 260(5111): 1130–1132CrossRefPubMedGoogle Scholar
  40. McCullough M J, Peplinski N G, Kinnell K R, Spitsbergen J M (2011). Glial cell line-derived neurotrophic factor protein content in rat skeletal muscle is altered by increased physical activity in vivo and in vitro. Neuroscience, 174: 234–244CrossRefPubMedGoogle Scholar
  41. Michalski B, Bain J R, Fahnestock M (2008). Long-term changes in neurotrophic factor expression in distal nerve stump following denervation and reinnervation with motor or sensory nerve. J Neurochem, 105(4): 1244–1252CrossRefPubMedGoogle Scholar
  42. Moore M W, Klein R D, Fariñas I, Sauer H, Armanini M, Phillips H, Reichardt L F, Ryan A M, Carver-Moore K, Rosenthal A (1996). Renal and neuronal abnormalities in mice lacking GDNF. Nature, 382(6586): 76–79CrossRefPubMedGoogle Scholar
  43. Mussini I, Marchioro L (1991). Low frequency nerve stimulation of rat EDL muscle: morphology of myofibers and neuromuscular junctions. BAM, 1(1): 71–81Google Scholar
  44. Nagano M, Suzuki H (2003). Quantitative analyses of expression of GDNF and neurotrophins during postnatal development in rat skeletal muscles. Neurosci Res, 45(4): 391–399CrossRefPubMedGoogle Scholar
  45. Naveilhan P, El Shamy WM, Ernfors P (1997). Differential regulation of mRNAs for GDNF and its receptors Ret and GDNFR alpha after sciatic nerve lesion in the mouse. Eur J Neurosci, 9(7): 1450–1460CrossRefPubMedGoogle Scholar
  46. Nguyen Q T, Parsadanian A S, Snider W D, Lichtman J W (1998). Hyperinnervation of neuromuscular junctions caused by GDNF overexpression in muscle. Science, 279(5357): 1725–1729CrossRefPubMedGoogle Scholar
  47. Niles L P, Armstrong K J, Rincón Castro L M, Dao C V, Sharma R, McMillan C R, Doering L C, Kirkham D L (2004). Neural stem cells express melatonin receptors and neurotrophic factors: colocalization of the MT1 receptor with neuronal and glial markers. BMC Neurosci, 5(1): 41CrossRefPubMedGoogle Scholar
  48. Oppenheim R W, Houenou L J, Johnson J E, Lin L F, Li L, Lo A C, Newsome A L, Prevette D M, Wang S (1995). Developing motor neurons rescued from programmed and axotomy-induced cell death by GDNF. Nature, 373(6512): 344–346CrossRefPubMedGoogle Scholar
  49. Oppenheim R W, Houenou L J, Parsadanian A S, Prevette D, Snider W D, Shen L (2000). Glial cell line-derived neurotrophic factor and developing mammalian motoneurons: regulation of programmed cell death among motoneuron subtypes. J Neurosci, 20(13): 5001–5011PubMedGoogle Scholar
  50. Pastor D, Viso-Leon MC, Jones J, Jaramillo-Merchan J, Toledo-Aral J J, Moraled J M, Martinez S (2011). Comparative effects between bone marrow and mesenchymal stem cell transplantation in GDNF expression and motor function recovery in a motorneuron degenerative mouse model. Sterm Cell Rec and RepGoogle Scholar
  51. Purves D, Snider WD, Voyvodic J T (1988). Trophic regulation of nerve cell morphology and innervation in the autonomic nervous system. Nature, 336(6195): 123–128CrossRefPubMedGoogle Scholar
  52. Reid B, Slater C R, Bewick G S (1999). Synaptic vesicle dynamics in rat fast and slow motor nerve terminals. J Neurosci, 19(7): 2511–2521PubMedGoogle Scholar
  53. Ribchester R R, Thomson D, Haddow L J, Ushkaryov Y A (1998). Enhancement of spontaneous transmitter release at neonatal mouse neuromuscular junctions by the glial cell line-derived neurotrophic factor (GDNF). J Physiol, 512(3): 635–641CrossRefPubMedGoogle Scholar
  54. Salvatore M F, Zhang J L, Large D M, Wilson P E, Gash C R, Thomas T C, Haycock J W, Bing G, Stanford J A, Gash D M, Gerhardt G A (2004). Striatal GDNF administration increases tyrosine hydroxylase phosphorylation in the rat striatum and substantia nigra. J Neurochem, 90(1): 245–254CrossRefPubMedGoogle Scholar
  55. Schatz D S, Kaufmann W A, Saria A, Humpel C (1999). Dopamine neurons in a simple GDNF-treated meso-striatal organotypic coculture model. Exp Brain Res, 127(3): 270–278CrossRefPubMedGoogle Scholar
  56. Sharma H S (2006). Post-traumatic application of brain-derived neurotrophic factor and glia-derived neurotrophic factor on the rat spinal cord enhances neuroprotection and improves motor function. Acta Neurochir Suppl (Wien), 96: 329–334CrossRefGoogle Scholar
  57. Shneider N A, Brown M N, Smith C A, Pickel J, Alvarez F J (2009). Gamma motor neurons express distinct genetic markers at birth and require muscle spindle-derived GDNF for postnatal survival. Neural Dev, 4(1): 42CrossRefPubMedGoogle Scholar
  58. Soler R M, Dolcet X, Encinas M, Egea J, Bayascas J R, Comella J X (1999). Receptors of the glial cell line-derived neurotrophic factor family of neurotrophic factors signal cell survival through the phosphatidylinositol 3-kinase pathway in spinal cord motoneurons. J Neurosci, 19(21): 9160–9169PubMedGoogle Scholar
  59. Spitsbergen J M, Stewart J S, Tuttle J B (1995). Altered regulation of nerve growth factor secretion by cultured VSMCs from hypertensive rats. Am J Physiol, 269(2 Pt 2): H621–H628PubMedGoogle Scholar
  60. Springer J E, Seeburger J L, He J, Gabrea A, Blankenhorn E P, Bergman L W (1995). cDNA sequence and differential mRNA regulation of two forms of glial cell line-derived neurotrophic factor in Schwann cells and rat skeletal muscle. Exp Neurol, 131(1): 47–52CrossRefPubMedGoogle Scholar
  61. Stoop R, Poo MM(1996). Synaptic modulation by neurotrophic factors: differential and synergistic effects of brain-derived neurotrophic factor and ciliary neurotrophic factor. J Neurosci, 16(10): 3256–3264PubMedGoogle Scholar
  62. Suter-Crazzolara C, Unsicker K (1994). GDNF is expressed in two forms in many tissues outside the CNS. Neuroreport, 5(18): 2486–2488CrossRefPubMedGoogle Scholar
  63. Suzuki H, Hase A, Kim B Y, Miyata Y, Nonaka I, Arahata K, Akazawa C (1998a). Up-regulation of glial cell line-derived neurotrophic factor (GDNF) expression in regenerating muscle fibers in neuromuscular diseases. Neurosci Lett, 257(3): 165–167CrossRefPubMedGoogle Scholar
  64. Suzuki H, Hase A, Miyata Y, Arahata K, Akazawa C (1998b). Prominent expression of glial cell line-derived neurotrophic factor in human skeletal muscle. J Comp Neurol, 402(3): 303–312CrossRefPubMedGoogle Scholar
  65. Trejo J L, Carro E, Torres-Aleman I (2001). Circulating insulin-like growth factor I mediates exercise-induced increases in the number of new neurons in the adult hippocampus. J Neurosci, 21(5): 1628–1634PubMedGoogle Scholar
  66. Trupp M, Rydén M, Jörnvall H, Funakoshi H, Timmusk T, Arenas E, Ibáñez C F (1995). Peripheral expression and biological activities of GDNF, a new neurotrophic factor for avian and mammalian peripheral neurons. J Cell Biol, 130(1): 137–148CrossRefPubMedGoogle Scholar
  67. Ulfhake B, Bergman E, Edstrom E, Fundin B T, Johnson H, Kullberg S, Ming Y (2000). Regulation of neurotrophin signaling in aging sensory and motoneurons: dissipation of target support? Mol Neurobiol, 21(3): 109–136CrossRefPubMedGoogle Scholar
  68. Vianney J M, Spitsbergen J M (2011). Cholinergic neurons regulate secretion of glial cell line-derived neurotrophic factor by skeletal muscle cells in culture. Brain Res, 1390: 1–9CrossRefPubMedGoogle Scholar
  69. Wang C Y, Yang F, He X, Chow A, Du J, Russell J T, Lu B (2001). Ca(2+) binding protein frequenin mediates GDNF-induced potentiation of Ca(2+) channels and transmitter release. Neuron, 32(1): 99–112CrossRefPubMedGoogle Scholar
  70. Wang C Y, Yang F, He X P, Je H S, Zhou J Z, Eckermann K, Kawamura D, Feng L, Shen L, Lu B (2002). Regulation of neuromuscular synapse development by glial cell line-derived neurotrophic factor and neurturin. J Biol Chem, 277(12): 10614–10625CrossRefPubMedGoogle Scholar
  71. Wehrwein E A, Roskelley E M, Spitsbergen J M (2002). GDNF is regulated in an activity-dependent manner in rat skeletal muscle. Muscle Nerve, 26(2): 206–211CrossRefPubMedGoogle Scholar
  72. Wood S J, Slater C R (1997). The contribution of postsynaptic folds to the safety factor for neuromuscular transmission in rat fast- and slowtwitch muscles. J Physiol, 500(Pt 1): 165–176PubMedGoogle Scholar
  73. Wu A, Ying Z, Gomez-Pinilla F (2008). Docosahexaenoic acid dietary supplementation enhances the effects of exercise on synaptic plasticity and cognition. Neurosci, 155(30): 751–759CrossRefGoogle Scholar
  74. Yan Q, Matheson C, Lopez O T (1995). In vivo neurotrophic effects of GDNF on neonatal and adult facial motor neurons. Nature, 373(6512): 341–344CrossRefPubMedGoogle Scholar
  75. Yang F, He X, Feng L, Mizuno K, Liu XW, Russell J, Xiong WC, Lu B (2001). PI-3 kinase and IP3 are both necessary and sufficient to mediate NT3-induced synaptic potentiation. Nat Neurosci, 4(1): 19–28CrossRefPubMedGoogle Scholar
  76. Yang L X, Nelson P G (2004). Glia cell line-derived neurotrophic factor regulates the distribution of acetylcholine receptors in mouse primary skeletal muscle cells. Neuroscience, 128(3): 497–509CrossRefPubMedGoogle Scholar
  77. Zhang L, Ma Z, Smith G M, Wen X, Pressman Y, Wood P M, Xu X M (2009). GDNF-enhanced axonal regeneration and myelination following spinal cord injury is mediated by primary effects on neurons. Glia, 57(11): 1178–1191CrossRefPubMedGoogle Scholar
  78. Zhao Z Q, Alam S, Oppenheim R W, Prevette D M, Evenson A, Parsadanian A (2004). Overexpression of glial cell line-derived neurotrophic factor in the CNS rescues motoneurons from programmed cell death and promotes their long-term survival following axotomy. Exp Neurol, 190(2): 356–372CrossRefPubMedGoogle Scholar
  79. Zhou H L, Yang H J, Li Y M, Wang Y, Yan L, Guo X L, Ba Y C, Liu S, Wang T H (2008). Changes in Glial cell line-derived neurotrophic factor expression in the rostral and caudal stumps of the transected adult rat spinal cord. Neurochem Res, 33(5): 927–937CrossRefPubMedGoogle Scholar
  80. Zwick M, Teng L, Mu X, Springer J E, Davis B M (2001). Overexpression of GDNF induces and maintains hyperinnervation of muscle fibers and multiple end-plate formation. Exp Neurol, 171(2): 342–350CrossRefPubMedGoogle Scholar

Copyright information

© Higher Education Press and Springer-Verlag Berlin Heidelberg 2013

Authors and Affiliations

  • John-Mary Vianney
    • 1
  • Monica J. Mccullough
    • 1
  • Amy M. Gyorkos
    • 1
  • John M. Spitsbergen
    • 1
  1. 1.Department of Biological SciencesWestern Michigan UniversityKalamazooUSA

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