Adenosine A2A receptor activation is necessary to gate the TrkB-dependent intramuscular nerve sprouting during muscle reinnervation after a nerve crush

Compelling evidence has demonstrated that rehabilitation through physical exercise, a non-invasive and non-surgical intervention, enhances muscle reinnervation and motor recovery after peripheral nerve injury (PNI) by increasing muscle-derived brain-derived neurotrophic factor (BDNF) expression and...

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Main Authors: Michael Di Palma, Davide Lattanzi, Patrizia Ambrogini, Stefano Sartini
Format: Article
Language:English
Published: Elsevier 2025-01-01
Series:Heliyon
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Online Access:http://www.sciencedirect.com/science/article/pii/S2405844024174725
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author Michael Di Palma
Davide Lattanzi
Patrizia Ambrogini
Stefano Sartini
author_facet Michael Di Palma
Davide Lattanzi
Patrizia Ambrogini
Stefano Sartini
author_sort Michael Di Palma
collection DOAJ
description Compelling evidence has demonstrated that rehabilitation through physical exercise, a non-invasive and non-surgical intervention, enhances muscle reinnervation and motor recovery after peripheral nerve injury (PNI) by increasing muscle-derived brain-derived neurotrophic factor (BDNF) expression and triggering TrkB-dependent axonal plasticity. Adenosine has been widely acknowledged to trigger TrkB via A2A receptor (A2AR). Since motor nerve terminals co-express TrkBs and A2ARs and depolarizing conditions increase muscle release of BDNF and adenosine, we examined whether A2ARs activation could recapitulate the functional recovery benefits of intermittent exercise after a nerve crush. Immunohistochemical and in situ proximity ligation assay (isPLA) analyses were used to localize A2ARs and A2A-TrkB heteroreceptor complexes at the neuromuscular level in undenervated animals. The reinnervation process of the soleus muscle was examined in both sedentary and trained animals ten days following a nerve crush injury. The effects of A2A and TrkB interplay on muscle fiber multiple-innervation was assessed using a functional approach. We confirmed that A2A immunoreactivity is mainly localized at the axonal level and provided evidence that A2ARs may form heteroreceptor complexes with TrKb at muscle plasmalemma. The pharmacological activation of either TrkBs or A2ARs mirrored the effect of motor activity on target muscle reinnervation after a nerve crush. Furthermore, the block of A2ARs abolished the effect of TrkBs agonism on nerve endings sprouting. Our results demonstrated that activation of adenosine A2ARs is required to gate the activity-related TrkB-dependent enhancement of axon sprouting during the reinnervation process after a nerve crush. Moreover, our isPLA data suggest that A2ARs can physically interact with TrkBs at the muscle plasmalemma.
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spelling doaj-art-e08eba1a25664fdcaf46c64041f7a5d92025-01-17T04:51:17ZengElsevierHeliyon2405-84402025-01-01111e41441Adenosine A2A receptor activation is necessary to gate the TrkB-dependent intramuscular nerve sprouting during muscle reinnervation after a nerve crushMichael Di Palma0Davide Lattanzi1Patrizia Ambrogini2Stefano Sartini3Department of Experimental and Clinical Medicine, Section of Neuroscience and Cell Biology, Università Politecnica Delle Marche, 60026, Ancona, Italy; Corresponding author.Department of Biomolecular Sciences, University of Urbino Carlo Bo, Urbino, ItalyDepartment of Biomolecular Sciences, University of Urbino Carlo Bo, Urbino, ItalyDepartment of Biomolecular Sciences, University of Urbino Carlo Bo, Urbino, Italy; Corresponding author.Compelling evidence has demonstrated that rehabilitation through physical exercise, a non-invasive and non-surgical intervention, enhances muscle reinnervation and motor recovery after peripheral nerve injury (PNI) by increasing muscle-derived brain-derived neurotrophic factor (BDNF) expression and triggering TrkB-dependent axonal plasticity. Adenosine has been widely acknowledged to trigger TrkB via A2A receptor (A2AR). Since motor nerve terminals co-express TrkBs and A2ARs and depolarizing conditions increase muscle release of BDNF and adenosine, we examined whether A2ARs activation could recapitulate the functional recovery benefits of intermittent exercise after a nerve crush. Immunohistochemical and in situ proximity ligation assay (isPLA) analyses were used to localize A2ARs and A2A-TrkB heteroreceptor complexes at the neuromuscular level in undenervated animals. The reinnervation process of the soleus muscle was examined in both sedentary and trained animals ten days following a nerve crush injury. The effects of A2A and TrkB interplay on muscle fiber multiple-innervation was assessed using a functional approach. We confirmed that A2A immunoreactivity is mainly localized at the axonal level and provided evidence that A2ARs may form heteroreceptor complexes with TrKb at muscle plasmalemma. The pharmacological activation of either TrkBs or A2ARs mirrored the effect of motor activity on target muscle reinnervation after a nerve crush. Furthermore, the block of A2ARs abolished the effect of TrkBs agonism on nerve endings sprouting. Our results demonstrated that activation of adenosine A2ARs is required to gate the activity-related TrkB-dependent enhancement of axon sprouting during the reinnervation process after a nerve crush. Moreover, our isPLA data suggest that A2ARs can physically interact with TrkBs at the muscle plasmalemma.http://www.sciencedirect.com/science/article/pii/S2405844024174725Peripheral nerve lesionExerciseTerminal axon sproutingMuscle reinnervationTropomyosin-related kinase B receptorAdenosine A2A receptor
spellingShingle Michael Di Palma
Davide Lattanzi
Patrizia Ambrogini
Stefano Sartini
Adenosine A2A receptor activation is necessary to gate the TrkB-dependent intramuscular nerve sprouting during muscle reinnervation after a nerve crush
Heliyon
Peripheral nerve lesion
Exercise
Terminal axon sprouting
Muscle reinnervation
Tropomyosin-related kinase B receptor
Adenosine A2A receptor
title Adenosine A2A receptor activation is necessary to gate the TrkB-dependent intramuscular nerve sprouting during muscle reinnervation after a nerve crush
title_full Adenosine A2A receptor activation is necessary to gate the TrkB-dependent intramuscular nerve sprouting during muscle reinnervation after a nerve crush
title_fullStr Adenosine A2A receptor activation is necessary to gate the TrkB-dependent intramuscular nerve sprouting during muscle reinnervation after a nerve crush
title_full_unstemmed Adenosine A2A receptor activation is necessary to gate the TrkB-dependent intramuscular nerve sprouting during muscle reinnervation after a nerve crush
title_short Adenosine A2A receptor activation is necessary to gate the TrkB-dependent intramuscular nerve sprouting during muscle reinnervation after a nerve crush
title_sort adenosine a2a receptor activation is necessary to gate the trkb dependent intramuscular nerve sprouting during muscle reinnervation after a nerve crush
topic Peripheral nerve lesion
Exercise
Terminal axon sprouting
Muscle reinnervation
Tropomyosin-related kinase B receptor
Adenosine A2A receptor
url http://www.sciencedirect.com/science/article/pii/S2405844024174725
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