Betaine-homocysteine S-methyltransferase deficiency causes increased susceptibility to noise-induced hearing loss associated to plasma hyperhomocysteinemia

Betaine-homocysteine S-methyltransferases (BHMTs) are methionine cycle enzymes that remethylate homocysteine; hence, their malfunction leads to hyperhomocysteinemia. Epidemiologic and experimental studies have revealed a correlation between hyperhomocysteinemia and hearing loss. Here, we have studie...

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Authors: Partearroyo, Teresa, Murillo-Cuesta, Silvia, Vallecillo, Néstor, Bermúdez-Muñoz, Jose Mª, Rodriguez-de la Rosa, Lourdes, Mandruzzato, Giacomo, Celaya, Adelaida M., Zeisel, Steven H., Pajares, María Ángeles, Varela-Moreiras, Gregorio, Varela-Nieto, Isabel
Format: article
Status:Versión enviada para evaluación y publicación
Publication Date:2019
Country:España
Institution:Consejo Superior de Investigaciones Científicas (CSIC)
Repository:DIGITAL.CSIC. Repositorio Institucional del CSIC
OAI Identifier:oai:digital.csic.es:10261/176630
Online Access:http://hdl.handle.net/10261/176630
Access Level:Open access
Keyword:ARHL
Cochlear injury
Methionine cycle
NIHL
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spelling Betaine-homocysteine S-methyltransferase deficiency causes increased susceptibility to noise-induced hearing loss associated to plasma hyperhomocysteinemiaPartearroyo, TeresaMurillo-Cuesta, SilviaVallecillo, NéstorBermúdez-Muñoz, Jose MªRodriguez-de la Rosa, LourdesMandruzzato, GiacomoCelaya, Adelaida M.Zeisel, Steven H.Pajares, María ÁngelesVarela-Moreiras, GregorioVarela-Nieto, IsabelARHLCochlear injuryMethionine cycleNIHLBetaine-homocysteine S-methyltransferases (BHMTs) are methionine cycle enzymes that remethylate homocysteine; hence, their malfunction leads to hyperhomocysteinemia. Epidemiologic and experimental studies have revealed a correlation between hyperhomocysteinemia and hearing loss. Here, we have studied the expression of methionine cycle genes in the mouse cochlea and the impact of knocking out the Bhmt gene in the auditory receptor. We evaluated age-related changes in mouse hearing by recording auditory brainstem responses before and following exposure to noise. Also, we measured cochlear cytoarchitecture, gene expression by RNA-arrays and quantitative RT-PCR, and metabolite levels in liver and plasma by HPLC. Our results indicate that there is an age-dependent strain-specific expression of methionine cycle genes in the mouse cochlea and a further regulation during the response to noise damage. Loss of Bhmt did not cause an evident impact in the hearing acuity of young mice, but it produced higher threshold shifts and poorer recovery following noise challenge. Hearing loss was associated with increased cochlear injury, outer hair cell loss, altered expression of cochlear methionine cycle genes, and hyperhomocysteinemia. Our results suggest that BHMT plays a central role in the homeostasis of cochlear methionine metabolism and that Bhmt2 up-regulation could carry out a compensatory role in cochlear protection against noise injury in the absence of BHMT.—Partearroyo, T., Murillo-Cuesta, S., Vallecillo, N., Bermúdez-Muñoz, J. M., Rodríguez-de la Rosa, L., Mandruzzato, G., Celaya, A. M., Zeisel, S. H., Pajares, M. A., Varela-Moreiras, G., Varela-Nieto, I. Betaine-homocysteine S-methyltransferase deficiency causes increased susceptibility to noise-induced hearing loss associated to plasma hyperhomocysteinemia.This work was supported by the Spanish Ministerio de Economía y Competitividad (MINECO)/ FEDER SAF2017-86107-R to I.V.-N., U.S. National Institutes of Health (NIH), National Institute of Diabetes and Digestive and Kidney Diseases (Grant DK056350 to S.H.Z.), CEU-Banco Santander precompetitive project (MUSPB047) and CEUBanco Santander consolidation project (MBS18C12) to T.P., and Puleva BioFoods (to I.V.-N., G.V.-M., and M.A.P.). G.M. was supported by TARGEAR (FP7 PEOPLE 2013 IAPP612261).Peer reviewedFederation of American Societies for Experimental BiologyAgencia Estatal de Investigación (España)Ministerio de Economía, Industria y Competitividad (España)Ministerio de Economía y Competitividad (España)National Institutes of Health (US)European CommissionNational Institutes of Health (US)Banco SantanderPulevaConsejo Superior de Investigaciones Científicas [https://ror.org/02gfc7t72]201920192019info:eu-repo/semantics/articlehttp://purl.org/coar/resource_type/c_6501Preprintinfo:eu-repo/semantics/submittedVersionhttp://hdl.handle.net/10261/176630reponame:DIGITAL.CSIC. Repositorio Institucional del CSICinstname:Consejo Superior de Investigaciones Científicas (CSIC)Inglés#PLACEHOLDER_PARENT_METADATA_VALUE##PLACEHOLDER_PARENT_METADATA_VALUE##PLACEHOLDER_PARENT_METADATA_VALUE#SAF2017-86107-R/AEI/10.13039/501100011033info:eu-repo/grantAgreement/AEI/Plan Estatal de Investigación Científica y Técnica y de Innovación 2017-2020/SAF2017-86107-Rinfo:eu-repo/grantAgreement/EC/FP7/612261https://doi.org/10.1096/fj.201801533RSíinfo:eu-repo/semantics/openAccessoai:digital.csic.es:10261/1766302026-05-22T06:33:51Z
dc.title.none.fl_str_mv Betaine-homocysteine S-methyltransferase deficiency causes increased susceptibility to noise-induced hearing loss associated to plasma hyperhomocysteinemia
title Betaine-homocysteine S-methyltransferase deficiency causes increased susceptibility to noise-induced hearing loss associated to plasma hyperhomocysteinemia
spellingShingle Betaine-homocysteine S-methyltransferase deficiency causes increased susceptibility to noise-induced hearing loss associated to plasma hyperhomocysteinemia
Partearroyo, Teresa
ARHL
Cochlear injury
Methionine cycle
NIHL
title_short Betaine-homocysteine S-methyltransferase deficiency causes increased susceptibility to noise-induced hearing loss associated to plasma hyperhomocysteinemia
title_full Betaine-homocysteine S-methyltransferase deficiency causes increased susceptibility to noise-induced hearing loss associated to plasma hyperhomocysteinemia
title_fullStr Betaine-homocysteine S-methyltransferase deficiency causes increased susceptibility to noise-induced hearing loss associated to plasma hyperhomocysteinemia
title_full_unstemmed Betaine-homocysteine S-methyltransferase deficiency causes increased susceptibility to noise-induced hearing loss associated to plasma hyperhomocysteinemia
title_sort Betaine-homocysteine S-methyltransferase deficiency causes increased susceptibility to noise-induced hearing loss associated to plasma hyperhomocysteinemia
dc.creator.none.fl_str_mv Partearroyo, Teresa
Murillo-Cuesta, Silvia
Vallecillo, Néstor
Bermúdez-Muñoz, Jose Mª
Rodriguez-de la Rosa, Lourdes
Mandruzzato, Giacomo
Celaya, Adelaida M.
Zeisel, Steven H.
Pajares, María Ángeles
Varela-Moreiras, Gregorio
Varela-Nieto, Isabel
author Partearroyo, Teresa
author_facet Partearroyo, Teresa
Murillo-Cuesta, Silvia
Vallecillo, Néstor
Bermúdez-Muñoz, Jose Mª
Rodriguez-de la Rosa, Lourdes
Mandruzzato, Giacomo
Celaya, Adelaida M.
Zeisel, Steven H.
Pajares, María Ángeles
Varela-Moreiras, Gregorio
Varela-Nieto, Isabel
author_role author
author2 Murillo-Cuesta, Silvia
Vallecillo, Néstor
Bermúdez-Muñoz, Jose Mª
Rodriguez-de la Rosa, Lourdes
Mandruzzato, Giacomo
Celaya, Adelaida M.
Zeisel, Steven H.
Pajares, María Ángeles
Varela-Moreiras, Gregorio
Varela-Nieto, Isabel
author2_role author
author
author
author
author
author
author
author
author
author
dc.contributor.none.fl_str_mv Agencia Estatal de Investigación (España)
Ministerio de Economía, Industria y Competitividad (España)
Ministerio de Economía y Competitividad (España)
National Institutes of Health (US)
European Commission
National Institutes of Health (US)
Banco Santander
Puleva
Consejo Superior de Investigaciones Científicas [https://ror.org/02gfc7t72]
dc.subject.none.fl_str_mv ARHL
Cochlear injury
Methionine cycle
NIHL
topic ARHL
Cochlear injury
Methionine cycle
NIHL
description Betaine-homocysteine S-methyltransferases (BHMTs) are methionine cycle enzymes that remethylate homocysteine; hence, their malfunction leads to hyperhomocysteinemia. Epidemiologic and experimental studies have revealed a correlation between hyperhomocysteinemia and hearing loss. Here, we have studied the expression of methionine cycle genes in the mouse cochlea and the impact of knocking out the Bhmt gene in the auditory receptor. We evaluated age-related changes in mouse hearing by recording auditory brainstem responses before and following exposure to noise. Also, we measured cochlear cytoarchitecture, gene expression by RNA-arrays and quantitative RT-PCR, and metabolite levels in liver and plasma by HPLC. Our results indicate that there is an age-dependent strain-specific expression of methionine cycle genes in the mouse cochlea and a further regulation during the response to noise damage. Loss of Bhmt did not cause an evident impact in the hearing acuity of young mice, but it produced higher threshold shifts and poorer recovery following noise challenge. Hearing loss was associated with increased cochlear injury, outer hair cell loss, altered expression of cochlear methionine cycle genes, and hyperhomocysteinemia. Our results suggest that BHMT plays a central role in the homeostasis of cochlear methionine metabolism and that Bhmt2 up-regulation could carry out a compensatory role in cochlear protection against noise injury in the absence of BHMT.—Partearroyo, T., Murillo-Cuesta, S., Vallecillo, N., Bermúdez-Muñoz, J. M., Rodríguez-de la Rosa, L., Mandruzzato, G., Celaya, A. M., Zeisel, S. H., Pajares, M. A., Varela-Moreiras, G., Varela-Nieto, I. Betaine-homocysteine S-methyltransferase deficiency causes increased susceptibility to noise-induced hearing loss associated to plasma hyperhomocysteinemia.
publishDate 2019
dc.date.none.fl_str_mv 2019
2019
2019
dc.type.none.fl_str_mv info:eu-repo/semantics/article
http://purl.org/coar/resource_type/c_6501
Preprint
info:eu-repo/semantics/submittedVersion
format article
status_str submittedVersion
dc.identifier.none.fl_str_mv http://hdl.handle.net/10261/176630
url http://hdl.handle.net/10261/176630
dc.language.none.fl_str_mv Inglés
language_invalid_str_mv Inglés
dc.relation.none.fl_str_mv #PLACEHOLDER_PARENT_METADATA_VALUE#
#PLACEHOLDER_PARENT_METADATA_VALUE#
#PLACEHOLDER_PARENT_METADATA_VALUE#
SAF2017-86107-R/AEI/10.13039/501100011033
info:eu-repo/grantAgreement/AEI/Plan Estatal de Investigación Científica y Técnica y de Innovación 2017-2020/SAF2017-86107-R
info:eu-repo/grantAgreement/EC/FP7/612261
https://doi.org/10.1096/fj.201801533R
Sí
dc.rights.none.fl_str_mv info:eu-repo/semantics/openAccess
eu_rights_str_mv openAccess
dc.publisher.none.fl_str_mv Federation of American Societies for Experimental Biology
publisher.none.fl_str_mv Federation of American Societies for Experimental Biology
dc.source.none.fl_str_mv reponame:DIGITAL.CSIC. Repositorio Institucional del CSIC
instname:Consejo Superior de Investigaciones Científicas (CSIC)
instname_str Consejo Superior de Investigaciones Científicas (CSIC)
reponame_str DIGITAL.CSIC. Repositorio Institucional del CSIC
collection DIGITAL.CSIC. Repositorio Institucional del CSIC
repository.name.fl_str_mv
repository.mail.fl_str_mv
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