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The Calcineurin-FoxO-MuRF1 signaling pathway regulates myofibril integrity in cardiomyocytes

Hirohito Shimizu1, Adam D Langenbacher1, Jie Huang1

  • 1Department of Molecular, Cell and Developmental Biology, University of California, Los Angeles, Los Angeles, United States.

Elife
|August 23, 2017
PubMed

Insights

Calcium overload in heart disease damages sarcomeres via a novel pathway. This involves Calcineurin, FoxO, and MuRF1, leading to proteasome degradation and myofibril breakdown.

Area of Science:

  • Cardiovascular Biology
  • Molecular Cardiology
  • Cellular Signaling

Background:

  • Altered calcium (Ca2+) handling is a hallmark of heart disease, contributing to structural remodeling and functional decline.
  • The direct impact of Ca2+ dysregulation on sarcomere structure remains poorly understood.

Purpose of the Study:

  • To investigate the direct effects of impaired Ca2+ homeostasis on myofibril integrity.
  • To elucidate the molecular mechanisms linking Ca2+ handling to sarcomere structure in a zebrafish model.

Main Methods:

  • Utilized a zebrafish ncxi (ncx1) mutant model with impaired Ca2+ handling.
  • Assessed myofibril integrity and expression of key proteins including MuRF1 and FoxO.
  • Employed knockdown of MuRF1, proteasome inhibition, FoxO overexpression, and Calcineurin inhibition.

Main Results:

  • ncx1-deficient hearts showed upregulated MuRF1 and myofibril disarray.
  • MuRF1 and proteasome inhibition preserved myofibril integrity in ncxi hearts.
  • Accumulation of FoxO in cardiomyocyte nuclei of ncxi hearts was observed.
  • FoxO overexpression induced MuRF1 and myofibril damage; Calcineurin inhibition protected against this.

Conclusions:

  • Revealed a novel Calcineurin-FoxO-MuRF1-proteasome signaling pathway activated by Ca2+ overload.
  • This pathway mediates the disruption of myofibril integrity in response to abnormal Ca2+ homeostasis.
  • Provides insights into mechanisms underlying cardiac structural deterioration in diseased hearts.
Keywords:
Ca2+ signalingCalcineurinFoxOMuRF1cardiomyopathycell biologydevelopmental biologysarcomerestem cellszebrafish

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