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 G Kalko ,Rafael Artuch,Monica Sciacco,Maria Angels Rodríguez,Sonia Paco,Raquel Montero,Cristina Jou,Mihael Rogac,Francina Munell,Isidre Ferrer,Julio Montoya,Gigliola Fagiolari,Maurizio Moggio,Manuel Roig-Quilis ,C Ortez ,Marija Meznarič ,Ester López‐Gallardo ,Linda De Meırleır ,Maja Jekovec-Vrhovšek ,A Nascimento ,J Colomer ,Eduardo Ruiz‐Pesini ,Ferrán Torner ,Boél De Paepe ,Cecilia Jiménez‐Mallebrera

doi:10.1186/1471-2164-15-91

Abstract

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.

Highlights

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
Genes differentially expressed in Mitochondrial DNA (mtDNA) depleted muscle versus control muscle Summary Using the statistical test RankProd we identified 336 unique genes that were significantly under-expressed and 437 that were significantly over-expressed at FDR < 0.05 in Mitochondrial DNA depletion syndrome (MDS) muscle compared to control muscle (Table 2)
In the present study we have demonstrated for the first time evidence of over-expression of several pro-apoptotic factors, caspase-3 enzymatic activation and DNA fragmentation in human skeletal muscle deficient for TK2

Summary

Introduction

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. The genetics and pathogenesis of mitochondrial disorders are complex because of the interaction of the mtDNA and nuclear genomes. The remaining of the over 1500 predicted mitochondrial proteins are encoded by the nuclear genome [4]. The majority of these nuclear genes are unknown

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