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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

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

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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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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

Keywords

  • ALS
  • Skeletal muscle
  • Exercise
  • NMJ
  • Neurotransmission
  • Motoneuron loss