Increased Cholinergic Tone Causes Pre-synaptic Neuromuscular Degeneration and is Associated with Impaired Diaphragm Function
Autor(a) principal: | |
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Data de Publicação: | 2021 |
Outros Autores: | , , , , , , , , , , , , |
Tipo de documento: | Artigo |
Idioma: | eng |
Título da fonte: | Repositório Institucional da UNESP |
Texto Completo: | http://dx.doi.org/10.1016/j.neuroscience.2020.12.025 http://hdl.handle.net/11449/207399 |
Resumo: | In vertebrates, muscle activity is dependent on acetylcholine (ACh) released from neuromuscular junctions (NMJs), and changes in cholinergic neurotransmission are linked to a variety of neuromuscular diseases, including congenital myasthenic syndromes (CMS). The storage and release of ACh depends on the activity of the Vesicular Acetylcholine Transporter (VAChT), a rate-limiting step for cholinergic neurotransmission whose loss of function mutations was shown to cause human congenital myasthenia. However, we know much less about increased VAChT activity, due to copy number variations, for example. Therefore, here we investigated the impact of increased VAChT expression and consequently ACh levels at the synaptic cleft of the diaphragm NMJs. We analyzed structure and function of nerve and muscles from a mouse model of cholinergic hyperfunction (ChAT-ChR2-EYFP) with increased expression of VAChT. Our results showed a significant increase of ACh released under evoked stimuli. However, we observed deleterious changes in synaptic vesicles cycle (impaired endocytosis and decrease in vesicles number), together with structural alterations of NMJs. Interestingly, ultrastructure analyses showed that synaptic vesicles from ChAT-ChR2-EYFP mice NMJs were larger, which might be related to increased ACh load. We also observed that these larger synaptic vesicles were less rounded in comparison with control. Finally, we showed that ChAT-ChR2-EYFP mice NMJs have compromised safety factor, possible due to the structural alterations we described. These findings reveal that physiological cholinergic activity is important to maintain the structure and function of the neuromuscular system and help to understand some of the neuromuscular adverse effects experienced by chronically increased NMJ neurotransmission, such as individuals treated with cholinesterase inhibitors. |
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Increased Cholinergic Tone Causes Pre-synaptic Neuromuscular Degeneration and is Associated with Impaired Diaphragm Functionacetylcholinecholinergic signalingneuromuscular junctionIn vertebrates, muscle activity is dependent on acetylcholine (ACh) released from neuromuscular junctions (NMJs), and changes in cholinergic neurotransmission are linked to a variety of neuromuscular diseases, including congenital myasthenic syndromes (CMS). The storage and release of ACh depends on the activity of the Vesicular Acetylcholine Transporter (VAChT), a rate-limiting step for cholinergic neurotransmission whose loss of function mutations was shown to cause human congenital myasthenia. However, we know much less about increased VAChT activity, due to copy number variations, for example. Therefore, here we investigated the impact of increased VAChT expression and consequently ACh levels at the synaptic cleft of the diaphragm NMJs. We analyzed structure and function of nerve and muscles from a mouse model of cholinergic hyperfunction (ChAT-ChR2-EYFP) with increased expression of VAChT. Our results showed a significant increase of ACh released under evoked stimuli. However, we observed deleterious changes in synaptic vesicles cycle (impaired endocytosis and decrease in vesicles number), together with structural alterations of NMJs. Interestingly, ultrastructure analyses showed that synaptic vesicles from ChAT-ChR2-EYFP mice NMJs were larger, which might be related to increased ACh load. We also observed that these larger synaptic vesicles were less rounded in comparison with control. Finally, we showed that ChAT-ChR2-EYFP mice NMJs have compromised safety factor, possible due to the structural alterations we described. These findings reveal that physiological cholinergic activity is important to maintain the structure and function of the neuromuscular system and help to understand some of the neuromuscular adverse effects experienced by chronically increased NMJ neurotransmission, such as individuals treated with cholinesterase inhibitors.Coordenação de Aperfeiçoamento de Pessoal de Nível Superior (CAPES)Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq)Fundação de Amparo à Pesquisa do Estado de Minas Gerais (FAPEMIG)Departamento de Morfologia ICB Universidade Federal de Minas GeraisDepartamento de Fisiologia e Biofísica ICB Universidade Federal de Minas GeraisDepartamento de Farmacologia ICB Universidade Federal de Minas GeraisDepartamento de Ciências Básicas da Vida Instituto de Ciências da Vida Universidade Federal de Juiz de Fora Campus Governador Valadares UFJFDepartamento de Farmacologia Instituto de Biociências UNESP, Distrito de Rubião Jr.Robarts Research Institute and Department of Physiology and Pharmacology and Anatomy & Cell Biology University of Western OntarioDepartamento de Medicina Faculdade Ciências Médicas de Minas Gerais FCMMGDepartamento de Farmacologia Instituto de Biociências UNESP, Distrito de Rubião Jr.CNPq: 150567/2019-7CNPq: 401071/2014-6FAPEMIG: APQ-00092-18Universidade Federal de Minas Gerais (UFMG)UFJFUniversidade Estadual Paulista (Unesp)University of Western OntarioFCMMGMagalhães-Gomes, Matheus P.S.Camargos, WallaceValadão, Priscila A.C.Garcias, Rubens S.Rodrigues, Hermann A.Andrade, Jéssica N.Teixeira, Vanessa P.Naves, Lígia A.Cavalcante, Walter L.G.Gallaci, Marcia [UNESP]Guatimosim, SilviaPrado, Vânia F.Prado, Marco A.M.Guatimosim, Cristina2021-06-25T10:54:34Z2021-06-25T10:54:34Z2021-04-15info:eu-repo/semantics/publishedVersioninfo:eu-repo/semantics/article31-42http://dx.doi.org/10.1016/j.neuroscience.2020.12.025Neuroscience, v. 460, p. 31-42.1873-75440306-4522http://hdl.handle.net/11449/20739910.1016/j.neuroscience.2020.12.0252-s2.0-85102062764Scopusreponame:Repositório Institucional da UNESPinstname:Universidade Estadual Paulista (UNESP)instacron:UNESPengNeuroscienceinfo:eu-repo/semantics/openAccess2021-10-23T17:09:10Zoai:repositorio.unesp.br:11449/207399Repositório InstitucionalPUBhttp://repositorio.unesp.br/oai/requestopendoar:29462021-10-23T17:09:10Repositório Institucional da UNESP - Universidade Estadual Paulista (UNESP)false |
dc.title.none.fl_str_mv |
Increased Cholinergic Tone Causes Pre-synaptic Neuromuscular Degeneration and is Associated with Impaired Diaphragm Function |
title |
Increased Cholinergic Tone Causes Pre-synaptic Neuromuscular Degeneration and is Associated with Impaired Diaphragm Function |
spellingShingle |
Increased Cholinergic Tone Causes Pre-synaptic Neuromuscular Degeneration and is Associated with Impaired Diaphragm Function Magalhães-Gomes, Matheus P.S. acetylcholine cholinergic signaling neuromuscular junction |
title_short |
Increased Cholinergic Tone Causes Pre-synaptic Neuromuscular Degeneration and is Associated with Impaired Diaphragm Function |
title_full |
Increased Cholinergic Tone Causes Pre-synaptic Neuromuscular Degeneration and is Associated with Impaired Diaphragm Function |
title_fullStr |
Increased Cholinergic Tone Causes Pre-synaptic Neuromuscular Degeneration and is Associated with Impaired Diaphragm Function |
title_full_unstemmed |
Increased Cholinergic Tone Causes Pre-synaptic Neuromuscular Degeneration and is Associated with Impaired Diaphragm Function |
title_sort |
Increased Cholinergic Tone Causes Pre-synaptic Neuromuscular Degeneration and is Associated with Impaired Diaphragm Function |
author |
Magalhães-Gomes, Matheus P.S. |
author_facet |
Magalhães-Gomes, Matheus P.S. Camargos, Wallace Valadão, Priscila A.C. Garcias, Rubens S. Rodrigues, Hermann A. Andrade, Jéssica N. Teixeira, Vanessa P. Naves, Lígia A. Cavalcante, Walter L.G. Gallaci, Marcia [UNESP] Guatimosim, Silvia Prado, Vânia F. Prado, Marco A.M. Guatimosim, Cristina |
author_role |
author |
author2 |
Camargos, Wallace Valadão, Priscila A.C. Garcias, Rubens S. Rodrigues, Hermann A. Andrade, Jéssica N. Teixeira, Vanessa P. Naves, Lígia A. Cavalcante, Walter L.G. Gallaci, Marcia [UNESP] Guatimosim, Silvia Prado, Vânia F. Prado, Marco A.M. Guatimosim, Cristina |
author2_role |
author author author author author author author author author author author author author |
dc.contributor.none.fl_str_mv |
Universidade Federal de Minas Gerais (UFMG) UFJF Universidade Estadual Paulista (Unesp) University of Western Ontario FCMMG |
dc.contributor.author.fl_str_mv |
Magalhães-Gomes, Matheus P.S. Camargos, Wallace Valadão, Priscila A.C. Garcias, Rubens S. Rodrigues, Hermann A. Andrade, Jéssica N. Teixeira, Vanessa P. Naves, Lígia A. Cavalcante, Walter L.G. Gallaci, Marcia [UNESP] Guatimosim, Silvia Prado, Vânia F. Prado, Marco A.M. Guatimosim, Cristina |
dc.subject.por.fl_str_mv |
acetylcholine cholinergic signaling neuromuscular junction |
topic |
acetylcholine cholinergic signaling neuromuscular junction |
description |
In vertebrates, muscle activity is dependent on acetylcholine (ACh) released from neuromuscular junctions (NMJs), and changes in cholinergic neurotransmission are linked to a variety of neuromuscular diseases, including congenital myasthenic syndromes (CMS). The storage and release of ACh depends on the activity of the Vesicular Acetylcholine Transporter (VAChT), a rate-limiting step for cholinergic neurotransmission whose loss of function mutations was shown to cause human congenital myasthenia. However, we know much less about increased VAChT activity, due to copy number variations, for example. Therefore, here we investigated the impact of increased VAChT expression and consequently ACh levels at the synaptic cleft of the diaphragm NMJs. We analyzed structure and function of nerve and muscles from a mouse model of cholinergic hyperfunction (ChAT-ChR2-EYFP) with increased expression of VAChT. Our results showed a significant increase of ACh released under evoked stimuli. However, we observed deleterious changes in synaptic vesicles cycle (impaired endocytosis and decrease in vesicles number), together with structural alterations of NMJs. Interestingly, ultrastructure analyses showed that synaptic vesicles from ChAT-ChR2-EYFP mice NMJs were larger, which might be related to increased ACh load. We also observed that these larger synaptic vesicles were less rounded in comparison with control. Finally, we showed that ChAT-ChR2-EYFP mice NMJs have compromised safety factor, possible due to the structural alterations we described. These findings reveal that physiological cholinergic activity is important to maintain the structure and function of the neuromuscular system and help to understand some of the neuromuscular adverse effects experienced by chronically increased NMJ neurotransmission, such as individuals treated with cholinesterase inhibitors. |
publishDate |
2021 |
dc.date.none.fl_str_mv |
2021-06-25T10:54:34Z 2021-06-25T10:54:34Z 2021-04-15 |
dc.type.status.fl_str_mv |
info:eu-repo/semantics/publishedVersion |
dc.type.driver.fl_str_mv |
info:eu-repo/semantics/article |
format |
article |
status_str |
publishedVersion |
dc.identifier.uri.fl_str_mv |
http://dx.doi.org/10.1016/j.neuroscience.2020.12.025 Neuroscience, v. 460, p. 31-42. 1873-7544 0306-4522 http://hdl.handle.net/11449/207399 10.1016/j.neuroscience.2020.12.025 2-s2.0-85102062764 |
url |
http://dx.doi.org/10.1016/j.neuroscience.2020.12.025 http://hdl.handle.net/11449/207399 |
identifier_str_mv |
Neuroscience, v. 460, p. 31-42. 1873-7544 0306-4522 10.1016/j.neuroscience.2020.12.025 2-s2.0-85102062764 |
dc.language.iso.fl_str_mv |
eng |
language |
eng |
dc.relation.none.fl_str_mv |
Neuroscience |
dc.rights.driver.fl_str_mv |
info:eu-repo/semantics/openAccess |
eu_rights_str_mv |
openAccess |
dc.format.none.fl_str_mv |
31-42 |
dc.source.none.fl_str_mv |
Scopus reponame:Repositório Institucional da UNESP instname:Universidade Estadual Paulista (UNESP) instacron:UNESP |
instname_str |
Universidade Estadual Paulista (UNESP) |
instacron_str |
UNESP |
institution |
UNESP |
reponame_str |
Repositório Institucional da UNESP |
collection |
Repositório Institucional da UNESP |
repository.name.fl_str_mv |
Repositório Institucional da UNESP - Universidade Estadual Paulista (UNESP) |
repository.mail.fl_str_mv |
|
_version_ |
1799964860202614784 |