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Running and swimming prevent the deregulation of the BDNF/TrkB neurotrophic signalling at the neuromuscular junction in mice with amyotrophic lateral sclerosis

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Abstract

Nerve-induced muscle contraction regulates the BDNF/TrkB neurotrophic signalling to retrogradely modulate neurotransmission and protect the neuromuscular junctions and motoneurons. In muscles with amyotrophic lateral sclerosis, this pathway is strongly misbalanced and neuromuscular junctions are destabilized, which may directly cause the motoneuron degeneration and muscular atrophy observed in this disease. Here, we sought to demonstrate (1) that physical exercise, whose recommendation has been controversial in amyotrophic lateral sclerosis, would be a good option for its therapy, because it normalizes and improves the altered neurotrophin pathway and (2) a plausible molecular mechanism underlying its positive effect. SOD1-G93A mice were trained following either running or swimming-based protocols since the beginning of the symptomatic phase (day 70 of age) until day 115. Next, the full BDNF pathway, including receptors, downstream kinases and proteins related with neurotransmission, was characterized and motoneuron survival was analysed. The results establish that amyotrophic lateral sclerosis-induced damaging molecular changes in the BDNF/TrkB pathway are reduced, prevented or even overcompensated by precisely defined exercise protocols that modulate TrkB isoforms and neurotransmission regulatory proteins and reduce motoneuron death. Altogether, the maintenance of the BDNF/TrkB signalling and the downstream pathway, particularly after the swimming protocol, adds new molecular evidence of the benefits of physical exercise to reduce the impact of amyotrophic lateral sclerosis. These results are encouraging since they reveal an improvement even starting the therapy after the onset of the disease.

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Abbreviations

ALS:

Amyotrophic lateral sclerosis

BDNF:

Brain-derived neurotrophic factor

NMJ:

Neuromuscular junction

NT4:

Neurotrophin-4

p75NTR :

p75 neurotrophin receptor

PDK1:

Phosphoinositide-dependent kinase-1

PKA:

Protein kinase A

PKC:

Protein kinase C

SM:

Sec1/Munc18-like

SNAP-25:

Synaptosomal-associated protein 25

SNARE:

SNAP (Soluble NSF Attachment Protein) receptor

TrkB.T1:

Truncated tropomyosin-related kinase B receptor

TrkB.FL:

Full-length tropomyosin-related kinase B receptor

WT:

Wild type

References

  1. Moloney EB, de Winter F, Verhaagen J (2014) ALS as a distal axonopathy: molecular mechanisms affecting neuromuscular junction stability in the presymptomatic stages of the disease. Front Neurosci 8:1–18. https://doi.org/10.3389/fnins.2014.00252

    Article  Google Scholar 

  2. Fischer LR, Culver DG, Tennant P et al (2004) Amyotrophic lateral sclerosis is a distal axonopathy: evidence in mice and man. Exp Neurol 185:232–240. https://doi.org/10.1016/j.expneurol.2003.10.004

    Article  PubMed  Google Scholar 

  3. Dadon-Nachum M, Melamed E, Offen D (2011) The “Dying-Back” phenomenon of motor neurons in ALS. J Mol Neurosci 43:470–477. https://doi.org/10.1007/s12031-010-9467-1

    Article  CAS  PubMed  Google Scholar 

  4. Just-Borràs L, Hurtado E, Cilleros-Mañé V et al (2019) Overview of Impaired BDNF signaling, their coupled downstream serine-threonine kinases and SNARE/SM complex in the neuromuscular junction of the amyotrophic lateral sclerosis model SOD1-G93A mice. Mol Neurobiol. https://doi.org/10.1007/s12035-019-1550-1

    Article  PubMed  Google Scholar 

  5. Cleveland DW, Williamson TL (1999) Slowing of axonal transport is a very early event in the toxicity ofALS–linked SOD1 mutants to motor neurons. Nat Neurosci 2:50–56. https://doi.org/10.1038/4553

    Article  PubMed  Google Scholar 

  6. Zhang B, Tu P, Abtahian F et al (1997) Neurofilaments and orthograde transport are reduced in ventral root axons of transgenic mice that express human SOD1 with a G93A mutation. J Cell Biol 139:1307–1315

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  7. Park KHJ, Vincent I (2008) Presymptomatic biochemical changes in hindlimb muscle of G93A human Cu/Zn superoxide dismutase 1 transgenic mouse model of amyotrophic lateral sclerosis. Biochim Biophys Acta Mol Basis Dis 1782:462–468. https://doi.org/10.1016/J.BBADIS.2008.04.001

    Article  CAS  Google Scholar 

  8. Dupuis L, Gonzalez De Aguilar J-L, Echaniz-Laguna A et al (2009) Muscle mitochondrial uncoupling dismantles neuromuscular junction and triggers distal degeneration of motor neurons. PLoS One 4:1–12. https://doi.org/10.1371/journal.pone.0005390

    Article  CAS  Google Scholar 

  9. Schmidt ERE, Pasterkamp RJ, van den Berg LH (2009) Axon guidance proteins: novel therapeutic targets for ALS? Prog Neurobiol 88:286–301. https://doi.org/10.1016/J.PNEUROBIO.2009.05.004

    Article  CAS  PubMed  Google Scholar 

  10. Boyer JG, Ferrier A, Kothary R (2013) More than a bystander: the contributions of intrinsic skeletal muscle defects in motor neuron diseases. Front Physiol 4:1–45. https://doi.org/10.3389/fphys.2013.00356

    Article  Google Scholar 

  11. Matthews VB, Åström M-B, Chan MHS et al (2009) Brain-derived neurotrophic factor is produced by skeletal muscle cells in response to contraction and enhances fat oxidation via activation of AMP-activated protein kinase. Diabetologia 52:1409–1418. https://doi.org/10.1007/s00125-009-1364-1

    Article  CAS  PubMed  Google Scholar 

  12. Hurtado E, Cilleros V, Nadal L et al (2017) Muscle contraction regulates BDNF/TrkB signaling to modulate synaptic function through presynaptic cPKCα and cPKCβI. Front Mol Neurosci 10:1–22. https://doi.org/10.3389/fnmol2017.00147

    Article  CAS  Google Scholar 

  13. Balkowiec A, Katz DM (2000) Activity-dependent release of endogenous brain-derived neurotrophic factor from primary sensory neurons detected by ELISA in situ. J Neurosci 20:7417–7423

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. Udina E, Cobianchi S, Allodi I, Navarro X (2011) Effects of activity-dependent strategies on regeneration and plasticity after peripheral nerve injuries. Ann Anat Anat Anzeiger 193:347–353. https://doi.org/10.1016/j.aanat.2011.02.012

    Article  CAS  Google Scholar 

  15. Lu B (2003) BDNF and activity-dependent synaptic modulation. Learn Mem 10:86–98. https://doi.org/10.1101/lm.54603

    Article  PubMed  PubMed Central  Google Scholar 

  16. Mantilla CB, Stowe JM, Sieck DC et al (2014) TrkB kinase activity maintains synaptic function and structural integrity at adult neuromuscular junctions. J Appl Physiol 117:910–920. https://doi.org/10.1152/japplphysiol.01386.2013

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. Nadal L, Garcia N, Hurtado E et al (2016) Presynaptic muscarinic acetylcholine autoreceptors (M1, M2 and M4 subtypes), adenosine receptors (A1 and A2A) and tropomyosin-related kinase B receptor (TrkB) modulate the developmental synapse elimination process at the neuromuscular junction. Mol Brain 9:1–19. https://doi.org/10.1186/s13041-016-0248-9

    Article  CAS  Google Scholar 

  18. Nadal L, Garcia N, Hurtado E et al (2017) Presynaptic muscarinic acetylcholine receptors and TrkB receptor cooperate in the elimination of redundant motor nerve terminals during development. Front Aging Neurosci 9:1–7. https://doi.org/10.3389/fnagi.2017.00024

    Article  CAS  Google Scholar 

  19. Simó A, Cilleros-Mañé V, Just-Borràs L et al (2019) nPKCε mediates SNAP-25 phosphorylation of Ser-187 in basal conditions and after synaptic activity at the neuromuscular junction. Mol Neurobiol. https://doi.org/10.1007/s12035-018-1462-5

    Article  PubMed  Google Scholar 

  20. Simó A, Just-Borràs L, Cilleros-Mañé V et al (2018) BDNF-TrkB signaling coupled to nPKCε and cPKCβI modulate the phosphorylation of the exocytotic protein Munc18-1 during synaptic activity at the neuromuscular junction. Front Mol Neurosci 11:207–227. https://doi.org/10.3389/fnmol.2018.00207

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. Hurtado E, Cilleros V, Just L et al (2017) Synaptic activity and muscle contraction increases PDK1 and PKCβI phosphorylation in the presynaptic membrane of the neuromuscular junction. Front Mol Neurosci 10:1–13. https://doi.org/10.3389/fnmol.2017.00270

    Article  CAS  Google Scholar 

  22. Turner BJ, Cheah IK, Macfarlane KJ et al (2003) Antisense peptide nucleic acid-mediated knockdown of the p75 neurotrophin receptor delays motor neuron disease in mutant SOD1 transgenic mice. J Neurochem 87:752–763. https://doi.org/10.1046/j.1471-4159.2003.02053.x

    Article  CAS  PubMed  Google Scholar 

  23. Zhai J, Zhou W, Li J et al (2011) The in vivo contribution of motor neuron TrkB receptors to mutant SOD1 motor neuron disease. Hum Mol Genet 20:4116–4131. https://doi.org/10.1093/hmg/ddr335

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. Yanpallewar SU, Barrick CA, Buckley H et al (2012) Deletion of the BDNF truncated receptor TrkB.T1 delays disease onset in a mouse model of amyotrophic lateral sclerosis. PLoS One 7:1–7. https://doi.org/10.1371/journal.pone.0039946

    Article  CAS  Google Scholar 

  25. Berchtold NC, Chinn G, Chou M et al (2005) Exercise primes a molecular memory for brain-derived neurotrophic factor protein induction in the rat hippocampus. Neuroscience 133:853–861. https://doi.org/10.1016/J.NEUROSCIENCE.2005.03.026

    Article  CAS  PubMed  Google Scholar 

  26. Cotman CW, Berchtold NC (2002) Exercise: a behavioral intervention to enhance brain health and plasticity. Trends Neurosci 25:295–301. https://doi.org/10.1016/S0166-2236(02)02143-4

    Article  CAS  PubMed  Google Scholar 

  27. Vaynman SS, Ying Z, Yin D, Gomez-Pinilla F (2006) Exercise differentially regulates synaptic proteins associated to the function of BDNF. Brain Res 1070:124–130. https://doi.org/10.1016/J.BRAINRES.2005.11.062

    Article  CAS  PubMed  Google Scholar 

  28. Wu C-W, Chang Y-T, Yu L et al (2008) Exercise enhances the proliferation of neural stem cells and neurite growth and survival of neuronal progenitor cells in dentate gyrus of middle-aged mice. J Appl Physiol 105:1585–1594. https://doi.org/10.1152/japplphysiol.90775.2008

    Article  PubMed  Google Scholar 

  29. Bello-Haas VD, Florence JM, Kloos AD et al (2007) A randomized controlled trial of resistance exercise in individuals with ALS. Neurology 68:2003–2007. https://doi.org/10.1212/01.wnl.0000264418.92308.a4

    Article  PubMed  Google Scholar 

  30. Drory VE, Goltsman E, Reznik JG et al (2001) The value of muscle exercise in patients with amyotrophic lateral sclerosis. J Neurol Sci 191:133–137. https://doi.org/10.1016/S0022-510X(01)00610-4

    Article  CAS  PubMed  Google Scholar 

  31. Pinto AC, Alves M, Nogueira A et al (1999) Can amyotrophic lateral sclerosis patients with respiratory insufficiency exercise? J Neurol Sci 169:69–75

    Article  CAS  PubMed  Google Scholar 

  32. Kaspar BK, Frost LM, Christian L et al (2005) Synergy of insulin-like growth factor-1 and exercise in amyotrophic lateral sclerosis. Ann Neurol 57:649–655. https://doi.org/10.1002/ana.20451

    Article  CAS  PubMed  Google Scholar 

  33. Kirkinezos IG, Hernandez D, Bradley WG, Moraes CT (2003) Regular exercise is beneficial to a mouse model of amyotrophic lateral sclerosis. Ann Neurol 53:804–807. https://doi.org/10.1002/ana.10597

    Article  PubMed  Google Scholar 

  34. McCrate ME, Kaspar BK (2008) Physical activity and neuroprotection in amyotrophic lateral sclerosis. Neuromol Med 10:108–117. https://doi.org/10.1007/s12017-008-8030-5

    Article  CAS  Google Scholar 

  35. Liebetanz D, Hagemann K, von Lewinski F et al (2004) Extensive exercise is not harmful in amyotrophic lateral sclerosis. Eur J Neurosci 20:3115–3120. https://doi.org/10.1111/j.1460-9568.2004.03769.x

    Article  PubMed  Google Scholar 

  36. Mahoney DJ, Rodriguez C, Devries M et al (2004) Effects of high-intensity endurance exercise training in the G93A mouse model of amyotrophic lateral sclerosis. Muscle Nerve 29:656–662

    Article  PubMed  Google Scholar 

  37. Veldink JH, Bär PR, Joosten EAJ et al (2003) Sexual differences in onset of disease and response to exercise in a transgenic model of ALS. Neuromusc Disord 13:737–743. https://doi.org/10.1016/S0960-8966(03)00104-4

    Article  CAS  PubMed  Google Scholar 

  38. Deforges S, Branchu J, Biondi O et al (2009) Motoneuron survival is promoted by specific exercise in a mouse model of amyotrophic lateral sclerosis. J Physiol 587:3561–3571. https://doi.org/10.1113/jphysiol.2009.169748

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  39. Elbasiouny SM, Schuster JE (2011) The effect of training on motoneuron survival in amyotrophic lateral sclerosis: which motoneuron type is saved? Front Physiol. https://doi.org/10.3389/fphys.2011.00018

    Article  PubMed  PubMed Central  Google Scholar 

  40. Frey D, Schneider C, Xu L et al (2000) Early and selective loss of neuromuscular synapse subtypes with low sprouting competence in motoneuron diseases. J Neurosci 20:2534–2542. https://doi.org/10.1523/JNEUROSCI.20-07-02534.2000

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  41. Hegedus J, Putman CT, Tyreman N, Gordon T (2008) Preferential motor unit loss in the SOD1 G93A transgenic mouse model of amyotrophic lateral sclerosis. J Physiol 586:3337–3351. https://doi.org/10.1113/jphysiol.2007.149286

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  42. Pun S, Santos AF, Saxena S et al (2006) Selective vulnerability and pruning of phasic motoneuron axons in motoneuron disease alleviated by CNTF. Nat Neurosci 9:408–419. https://doi.org/10.1038/nn1653

    Article  CAS  PubMed  Google Scholar 

  43. Grondard C, Biondi O, Pariset C et al (2008) Exercise-induced modulation of calcineurin activity parallels the time course of myofibretransitions. J Cell Physiol 2008:126–135. https://doi.org/10.1002/jcp.21168

    Article  CAS  Google Scholar 

  44. Ferrante RJ, Klein AM, Dedeoglu A, Beal MF (2001) Therapeutic efficacy of EGb761 (Gingko biloba extract) in a transgenic mouse model of amyotrophic lateral sclerosis. J Mol Neurosci 17:89–96. https://doi.org/10.1385/JMN:17:1:89

    Article  CAS  PubMed  Google Scholar 

  45. McCombe PA, Henderson RD (2010) Effects of gender in amyotrophic lateral sclerosis. Gend Med 7:557–570. https://doi.org/10.1016/j.genm.2010.11.010

    Article  PubMed  Google Scholar 

  46. Dell RB, Holleran S, Ramakrishnan R (2002) Sample size determination. ILAR J 43:207–213. https://doi.org/10.1093/ilar.43.4.207

    Article  CAS  PubMed  Google Scholar 

  47. Snedecor GW, Cochran WG (1989) Statistical methods applied to experiments in agriculture and biology, 8th edn. Iowa State University Press, Ames

    Google Scholar 

  48. Loeffler J-P, Picchiarelli G, Dupuis L, Gonzalez De Aguilar J-L (2016) The role of skeletal muscle in amyotrophic lateral sclerosis. Brain Pathol 26:227–236. https://doi.org/10.1111/bpa.12350

    Article  PubMed  PubMed Central  Google Scholar 

  49. Obis T, Hurtado E, Nadal L et al (2015) The novel protein kinase C epsilon isoform modulates acetylcholine release in the rat neuromuscular junction. Mol Brain 8:1–16. https://doi.org/10.1186/s13041-015-0171-5

    Article  CAS  Google Scholar 

  50. Besalduch N, Tomàs M, Santafé MM et al (2010) Synaptic activity-related classical protein kinase C isoform localization in the adult rat neuromuscular synapse. J Comp Neurol 518:211–228. https://doi.org/10.1002/cne.22220

    Article  CAS  PubMed  Google Scholar 

  51. Mantilla CB, Zhan W-Z, Sieck GC (2004) Neurotrophins improve neuromuscular transmission in the adult rat diaphragm. Muscle Nerve 29:381–386

    Article  CAS  PubMed  Google Scholar 

  52. Tomàs J, Garcia N, Lanuza MA et al (2017) Presynaptic membrane receptors modulate ACh release, axonal competition and synapse elimination during neuromuscular junction development. Front Mol Neurosci 10:132. https://doi.org/10.3389/fnmol.2017.00132

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  53. Pousinha PA, Diogenes MJ, Ribeiro JA, Sebastião AM (2006) Triggering of BDNF facilitatory action on neuromuscular transmission by adenosine A2A receptors. Neurosci Lett 404:143–147. https://doi.org/10.1016/j.neulet.2006.05.036

    Article  CAS  PubMed  Google Scholar 

  54. Wiese S, Jablonka S, Holtmann B et al (2007) Adenosine receptor A2A-R contributes to motoneuron survival by transactivating the tyrosine kinase receptor TrkB. Proc Natl Acad Sci 104:17210–17215. https://doi.org/10.1073/pnas.0705267104

    Article  PubMed  PubMed Central  Google Scholar 

  55. Gordon T, Tyreman N, Li S et al (2010) Functional over-load saves motor units in the SOD1-G93A transgenic mouse model of amyotrophic lateral sclerosis. Neurobiol Dis 37:412–422. https://doi.org/10.1016/j.nbd.2009.10.021

    Article  CAS  PubMed  Google Scholar 

  56. Lunetta C, Lizio A, Sansone VA et al (2016) Strictly monitored exercise programs reduce motor deterioration in ALS: preliminary results of a randomized controlled trial. J Neurol 263:52–60. https://doi.org/10.1007/s00415-015-7924-z

    Article  PubMed  Google Scholar 

  57. Meyer R, Spittel S, Steinfurth L et al (2018) Patient-reported outcome of physical therapy in amyotrophic lateral sclerosis: observational online study. JMIR Rehabil Assist Technol. https://doi.org/10.2196/10099

    Article  PubMed  PubMed Central  Google Scholar 

  58. Merico A, Cavinato M, Gregorio C et al (2018) Effects of combined endurance and resistance training in Amyotrophic Lateral Sclerosis: a pilot, randomized, controlled study. Eur J Transl Myol 28:72–78. https://doi.org/10.4081/ejtm.2018.7278

    Article  Google Scholar 

  59. Gómez-Pinilla F, Ying Z, Opazo P et al (2001) Differential regulation by exercise of BDNF and NT-3 in rat spinal cord and skeletal muscle. Eur J Neurosci 13:1078–1084. https://doi.org/10.1046/j.0953-816x.2001.01484.x

    Article  PubMed  Google Scholar 

  60. Acsadi G, Anguelov RA, Yang H et al (2002) Increased survival and function of SOD1 mice after glial cell-derived neurotrophic factor gene therapy. Hum Gene Ther 13:1047–1059. https://doi.org/10.1089/104303402753812458

    Article  CAS  PubMed  Google Scholar 

  61. Manabe Y, Nagano I, Gazi MSA et al (2002) Adenovirus-mediated gene transfer of glial cell line-derived neurotrophic factor prevents motor neuron loss of transgenic model mice for amyotrophic lateral sclerosis. Apoptosis 7:329–334

    Article  CAS  PubMed  Google Scholar 

  62. Sun W, Funakoshi H, Nakamura T (2002) Overexpression of HGF retards disease progression and prolongs life span in a transgenic mouse model of ALS. J Neurosci 22:6537–6548

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  63. Santafé MM, Garcia N, Tomàs M et al (2014) The interaction between tropomyosin-related kinase B receptors and serine kinases modulates acetylcholine release in adult neuromuscular junctions. Neurosci Lett 561:171–175. https://doi.org/10.1016/j.neulet.2013.12.073

    Article  CAS  PubMed  Google Scholar 

  64. Garcia N, Tomàs M, Santafe MM et al (2010) Localization of brain-derived neurotrophic factor, neurotrophin-4, tropomyosin-related kinase b receptor, and p75NTR receptor by high-resolution immunohistochemistry on the adult mouse neuromuscular junction. J Peripher Nerv Syst 15:40–49

    Article  CAS  PubMed  Google Scholar 

  65. Gómez-Pinilla F, Ying Z, Roy RR et al (2002) Voluntary exercise induces a BDNF-mediated mechanism that promotes neuroplasticity. J Neurophysiol 88:2187–2195. https://doi.org/10.1152/jn.00152.2002

    Article  PubMed  Google Scholar 

  66. Cuppini R, Sartini S, Agostini D et al (2007) Bdnf expression in rat skeletal muscle after acute or repeated exercise. Arch Ital Biol 145:99–110

    CAS  PubMed  Google Scholar 

  67. Zoladz JA, Pilc A (2010) The effect of physical activity on the brain derived neurotrophic factor: from animal to human studies. J Physiol Pharmacol 61:533–541

    CAS  PubMed  Google Scholar 

  68. Li X, Wu Q, Xie C et al (2018) Blocking of BDNF-TrkB signaling inhibits the promotion effect of neurological function recovery after treadmill training in rats with spinal cord injury. Spinal Cord. https://doi.org/10.1038/s41393-018-0173-0

    Article  PubMed  Google Scholar 

  69. Küst BM, Copray JCVM, Brouwer N et al (2002) Elevated levels of neurotrophins in human biceps brachii tissue of amyotrophic lateral sclerosis. Exp Neurol 177:419–427. https://doi.org/10.1006/exnr.2002.8011

    Article  CAS  PubMed  Google Scholar 

  70. Henriques (2010) Neurotrophic growth factors for the treatment of amyotrophic lateral sclerosis: where do we stand? Front Neurosci 4:1–14. https://doi.org/10.3389/fnins.2010.00032

    Article  Google Scholar 

  71. Nagahara AH, Tuszynski MH (2011) Potential therapeutic uses of BDNF in neurological and psychiatric disorders. Nat Rev Drug Discov 10:209–219. https://doi.org/10.1038/nrd3366

    Article  CAS  PubMed  Google Scholar 

  72. Eide FF, Vining ER, Eide BL et al (1996) Naturally occurring truncated trkB receptors have dominant inhibitory effects on brain-derived neurotrophic factor signaling. J Neurosci 16:3123–3129. https://doi.org/10.1523/JNEUROSCI.16-10-03123.1996

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  73. Gonzalez M, Ruggiero FP, Chang Q et al (1999) Disruption of Trkb-mediated signaling induces disassembly of postsynaptic receptor clusters at neuromuscular junctions. Neuron 24:567–583

    Article  CAS  PubMed  Google Scholar 

  74. Dorsey SG, Lovering RM, Renn CL et al (2011) Genetic deletion of trkB.T1 increases neuromuscular function. Am J Physiol Cell Physiol 302:141–153. https://doi.org/10.1152/ajpcell.00469.2010

    Article  CAS  Google Scholar 

  75. Skup M, Dwornik A, Macias M et al (2002) Long-term locomotor training up-regulates TrkB(FL) receptor-like proteins, brain-derived neurotrophic factor, and neurotrophin 4 with different topographies of expression in oligodendroglia and neurons in the spinal cord. Exp Neurol 176:289–307

    Article  CAS  PubMed  Google Scholar 

  76. Brambilla L, Martorana F, Guidotti G, Rossi D (2018) Dysregulation of astrocytic HMGB1 signaling in amyotrophic lateral sclerosis. Front Neurosci. https://doi.org/10.3389/fnins.2018.00622

    Article  PubMed  PubMed Central  Google Scholar 

  77. Liao B, Zhao W, Beers DR et al (2012) Transformation from a neuroprotective to a neurotoxic microglial phenotype in a mouse model of ALS. Exp Neurol 237:147–152. https://doi.org/10.1016/j.expneurol.2012.06.011

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  78. Liu J-X, Brännström T, Andersen PM, Pedrosa-Domellöf F (2013) Distinct changes in synaptic protein composition at neuromuscular junctions of extraocular muscles versus limb muscles of ALS donors. PLoS One 8:1–12. https://doi.org/10.1371/journal.pone.0057473

    Article  CAS  Google Scholar 

  79. Scott ALM, Ramer MS (2010) Schwann cell p75NTR prevents spontaneous sensory reinnervation of the adult spinal cord. Brain 133:421–432. https://doi.org/10.1093/brain/awp316

    Article  PubMed  Google Scholar 

  80. Bussmann KA, Sofroniew M (1999) Re-expression of p75NTR by adult motor neurons after axotomy is triggered by retrograde transport of a positive signal from axons regrowing through damaged or denervated peripheral nerve tissue. Neuroscience 91:273–281. https://doi.org/10.1016/S0306-4522(98)00562-4

    Article  CAS  PubMed  Google Scholar 

  81. Meeker R, Williams K (2014) Dynamic nature of the p75 neurotrophin receptor in response to injury and disease. J Neuroimmune Pharmacol 9:615–628. https://doi.org/10.1007/s11481-014-9566-9

    Article  PubMed  PubMed Central  Google Scholar 

  82. Kaal EC, Joosten EA, Bär PR (1997) Prevention of apoptotic motoneuron death in vitro by neurotrophins and muscle extract. Neurochem Int 31:193–201

    Article  CAS  PubMed  Google Scholar 

  83. Belluardo N, Westerblad H, Mudó G et al (2001) Neuromuscular junction disassembly and muscle fatigue in mice lacking neurotrophin-4. Mol Cell Neurosci 18:56–67. https://doi.org/10.1006/mcne.2001.1001

    Article  CAS  PubMed  Google Scholar 

  84. Obis T, Besalduch N, Hurtado E et al (2015) The novel protein kinase C epsilon isoform at the adult neuromuscular synapse: location, regulation by synaptic activity-dependent muscle contraction through TrkB signaling and coupling to ACh release. Mol Brain 8:1–16. https://doi.org/10.1186/s13041-015-0098-x

    Article  CAS  Google Scholar 

  85. Nagy G, Matti U, Nehring RB et al (2002) Protein kinase C-dependent phosphorylation of synaptosome-associated protein of 25 kDa at Ser187 potentiates vesicle recruitment. J Neurosci 22:9278–9286. https://doi.org/10.1523/JNEUROSCI.22-21-09278.2002

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  86. Lai C-Y, Liu Y-J, Lai H-L et al (2018) The D2 dopamine receptor interferes with the protective effect of the A2A adenosine receptor on TDP-43 mislocalization in experimental models of motor neuron degeneration. Front Neurosci. https://doi.org/10.3389/fnins.2018.00187

    Article  PubMed  PubMed Central  Google Scholar 

  87. Bilak M, Wu L, Wang Q et al (2004) PGE2 receptors rescue motor neurons in a model of amyotrophic lateral sclerosis. Ann Neurol 56:240–248. https://doi.org/10.1002/ana.20179

    Article  CAS  PubMed  Google Scholar 

  88. Carreras I, Yuruker S, Aytan N et al (2010) Moderate exercise delays the motor performance decline in a transgenic model of ALS. Brain Res 1313:192–201. https://doi.org/10.1016/j.brainres.2009.11.051

    Article  CAS  PubMed  Google Scholar 

  89. Williams TL, Day NC, Ince PG et al (1997) Calcium-permeable alpha-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid receptors: a molecular determinant of selective vulnerability in amyotrophic lateral sclerosis. Ann Neurol 42:200–207. https://doi.org/10.1002/ana.410420211

    Article  CAS  PubMed  Google Scholar 

  90. Alexianu ME, Robbins E, Carswell S, Appel SH (1998) 1Alpha, 25 dihydroxyvitamin D3-dependent up-regulation of calcium-binding proteins in motoneuron cells. J Neurosci Res 51:58. https://doi.org/10.1002/(SICI)1097-4547(19980101)51:1%3c58:AID-JNR6%3e3.0.CO;2-K

    Article  CAS  PubMed  Google Scholar 

  91. Menzies FM, Grierson AJ, Cookson MR et al (2004) Selective loss of neurofilament expression in Cu/Zn superoxide dismutase (SOD1) linked amyotrophic lateral sclerosis. J Neurochem 82:1118–1128. https://doi.org/10.1046/j.1471-4159.2002.01045.x

    Article  Google Scholar 

  92. Gerber YN, Sabourin J-C, Hugnot J-P, Perrin FE (2012) Unlike physical exercise, modified environment increases the lifespan of SOD1G93A mice however both conditions induce cellular changes. PLoS One. https://doi.org/10.1371/journal.pone.0045503

    Article  PubMed  PubMed Central  Google Scholar 

  93. Leenders AGM, Sheng Z-H (2005) Modulation of neurotransmitter release by the second messenger-activated protein kinases: implications for presynaptic plasticity. Pharmacol Ther 105:69–84. https://doi.org/10.1016/j.pharmthera.2004.10.012

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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Acknowledgements

This work was possible with the financial support of Ministerio de Economía, Industria y Competitividad, the Agencia Estatal de Investigación (AEI) and the European Regional Development Fund (ERDF) (SAF2015-67143-P) and the support of the Universitat Rovira i Virgili (URV) (2014PFR-URV-B2-83 and 2017PFR-URV-B2-85) and the Catalan Government (2014SGR344 and 2017SGR704). VC has been supported by the Ministerio de Economía y Competitividad (MINECO) under the framework of the Sistema Nacional de Garantía Juvenil, the European Social Fund (ESF) and the Iniciativa de Empleo Juvenil (IEJ). LJ has been supported by Universitat Rovira i Virgili.

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Author notes

  1. Maria A. Lanuza, Josep Tomàs and Neus Garcia contributed equally to this work.

Authors and Affiliations

  1. Unitat d’Histologia i Neurobiologia (UHNEUROB), Facultat de Medicina i Ciències de la Salut, Universitat Rovira i Virgili. Sant Llorenç 21, 43201, Reus, Spain

    Laia Just-Borràs, Erica Hurtado, Víctor Cilleros-Mañé, Marta Tomàs, Neus Garcia, Josep Tomàs & Maria A. Lanuza

  2. UMR-S1124, INSERM, Faculté des Sciences Fondamentales et Biomédicales, Université Paris Descartes, 45 Rue des Saints-Pères, 75006, Paris, France

    Olivier Biondi & Frédéric Charbonnier

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  1. Laia Just-Borràs
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  2. Erica Hurtado
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  3. Víctor Cilleros-Mañé
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  6. Marta Tomàs
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  8. Josep Tomàs
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  9. Maria A. Lanuza
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Contributions

Data collection: LJ, EH, VC, MT. Quantitative analysis and statistics: LJ. Graphical abstract design: LJ. Data interpretation: LJ, EH, VC, OB, FC, JT, MAL, NG. Literature search: LJ, EH, VC, JT, MAL, NG. Manuscript preparation: LJ, EH, VC, JT, MAL, NG. Conception and design: JT, MAL, NG. All authors read and approved the final manuscript.

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Correspondence to Josep Tomàs or Maria A. Lanuza.

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Just-Borràs, L., Hurtado, E., Cilleros-Mañé, V. et al. Running and swimming prevent the deregulation of the BDNF/TrkB neurotrophic signalling at the neuromuscular junction in mice with amyotrophic lateral sclerosis. Cell. Mol. Life Sci. 77, 3027–3040 (2020). https://doi.org/10.1007/s00018-019-03337-5

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  • DOI: https://doi.org/10.1007/s00018-019-03337-5

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