The MEF2 transcriptional target DMPK induces loss of sarcomere structure and cardiomyopathy

Amin Damanafshan, Ies Elzenaar, Benoit Samson-Couterie, Ingeborg van der Made, Meriem Bourajjaj, Maarten M. van den Hoogenhof, Henk A. van Veen, Daisy I. Picavet, Abdelaziz Beqqali, Elisabeth Ehler, Leon J. DeWindt, Yigal M. Pinto, Ralph J. van Oort*

*Corresponding author for this work

Research output: Contribution to journalArticleAcademicpeer-review

6 Citations (Web of Science)

Abstract

Aims The pathology of heart failure is characterized by poorly contracting and dilated ventricles. At the cellular level, this is associated with lengthening of individual cardiomyocytes and loss of sarcomeres. While it is known that the transcription factor myocyte enhancer factor-2 (MEF2) is involved in this cardiomyocyte remodelling, the underlying mechanism remains to be elucidated. Here, we aim to mechanistically link MEF2 target genes with loss of sarcomeres during cardiomyocyte remodelling. Methods and results Neonatal rat cardiomyocytes overexpressing MEF2 elongated and lost their sarcomeric structure. We identified myotonic dystrophy protein kinase (DMPK) as direct MEF2 target gene involved in this process. Adenoviral overexpression of DMPK E, the isoform upregulated in heart failure, resulted in severe loss of sarcomeres in vitro, and transgenic mice overexpressing DMPK E displayed disruption of sarcomere structure and cardiomyopathy in vivo. Moreover, we found a decreased expression of sarcomeric genes following DMPK E gain-of-function. These genes are targets of the transcription factor serum response factor (SRF) and we found that DMPK E acts as inhibitor of SRF transcriptional activity. Conclusion Our data indicate that MEF2-induced loss of sarcomeres is mediated by DMPK via a decrease in sarcomeric gene expression by interfering with SRF transcriptional activity. Together, these results demonstrate an unexpected role for DMPK as a direct mediator of adverse cardiomyocyte remodelling and heart failure.
Original languageEnglish
Pages (from-to)1474-1486
Number of pages13
JournalCardiovascular Research
Volume114
Issue number11
DOIs
Publication statusPublished - 1 Sep 2018

Keywords

  • Heart failure
  • Sarcomere
  • MEF2
  • DMPK
  • DYSTROPHY PROTEIN-KINASE
  • SERUM RESPONSE FACTOR
  • MYOTONIC-DYSTROPHY
  • HEART-FAILURE
  • DILATED CARDIOMYOPATHY
  • GENE-EXPRESSION
  • CARDIAC-HYPERTROPHY
  • SIGNALING PATHWAYS
  • MICE
  • PHOSPHORYLATION

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