Transcriptomic profiling of TK2 deficient human skeletal muscle suggests a role for the p53 signalling pathway and identifies growth and differentiation factor-15 as a potential novel biomarker for mitochondrial myopathies

BACKGROUND: Mutations in the gene encoding thymidine kinase 2 (TK2) result in the myopathic form of mitochondrial DNA depletion syndrome which is a mitochondrial encephalomyopathy presenting in children. In order to unveil some of the mechanisms involved in this pathology and to identify potential b...

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Autores: Kalko, Susana, Paco Mercader, Sonia, Jou, Cristina, Rodríguez, María Angeles, Meznaric, Marija, Rogac, Mihael, Jekovec-Vrhovsek, Maja, Sciacco, Monica, Moggio, Maurizio, Fagiolari, Gigliola, De Paepe, Boel, De Meirleir, Linda, Ferrer, Isidro (Ferrer Abizanda), Roig Quilis, Manuel, Munell Casadesús, Francina, Montoya, Julio, López Gallardo, Ester, Ruiz Pesini, Eduardo, Artuch Iriberri, Rafael, Montero Sánchez, Raquel, Torner Rubies, Ferran, Nascimento, Andrés, Ortez, Carlos Ignacio, Colomer Oferil, Jaume, Jiménez Mallebrera, Cecilia
Tipo de recurso: artículo
Estado:Versión publicada
Fecha de publicación:2014
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:2445/113597
Acceso en línea:https://hdl.handle.net/2445/113597
Access Level:acceso abierto
Palabra clave:Expressió gènica
Bioinformàtica
Microxips d'ADN
ADN mitocondrial
Apoptosi
Malalties del sistema nerviós central
Infants
Gene expression
Bioinformatics
DNA microarrays
Mitochondrial DNA
Apoptosis
Central nervous system diseases
Children
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spelling Transcriptomic profiling of TK2 deficient human skeletal muscle suggests a role for the p53 signalling pathway and identifies growth and differentiation factor-15 as a potential novel biomarker for mitochondrial myopathiesKalko, SusanaPaco Mercader, SoniaJou, CristinaRodríguez, María AngelesMeznaric, MarijaRogac, MihaelJekovec-Vrhovsek, MajaSciacco, MonicaMoggio, MaurizioFagiolari, GigliolaDe Paepe, BoelDe Meirleir, LindaFerrer, Isidro (Ferrer Abizanda)Roig Quilis, ManuelMunell Casadesús, FrancinaMontoya, JulioLópez Gallardo, EsterRuiz Pesini, EduardoArtuch Iriberri, RafaelMontero Sánchez, RaquelTorner Rubies, FerranNascimento, AndrésOrtez, Carlos IgnacioColomer Oferil, JaumeJiménez Mallebrera, CeciliaExpressió gènicaBioinformàticaMicroxips d'ADNADN mitocondrialApoptosiMalalties del sistema nerviós centralInfantsGene expressionBioinformaticsDNA microarraysMitochondrial DNAApoptosisCentral nervous system diseasesChildrenBACKGROUND: Mutations in the gene encoding thymidine kinase 2 (TK2) result in the myopathic form of mitochondrial DNA depletion syndrome which is a mitochondrial encephalomyopathy presenting in children. In order to unveil some of the mechanisms involved in this pathology and to identify potential biomarkers and therapeutic targets we have investigated the gene expression profile of human skeletal muscle deficient for TK2 using cDNA microarrays. RESULTS: We have analysed the whole transcriptome of skeletal muscle from patients with TK2 mutations and compared it to normal muscle and to muscle from patients with other mitochondrial myopathies. We have identified a set of over 700 genes which are differentially expressed in TK2 deficient muscle. Bioinformatics analysis reveals important changes in muscle metabolism, in particular, in glucose and glycogen utilisation, and activation of the starvation response which affects aminoacid and lipid metabolism. We have identified those transcriptional regulators which are likely to be responsible for the observed changes in gene expression. CONCLUSION: Our data point towards the tumor suppressor p53 as the regulator at the centre of a network of genes which are responsible for a coordinated response to TK2 mutations which involves inflammation, activation of muscle cell death by apoptosis and induction of growth and differentiation factor 15 (GDF-15) in muscle and serum. We propose that GDF-15 may represent a potential novel biomarker for mitochondrial dysfunction although further studies are required.BioMed Central2017201720142017info:eu-repo/semantics/articleinfo:eu-repo/semantics/publishedVersion22 p.application/pdfhttps://hdl.handle.net/2445/113597Articles publicats en revistes (Patologia i Terapèutica Experimental)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/10.1186/1471-2164-15-91Bmc Genomics, 2014, num. 15, p. 91https://doi.org/10.1186/1471-2164-15-91cc-by (c) Kalko, Susana et al., 2014http://creativecommons.org/licenses/by/3.0/esinfo:eu-repo/semantics/openAccessoai:recercat.cat:2445/1135972026-05-29T05:05:01Z
dc.title.none.fl_str_mv Transcriptomic profiling of TK2 deficient human skeletal muscle suggests a role for the p53 signalling pathway and identifies growth and differentiation factor-15 as a potential novel biomarker for mitochondrial myopathies
title Transcriptomic profiling of TK2 deficient human skeletal muscle suggests a role for the p53 signalling pathway and identifies growth and differentiation factor-15 as a potential novel biomarker for mitochondrial myopathies
spellingShingle Transcriptomic profiling of TK2 deficient human skeletal muscle suggests a role for the p53 signalling pathway and identifies growth and differentiation factor-15 as a potential novel biomarker for mitochondrial myopathies
Kalko, Susana
Expressió gènica
Bioinformàtica
Microxips d'ADN
ADN mitocondrial
Apoptosi
Malalties del sistema nerviós central
Infants
Gene expression
Bioinformatics
DNA microarrays
Mitochondrial DNA
Apoptosis
Central nervous system diseases
Children
title_short Transcriptomic profiling of TK2 deficient human skeletal muscle suggests a role for the p53 signalling pathway and identifies growth and differentiation factor-15 as a potential novel biomarker for mitochondrial myopathies
title_full Transcriptomic profiling of TK2 deficient human skeletal muscle suggests a role for the p53 signalling pathway and identifies growth and differentiation factor-15 as a potential novel biomarker for mitochondrial myopathies
title_fullStr Transcriptomic profiling of TK2 deficient human skeletal muscle suggests a role for the p53 signalling pathway and identifies growth and differentiation factor-15 as a potential novel biomarker for mitochondrial myopathies
title_full_unstemmed Transcriptomic profiling of TK2 deficient human skeletal muscle suggests a role for the p53 signalling pathway and identifies growth and differentiation factor-15 as a potential novel biomarker for mitochondrial myopathies
title_sort Transcriptomic profiling of TK2 deficient human skeletal muscle suggests a role for the p53 signalling pathway and identifies growth and differentiation factor-15 as a potential novel biomarker for mitochondrial myopathies
dc.creator.none.fl_str_mv Kalko, Susana
Paco Mercader, Sonia
Jou, Cristina
Rodríguez, María Angeles
Meznaric, Marija
Rogac, Mihael
Jekovec-Vrhovsek, Maja
Sciacco, Monica
Moggio, Maurizio
Fagiolari, Gigliola
De Paepe, Boel
De Meirleir, Linda
Ferrer, Isidro (Ferrer Abizanda)
Roig Quilis, Manuel
Munell Casadesús, Francina
Montoya, Julio
López Gallardo, Ester
Ruiz Pesini, Eduardo
Artuch Iriberri, Rafael
Montero Sánchez, Raquel
Torner Rubies, Ferran
Nascimento, Andrés
Ortez, Carlos Ignacio
Colomer Oferil, Jaume
Jiménez Mallebrera, Cecilia
author Kalko, Susana
author_facet Kalko, Susana
Paco Mercader, Sonia
Jou, Cristina
Rodríguez, María Angeles
Meznaric, Marija
Rogac, Mihael
Jekovec-Vrhovsek, Maja
Sciacco, Monica
Moggio, Maurizio
Fagiolari, Gigliola
De Paepe, Boel
De Meirleir, Linda
Ferrer, Isidro (Ferrer Abizanda)
Roig Quilis, Manuel
Munell Casadesús, Francina
Montoya, Julio
López Gallardo, Ester
Ruiz Pesini, Eduardo
Artuch Iriberri, Rafael
Montero Sánchez, Raquel
Torner Rubies, Ferran
Nascimento, Andrés
Ortez, Carlos Ignacio
Colomer Oferil, Jaume
Jiménez Mallebrera, Cecilia
author_role author
author2 Paco Mercader, Sonia
Jou, Cristina
Rodríguez, María Angeles
Meznaric, Marija
Rogac, Mihael
Jekovec-Vrhovsek, Maja
Sciacco, Monica
Moggio, Maurizio
Fagiolari, Gigliola
De Paepe, Boel
De Meirleir, Linda
Ferrer, Isidro (Ferrer Abizanda)
Roig Quilis, Manuel
Munell Casadesús, Francina
Montoya, Julio
López Gallardo, Ester
Ruiz Pesini, Eduardo
Artuch Iriberri, Rafael
Montero Sánchez, Raquel
Torner Rubies, Ferran
Nascimento, Andrés
Ortez, Carlos Ignacio
Colomer Oferil, Jaume
Jiménez Mallebrera, Cecilia
author2_role author
author
author
author
author
author
author
author
author
author
author
author
author
author
author
author
author
author
author
author
author
author
author
author
dc.subject.none.fl_str_mv Expressió gènica
Bioinformàtica
Microxips d'ADN
ADN mitocondrial
Apoptosi
Malalties del sistema nerviós central
Infants
Gene expression
Bioinformatics
DNA microarrays
Mitochondrial DNA
Apoptosis
Central nervous system diseases
Children
topic Expressió gènica
Bioinformàtica
Microxips d'ADN
ADN mitocondrial
Apoptosi
Malalties del sistema nerviós central
Infants
Gene expression
Bioinformatics
DNA microarrays
Mitochondrial DNA
Apoptosis
Central nervous system diseases
Children
description BACKGROUND: Mutations in the gene encoding thymidine kinase 2 (TK2) result in the myopathic form of mitochondrial DNA depletion syndrome which is a mitochondrial encephalomyopathy presenting in children. In order to unveil some of the mechanisms involved in this pathology and to identify potential biomarkers and therapeutic targets we have investigated the gene expression profile of human skeletal muscle deficient for TK2 using cDNA microarrays. RESULTS: We have analysed the whole transcriptome of skeletal muscle from patients with TK2 mutations and compared it to normal muscle and to muscle from patients with other mitochondrial myopathies. We have identified a set of over 700 genes which are differentially expressed in TK2 deficient muscle. Bioinformatics analysis reveals important changes in muscle metabolism, in particular, in glucose and glycogen utilisation, and activation of the starvation response which affects aminoacid and lipid metabolism. We have identified those transcriptional regulators which are likely to be responsible for the observed changes in gene expression. CONCLUSION: Our data point towards the tumor suppressor p53 as the regulator at the centre of a network of genes which are responsible for a coordinated response to TK2 mutations which involves inflammation, activation of muscle cell death by apoptosis and induction of growth and differentiation factor 15 (GDF-15) in muscle and serum. We propose that GDF-15 may represent a potential novel biomarker for mitochondrial dysfunction although further studies are required.
publishDate 2014
dc.date.none.fl_str_mv 2014
2017
2017
2017
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/2445/113597
url https://hdl.handle.net/2445/113597
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/10.1186/1471-2164-15-91
Bmc Genomics, 2014, num. 15, p. 91
https://doi.org/10.1186/1471-2164-15-91
dc.rights.none.fl_str_mv cc-by (c) Kalko, Susana et al., 2014
http://creativecommons.org/licenses/by/3.0/es
info:eu-repo/semantics/openAccess
rights_invalid_str_mv cc-by (c) Kalko, Susana et al., 2014
http://creativecommons.org/licenses/by/3.0/es
eu_rights_str_mv openAccess
dc.format.none.fl_str_mv 22 p.
application/pdf
dc.publisher.none.fl_str_mv BioMed Central
publisher.none.fl_str_mv BioMed Central
dc.source.none.fl_str_mv Articles publicats en revistes (Patologia i Terapèutica Experimental)
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 15,811543

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