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

BMC Genomics

Research Article

Ester López-Gallardo¹  Julio Montoya¹  Eduardo Ruiz-Pesini¹  Susana Graciela Kalko²  Rafael Artuch³  Raquel Montero³  Mihael Rogac⁴  Maja Jekovec-Vrhovsek⁴  Marija Meznaric⁵  Isidre Ferrer⁶  Linda De Meirleir⁷  Boel De Paepe⁷  Carlos Ortez⁸  Sonia Paco⁸  Maria Angels Rodríguez⁸  Andres Nascimento⁹  Cecilia Jimenez-Mallebrera⁹  Jaume Colomer⁹  Cristina Jou^1,10  Francina Munell^1,11  Manel Roig-Quilis^1,11  Ferran Torner^1,12  Monica Sciacco^1,13  Gigliola Fagiolari^1,13  Maurizio Moggio^1,13 

[1] Biochemistry and Molecular Biology Department, University of Zaragoza, Zaragoza, Spain;Center for Biomedical Research on Rare Diseases (CIBERER), Instituto de Salud Carlos III, Madrid, Spain;Bioinformatics Core Facility, IDIBAPS, Hospital Clinic, Barcelona, Spain;Center for Biomedical Research on Rare Diseases (CIBERER), Instituto de Salud Carlos III, Madrid, Spain;Clinical Biochemistry Department, Hospital Sant Joan de Déu, Barcelona, Spain;Department of Child, Adolescent, and Developmental Neurology, Children’s Hospital, University Medical Centre Ljubljana, Ljubljana, Slovenia;Institute of Anatomy, Faculty of Medicine, University of Ljubljana, Ljubljana, Slovenia;Institute of Neuropathology, Hospital de Bellvitge, Barcelona, Spain;Laboratory for Neuropathology, Ghent University Hospital, Ghent, Belgium;Neuromuscular Unit, Neurology Department, Fundación Sant Joan de Déu, Hospital Sant Joan de Déu, Barcelona, Spain;Neuromuscular Unit, Neurology Department, Fundación Sant Joan de Déu, Hospital Sant Joan de Déu, Barcelona, Spain;Center for Biomedical Research on Rare Diseases (CIBERER), Instituto de Salud Carlos III, Madrid, Spain;Neuromuscular Unit, Neurology Department, Fundación Sant Joan de Déu, Hospital Sant Joan de Déu, Barcelona, Spain;Pathology Department, Hospital Sant Joan de Déu, Barcelona, Spain;Neuropaediatrics Department, Vall d’Hebron Hospital, Barcelona, Spain;Orthopaedic Surgery & Traumatology Department, Hospital Sant Joan de Déu, Barcelona, Spain;U.O.S. Diagnostica Malattie Neuromuscolari, Fondazione Ospedale Maggiore Mangiagalli e Regina Elena, IRCCS, Milan, Italy;

关键词: Gene expression;    Microarrays;    Bioinformatics;    Mitochondrial DNA;    Mitochondrial DNA depletion;    Mitochondrial encephalomyopathy;    Thymidine kinase 2;    Skeletal muscle;    p53;    Apoptosis;    GDF-15;   

DOI  :  10.1186/1471-2164-15-91

 received in 2013-05-21, accepted in 2014-01-28,  发布年份 2014

来源: Springer

【 摘 要 】

BackgroundMutations 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.ResultsWe 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.ConclusionOur 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.

【 授权许可】

Unknown   
© Kalko et al.; licensee BioMed Central Ltd. 2014. This article is published under license to BioMed Central Ltd. This is an open access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.