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.

Abstract

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.

• Authors: Susana Graciela Kalko, Sonia Paco, Cristina Jou, Maria Angels Rodríguez, Marija Meznaric, Mihael Rogac, Maja Jekovec-Vrhovsek, Monica Sciacco, Maurizio Moggio, Gigliola Fagiolari, Boel De Paepe, Linda De Meirleir, Isidre Ferrer, Manel Roig-Quilis, Francina Munell, Julio Montoya, Ester López-Gallardo, Eduardo Ruiz-Pesini, Rafael Artuch, Raquel Montero, Ferran Torner, Andres Nascimento, Carlos Ortez, Jaume Colomer, Cecilia Jimenez-Mallebrera
• Journal: BMC genomics (BMC Genomics) Vol. 15 Pg. 91 (Feb 01 2014) ISSN: 1471-2164 [Electronic] England
• PMID: 24484525 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Biomarkers
• DNA, Mitochondrial
• Growth Differentiation Factor 15
• TP53 protein, human
• Tumor Suppressor Protein p53
• thymidine kinase 2
• Thymidine Kinase
• Caspase 3

Topics

• Adolescent
• Adult
• Biomarkers (metabolism)
• Caspase 3 (metabolism)
• Child
• Child, Preschool
• Computational Biology
• DNA, Mitochondrial (genetics, metabolism)
• Gene Expression Profiling
• Growth Differentiation Factor 15 (blood, genetics, metabolism)
• Humans
• Infant
• Mitochondrial Myopathies (genetics, pathology)
• Muscle, Skeletal (metabolism, pathology)
• Signal Transduction
• Thymidine Kinase (genetics, metabolism)
• Tumor Suppressor Protein p53 (metabolism)