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 myopathiesReport as inadecuate




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 - Download this document for free, or read online. Document in PDF available to download.

BMC Genomics

, 15:91

Human and rodent genomics

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.

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

MDSMitochondrial DNA depletion syndrome

TK2Thymidine kinase

FDRFalse-discovery-rate

FCFold-change

GOGene ontology

IPAIngenuity Pathway Analysis

GDF-15Growth and differentiation factor 15

CPEOChronic progressive external opthalmoplegia

KSSKearns-Sayre syndrome.

Electronic supplementary materialThe online version of this article doi:10.1186-1471-2164-15-91 contains supplementary material, which is available to authorized users.

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Author: Susana Graciela Kalko - Sonia Paco - Cristina Jou - Maria Angels Rodríguez - Marija Meznaric - Mihael Rogac - Maja Jekov

Source: https://link.springer.com/







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