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

Cardiovasc Res. 2018 Sep 1;114(11):1474-1486. doi: 10.1093/cvr/cvy091.

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Animals, Genetically Modified
  • Animals, Newborn
  • Cardiomyopathies / enzymology*
  • Cardiomyopathies / genetics
  • Cardiomyopathies / pathology
  • Cardiomyopathies / physiopathology
  • Disease Models, Animal
  • HEK293 Cells
  • Heart Failure / enzymology*
  • Heart Failure / genetics
  • Heart Failure / pathology
  • Heart Failure / physiopathology
  • Humans
  • MEF2 Transcription Factors / genetics
  • MEF2 Transcription Factors / metabolism*
  • Male
  • Mice, Inbred C57BL
  • Myocytes, Cardiac / enzymology*
  • Myocytes, Cardiac / ultrastructure
  • Myotonin-Protein Kinase / genetics
  • Myotonin-Protein Kinase / metabolism*
  • Phosphorylation
  • Rats, Wistar
  • Sarcomeres / enzymology*
  • Sarcomeres / genetics
  • Sarcomeres / ultrastructure
  • Serum Response Factor / genetics
  • Serum Response Factor / metabolism
  • Signal Transduction
  • Transcription Factors / genetics
  • Transcription Factors / metabolism
  • Transcription, Genetic
  • Ventricular Remodeling*

Substances

  • DMPK protein, mouse
  • MEF2 Transcription Factors
  • Serum Response Factor
  • Srf protein, mouse
  • Transcription Factors
  • serum response factor, rat
  • Dmpk protein, rat
  • Myotonin-Protein Kinase