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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Authors: Kalko SG, Paco S, Jou C, Rodríguez MA, Meznaric M, Rogac M, Jekovec-Vrhovsek M, Sciacco M, Moggio M, Fagiolari G, De Paepe B, De Meirleir L, Ferrer I, Roig-Quilis M, Munell F, Montoya J, López-Gallardo E, Ruiz-Pesini E, Artuch R, Montero R, Torner F, Nascimento A, Ortez C, Colomer J, Jimenez-Mallebrera C
Format: article
Status:Published version
Publication Date:2014
Country:España
Institution:Fundació Sant Joan de Déu
Repository:r-FSJD. Repositorio Institucional de Producción Científica de la Fundació Sant Joan de Déu
OAI Identifier:oai:fsjd.fundanetsuite.com:p5400
Online Access:https://fsjd.fundanetsuite.com/Publicaciones/ProdCientif/PublicacionFrw.aspx?id=5400
Access Level:Open access
Keyword:Gene expression
Microarrays
Bioinformatics
Mitochondrial DNA
Mitochondrial DNA depletion
Mitochondrial encephalomyopathy
Thymidine kinase 2
Skeletal muscle
p53
Apoptosis
GDF-15
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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 SGPaco SJou CRodríguez MAMeznaric MRogac MJekovec-Vrhovsek MSciacco MMoggio MFagiolari GDe Paepe BDe Meirleir LFerrer IRoig-Quilis MMunell FMontoya JLópez-Gallardo ERuiz-Pesini EArtuch RMontero RTorner FNascimento AOrtez CColomer JJimenez-Mallebrera CGene expressionMicroarraysBioinformaticsMitochondrial DNAMitochondrial DNA depletionMitochondrial encephalomyopathyThymidine kinase 2Skeletal musclep53ApoptosisGDF-15Background: 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.BMC2014info:eu-repo/semantics/articleinfo:eu-repo/semantics/publishedVersionhttps://fsjd.fundanetsuite.com/Publicaciones/ProdCientif/PublicacionFrw.aspx?id=5400BMC GENOMICSISSN: 14712164reponame:r-FSJD. Repositorio Institucional de Producción Científica de la Fundació Sant Joan de Déuinstname:Fundació Sant Joan de DéuInglésinfo:eu-repo/semantics/openAccessoai:fsjd.fundanetsuite.com:p54002026-05-27T12:37:41Z
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 SG
Gene expression
Microarrays
Bioinformatics
Mitochondrial DNA
Mitochondrial DNA depletion
Mitochondrial encephalomyopathy
Thymidine kinase 2
Skeletal muscle
p53
Apoptosis
GDF-15
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 SG
Paco S
Jou C
Rodríguez MA
Meznaric M
Rogac M
Jekovec-Vrhovsek M
Sciacco M
Moggio M
Fagiolari G
De Paepe B
De Meirleir L
Ferrer I
Roig-Quilis M
Munell F
Montoya J
López-Gallardo E
Ruiz-Pesini E
Artuch R
Montero R
Torner F
Nascimento A
Ortez C
Colomer J
Jimenez-Mallebrera C
author Kalko SG
author_facet Kalko SG
Paco S
Jou C
Rodríguez MA
Meznaric M
Rogac M
Jekovec-Vrhovsek M
Sciacco M
Moggio M
Fagiolari G
De Paepe B
De Meirleir L
Ferrer I
Roig-Quilis M
Munell F
Montoya J
López-Gallardo E
Ruiz-Pesini E
Artuch R
Montero R
Torner F
Nascimento A
Ortez C
Colomer J
Jimenez-Mallebrera C
author_role author
author2 Paco S
Jou C
Rodríguez MA
Meznaric M
Rogac M
Jekovec-Vrhovsek M
Sciacco M
Moggio M
Fagiolari G
De Paepe B
De Meirleir L
Ferrer I
Roig-Quilis M
Munell F
Montoya J
López-Gallardo E
Ruiz-Pesini E
Artuch R
Montero R
Torner F
Nascimento A
Ortez C
Colomer J
Jimenez-Mallebrera C
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 Gene expression
Microarrays
Bioinformatics
Mitochondrial DNA
Mitochondrial DNA depletion
Mitochondrial encephalomyopathy
Thymidine kinase 2
Skeletal muscle
p53
Apoptosis
GDF-15
topic Gene expression
Microarrays
Bioinformatics
Mitochondrial DNA
Mitochondrial DNA depletion
Mitochondrial encephalomyopathy
Thymidine kinase 2
Skeletal muscle
p53
Apoptosis
GDF-15
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
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://fsjd.fundanetsuite.com/Publicaciones/ProdCientif/PublicacionFrw.aspx?id=5400
url https://fsjd.fundanetsuite.com/Publicaciones/ProdCientif/PublicacionFrw.aspx?id=5400
dc.language.none.fl_str_mv Inglés
language_invalid_str_mv Inglés
dc.rights.none.fl_str_mv info:eu-repo/semantics/openAccess
eu_rights_str_mv openAccess
dc.publisher.none.fl_str_mv BMC
publisher.none.fl_str_mv BMC
dc.source.none.fl_str_mv BMC GENOMICS
ISSN: 14712164
reponame:r-FSJD. Repositorio Institucional de Producción Científica de la Fundació Sant Joan de Déu
instname:Fundació Sant Joan de Déu
instname_str Fundació Sant Joan de Déu
reponame_str r-FSJD. Repositorio Institucional de Producción Científica de la Fundació Sant Joan de Déu
collection r-FSJD. Repositorio Institucional de Producción Científica de la Fundació Sant Joan de Déu
repository.name.fl_str_mv
repository.mail.fl_str_mv
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