Unveiling the Metabolic changes on muscle cell metabolism underlying p-phenylenediamine toxicity

Rhabdomyolysis is a disorder characterized by acute damage of the sarcolemma of the skeletal muscle leading to release of potentially toxic muscle cell components into the circulation, most notably creatine phosphokinase (CK) and myoglobulin, and is frequently accompanied by myoglobinuria. In the pr...

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Autores: Marín de Mas, Igor Bartolomé, Marín Martínez, Silvia, Pachón, Gisela, Rodríguez Prados, Juan C., Vizán Carralcázar, Pedro, Centelles Serra, Josep Joan, Tauler Ferré, Romà, Azqueta, Amaya, Selivanov, Vitaly, López de Ceraín, Adela, Cascante i Serratosa, Marta
Tipo de recurso: artículo
Estado:Versión publicada
Fecha de publicación:2017
País:España
Institución:Varias* (Consorci de Biblioteques Universitáries de Catalunya, Centre de Serveis Científics i Acadèmics de Catalunya)
Repositorio:Recercat. Dipósit de la Recerca de Catalunya
OAI Identifier:oai:recercat.cat:2445/120101
Acceso en línea:https://hdl.handle.net/2445/120101
Access Level:acceso abierto
Palabra clave:Malalties de l'aparell locomotor
Trastorns del metabolisme
Enfermedades del aparato locomotor
Disorders of metabolism
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spelling Unveiling the Metabolic changes on muscle cell metabolism underlying p-phenylenediamine toxicityMarín de Mas, Igor BartoloméMarín Martínez, SilviaPachón, GiselaRodríguez Prados, Juan C.Vizán Carralcázar, PedroCentelles Serra, Josep JoanTauler Ferré, RomàAzqueta, AmayaSelivanov, VitalyLópez de Ceraín, AdelaCascante i Serratosa, MartaMalalties de l'aparell locomotorTrastorns del metabolismeEnfermedades del aparato locomotorDisorders of metabolismRhabdomyolysis is a disorder characterized by acute damage of the sarcolemma of the skeletal muscle leading to release of potentially toxic muscle cell components into the circulation, most notably creatine phosphokinase (CK) and myoglobulin, and is frequently accompanied by myoglobinuria. In the present work, we evaluated the toxicity of p-phenylenediamine (PPD), a main component of hair dyes which is reported to induce rhabdomyolysis. We studied the metabolic effect of this compound in vivo with Wistar rats and in vitro with C2C12 muscle cells. To this aim we have combined multi-omic experimental measurements with computational approaches using model-driven methods. The integrative study presented here has unveiled the metabolic disorders associated to PPD exposure that may underlay the aberrant metabolism observed in rhabdomyolys disease. Animals treated with lower doses of PPD (10 and 20 mg/kg) showed depressed activity and myoglobinuria after 10 h of treatment. We measured the serum levels of aspartate aminotransferase (AST), alanine aminotransferase (ALT), and creatine kinase (CK) in rats after 24, 48, and 72 h of PPD exposure. At all times, treatment with PPD at higher doses (40 and 60 mg/kg) showed an increase of AST and ALT, and also an increase of lactate dehydrogenase (LDH) and CK after 24 h. Blood packed cell volume and hemoglobin levels, as well as organs weight at 48 and 72 h, were also measured. No significant differences were observed in these parameters under any condition. PPD induce cell cycle arrest in S phase and apoptosis (40% or early apoptotic cells) on mus musculus mouse C2C12 cells after 24 h of treatment. Incubation of mus musculus mouse C2C12 cells with [1,2-13C2]-glucose during 24 h, subsequent quantification of 13C isotopologues distribution in key metabolites of glucose metabolic network and a computational fluxomic analysis using in-house developed software (Isodyn) showed that PPD is inhibiting glycolysis, non-oxidative pentose phosphate pathway, glycogen turnover, and ATPAse reaction leading to a reduction in ATP synthesis. These findings unveil the glucose metabolism collapse, which is consistent with a decrease in cell viability observed in PPD-treated C2C12 cells and with the myoglubinuria and other effects observed in Wistar Rats treated with PPD. These findings shed new light on muscle dysfunction associated to PPD exposure, opening new avenues for cost-effective therapies in Rhabdomyolysis disease.Frontiers Media2018201820172018info:eu-repo/semantics/articleinfo:eu-repo/semantics/publishedVersion12 p.application/pdfhttps://hdl.handle.net/2445/120101Articles publicats en revistes (Bioquímica i Biomedicina Molecular)reponame:Recercat. Dipósit de la Recerca de Catalunyainstname:Varias* (Consorci de Biblioteques Universitáries de Catalunya, Centre de Serveis Científics i Acadèmics de Catalunya)InglésReproducció del document publicat a: https://doi.org/10.3389/fmolb.2017.00008Frontiers in Molecular Biosciences, 2017, vol. 4, num. 8https://doi.org/10.3389/fmolb.2017.00008info:eu-repo/grantAgreement/EC/FP7/320737cc-by (c) Marín de Mas, Igor Bartolomé et al., 2017http://creativecommons.org/licenses/by/3.0/esinfo:eu-repo/semantics/openAccessoai:recercat.cat:2445/1201012026-05-29T05:05:01Z
dc.title.none.fl_str_mv Unveiling the Metabolic changes on muscle cell metabolism underlying p-phenylenediamine toxicity
title Unveiling the Metabolic changes on muscle cell metabolism underlying p-phenylenediamine toxicity
spellingShingle Unveiling the Metabolic changes on muscle cell metabolism underlying p-phenylenediamine toxicity
Marín de Mas, Igor Bartolomé
Malalties de l'aparell locomotor
Trastorns del metabolisme
Enfermedades del aparato locomotor
Disorders of metabolism
title_short Unveiling the Metabolic changes on muscle cell metabolism underlying p-phenylenediamine toxicity
title_full Unveiling the Metabolic changes on muscle cell metabolism underlying p-phenylenediamine toxicity
title_fullStr Unveiling the Metabolic changes on muscle cell metabolism underlying p-phenylenediamine toxicity
title_full_unstemmed Unveiling the Metabolic changes on muscle cell metabolism underlying p-phenylenediamine toxicity
title_sort Unveiling the Metabolic changes on muscle cell metabolism underlying p-phenylenediamine toxicity
dc.creator.none.fl_str_mv Marín de Mas, Igor Bartolomé
Marín Martínez, Silvia
Pachón, Gisela
Rodríguez Prados, Juan C.
Vizán Carralcázar, Pedro
Centelles Serra, Josep Joan
Tauler Ferré, Romà
Azqueta, Amaya
Selivanov, Vitaly
López de Ceraín, Adela
Cascante i Serratosa, Marta
author Marín de Mas, Igor Bartolomé
author_facet Marín de Mas, Igor Bartolomé
Marín Martínez, Silvia
Pachón, Gisela
Rodríguez Prados, Juan C.
Vizán Carralcázar, Pedro
Centelles Serra, Josep Joan
Tauler Ferré, Romà
Azqueta, Amaya
Selivanov, Vitaly
López de Ceraín, Adela
Cascante i Serratosa, Marta
author_role author
author2 Marín Martínez, Silvia
Pachón, Gisela
Rodríguez Prados, Juan C.
Vizán Carralcázar, Pedro
Centelles Serra, Josep Joan
Tauler Ferré, Romà
Azqueta, Amaya
Selivanov, Vitaly
López de Ceraín, Adela
Cascante i Serratosa, Marta
author2_role author
author
author
author
author
author
author
author
author
author
dc.subject.none.fl_str_mv Malalties de l'aparell locomotor
Trastorns del metabolisme
Enfermedades del aparato locomotor
Disorders of metabolism
topic Malalties de l'aparell locomotor
Trastorns del metabolisme
Enfermedades del aparato locomotor
Disorders of metabolism
description Rhabdomyolysis is a disorder characterized by acute damage of the sarcolemma of the skeletal muscle leading to release of potentially toxic muscle cell components into the circulation, most notably creatine phosphokinase (CK) and myoglobulin, and is frequently accompanied by myoglobinuria. In the present work, we evaluated the toxicity of p-phenylenediamine (PPD), a main component of hair dyes which is reported to induce rhabdomyolysis. We studied the metabolic effect of this compound in vivo with Wistar rats and in vitro with C2C12 muscle cells. To this aim we have combined multi-omic experimental measurements with computational approaches using model-driven methods. The integrative study presented here has unveiled the metabolic disorders associated to PPD exposure that may underlay the aberrant metabolism observed in rhabdomyolys disease. Animals treated with lower doses of PPD (10 and 20 mg/kg) showed depressed activity and myoglobinuria after 10 h of treatment. We measured the serum levels of aspartate aminotransferase (AST), alanine aminotransferase (ALT), and creatine kinase (CK) in rats after 24, 48, and 72 h of PPD exposure. At all times, treatment with PPD at higher doses (40 and 60 mg/kg) showed an increase of AST and ALT, and also an increase of lactate dehydrogenase (LDH) and CK after 24 h. Blood packed cell volume and hemoglobin levels, as well as organs weight at 48 and 72 h, were also measured. No significant differences were observed in these parameters under any condition. PPD induce cell cycle arrest in S phase and apoptosis (40% or early apoptotic cells) on mus musculus mouse C2C12 cells after 24 h of treatment. Incubation of mus musculus mouse C2C12 cells with [1,2-13C2]-glucose during 24 h, subsequent quantification of 13C isotopologues distribution in key metabolites of glucose metabolic network and a computational fluxomic analysis using in-house developed software (Isodyn) showed that PPD is inhibiting glycolysis, non-oxidative pentose phosphate pathway, glycogen turnover, and ATPAse reaction leading to a reduction in ATP synthesis. These findings unveil the glucose metabolism collapse, which is consistent with a decrease in cell viability observed in PPD-treated C2C12 cells and with the myoglubinuria and other effects observed in Wistar Rats treated with PPD. These findings shed new light on muscle dysfunction associated to PPD exposure, opening new avenues for cost-effective therapies in Rhabdomyolysis disease.
publishDate 2017
dc.date.none.fl_str_mv 2017
2018
2018
2018
dc.type.none.fl_str_mv info:eu-repo/semantics/article
info:eu-repo/semantics/publishedVersion
format article
status_str publishedVersion
dc.identifier.none.fl_str_mv https://hdl.handle.net/2445/120101
url https://hdl.handle.net/2445/120101
dc.language.none.fl_str_mv Inglés
language_invalid_str_mv Inglés
dc.relation.none.fl_str_mv Reproducció del document publicat a: https://doi.org/10.3389/fmolb.2017.00008
Frontiers in Molecular Biosciences, 2017, vol. 4, num. 8
https://doi.org/10.3389/fmolb.2017.00008
info:eu-repo/grantAgreement/EC/FP7/320737
dc.rights.none.fl_str_mv cc-by (c) Marín de Mas, Igor Bartolomé et al., 2017
http://creativecommons.org/licenses/by/3.0/es
info:eu-repo/semantics/openAccess
rights_invalid_str_mv cc-by (c) Marín de Mas, Igor Bartolomé et al., 2017
http://creativecommons.org/licenses/by/3.0/es
eu_rights_str_mv openAccess
dc.format.none.fl_str_mv 12 p.
application/pdf
dc.publisher.none.fl_str_mv Frontiers Media
publisher.none.fl_str_mv Frontiers Media
dc.source.none.fl_str_mv Articles publicats en revistes (Bioquímica i Biomedicina Molecular)
reponame:Recercat. Dipósit de la Recerca de Catalunya
instname:Varias* (Consorci de Biblioteques Universitáries de Catalunya, Centre de Serveis Científics i Acadèmics de Catalunya)
instname_str Varias* (Consorci de Biblioteques Universitáries de Catalunya, Centre de Serveis Científics i Acadèmics de Catalunya)
reponame_str Recercat. Dipósit de la Recerca de Catalunya
collection Recercat. Dipósit de la Recerca de Catalunya
repository.name.fl_str_mv
repository.mail.fl_str_mv
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score 15,81155

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