Pygopus maintains heart function in aging Drosophila independently of canonical Wnt signaling

Circ Cardiovasc Genet. 2013 Oct;6(5):472-80. doi: 10.1161/CIRCGENETICS.113.000253. Epub 2013 Sep 17.


Background: Heart function declines with age, but the genetic factors underlying such deterioration are largely unknown. Wnt signaling is known to play a role in heart development, but it has not been shown to be important in adult heart function. We have investigated the nuclear adapter protein encoded by pygopus (pygo), which mediates canonical Wnt signaling, for roles in aging-related cardiac dysfunction.

Methods and results: Using the Drosophila heart model, we show that cardiac-specific pygo knockdown in adult flies causes a significant (4- to 5-fold) increase in cardiac arrhythmias (P<0.001) that worsened with age and caused a significant decrease in contractility (-54%; P<0.001) with systolic dysfunction. Immunohistochemistry revealed structural abnormalities that worsened with age, and both functional and morphological alterations were ameliorated by pygo overexpression. Unexpectedly, knockdown of 2 other Wnt signaling components, β-cat/armadillo or TCF/pangolin, had relatively milder effects on cardiac function. Double-heterozygous combinations of mutants for pygo and canonical Wnt signaling components had no additional effect on heart function over pygo heterozygotes alone. However, double knockdown of pygo and Ca2+/calmodulin-dependent protein kinase II caused additional arrhythmia compared with pygo knockdown alone, suggesting that some of the effects of pygo are mediated by Ca2+ signaling. In the isoproterenol-induced hypertrophic mouse model, we show that Pygo1 protein levels are increased.

Conclusions: Our data indicate that Pygo plays a critical role in adult heart function that is Wnt signaling independent and is likely conserved in mammals.

Keywords: arrhythmias, cardiac; atrial fibrillation; cardiac defects; cardiomyopathies; hypertrophy; physiopathology; systolic time interval.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Aging*
  • Animals
  • Arrhythmias, Cardiac / metabolism
  • Arrhythmias, Cardiac / pathology
  • Calcium Signaling
  • Calcium-Calmodulin-Dependent Protein Kinases / antagonists & inhibitors
  • Calcium-Calmodulin-Dependent Protein Kinases / genetics
  • Calcium-Calmodulin-Dependent Protein Kinases / metabolism
  • Drosophila / metabolism
  • Drosophila Proteins / antagonists & inhibitors
  • Drosophila Proteins / genetics
  • Drosophila Proteins / metabolism*
  • Heart / physiology*
  • Heterozygote
  • Immunohistochemistry
  • Intracellular Signaling Peptides and Proteins / antagonists & inhibitors
  • Intracellular Signaling Peptides and Proteins / genetics
  • Intracellular Signaling Peptides and Proteins / metabolism*
  • Models, Animal
  • RNA Interference
  • RNA, Small Interfering / metabolism
  • Repressor Proteins / antagonists & inhibitors
  • Repressor Proteins / genetics
  • Repressor Proteins / metabolism
  • Wnt Proteins / metabolism*
  • Wnt Signaling Pathway


  • Drosophila Proteins
  • Intracellular Signaling Peptides and Proteins
  • RNA, Small Interfering
  • Repressor Proteins
  • Wnt Proteins
  • pan protein, Drosophila
  • pygo protein, Drosophila
  • CASK protein, Drosophila
  • Calcium-Calmodulin-Dependent Protein Kinases