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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

Susana Graciela Kalko1, Sonia Paco2, Cristina Jou23, Maria Angels Rodríguez2, Marija Meznaric4, Mihael Rogac5, Maja Jekovec-Vrhovsek5, Monica Sciacco6, Maurizio Moggio6, Gigliola Fagiolari6, Boel De Paepe7, Linda De Meirleir7, Isidre Ferrer8, Manel Roig-Quilis9, Francina Munell9, Julio Montoya1011, Ester López-Gallardo1011, Eduardo Ruiz-Pesini1011, Rafael Artuch1112, Raquel Montero1112, Ferran Torner13, Andres Nascimento112, Carlos Ortez2, Jaume Colomer112 and Cecilia Jimenez-Mallebrera112*

Author Affiliations

1 Bioinformatics Core Facility, IDIBAPS, Hospital Clinic, Barcelona, Spain

2 Neuromuscular Unit, Neurology Department, Fundación Sant Joan de Déu, Hospital Sant Joan de Déu, Barcelona, Spain

3 Pathology Department, Hospital Sant Joan de Déu, Barcelona, Spain

4 Institute of Anatomy, Faculty of Medicine, University of Ljubljana, Ljubljana, Slovenia

5 Department of Child, Adolescent, and Developmental Neurology, Children’s Hospital, University Medical Centre Ljubljana, Ljubljana, Slovenia

6 U.O.S. Diagnostica Malattie Neuromuscolari, Fondazione Ospedale Maggiore Mangiagalli e Regina Elena, IRCCS, Milan, Italy

7 Laboratory for Neuropathology, Ghent University Hospital, Ghent, Belgium

8 Institute of Neuropathology, Hospital de Bellvitge, Barcelona, Spain

9 Neuropaediatrics Department, Vall d’Hebron Hospital, Barcelona, Spain

10 Biochemistry and Molecular Biology Department, University of Zaragoza, Zaragoza, Spain

11 Center for Biomedical Research on Rare Diseases (CIBERER), Instituto de Salud Carlos III, Madrid, Spain

12 Clinical Biochemistry Department, Hospital Sant Joan de Déu, Barcelona, Spain

13 Orthopaedic Surgery & Traumatology Department, Hospital Sant Joan de Déu, Barcelona, Spain

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BMC Genomics 2014, 15:91  doi:10.1186/1471-2164-15-91

Published: 1 February 2014



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.


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.


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.

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